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Regulatory CMC strategies for gene and cell therapies during mergers and acquisitions: a survey of industry views

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Regulatory CMC strategies for gene and cell therapies during mergers and acquisitions: a survey of industry views

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REGULATORY CMC STRATEGIES FOR GENE AND CELL THERAPIES DURING
MERGERS AND ACQUISITIONS: A SURVEY OF INDUSTRY VIEWS

by

Hai Luong

A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE

August 2022

Copyright 2022 Hai Luong

ii
Dedication
This dissertation is dedicated to my mother, Lanh Nguyen, who has always been my
biggest fan. Your “proud to be” moments drove me to aim high and set goals far beyond reach.
Your life experiences taught me to overcome circumstances where most would give up. You
instilled adversity in me as we struggled from nothing to achieving our goals and more. I will
continue to strive for all the visions we seek and chase our dreams. It is because of you I have
become the man I am today.

iii
Acknowledgments
First of all, I would to express my sincere gratitude to the dissertation committee
members: Dr. Francis Richmond, Dr. Susan Bain, Dr. Benson Kuo, and Dr. Mary Ellen Cosenza.
Thank you all for your continued support, thought provoking feedback, and valuable expertise
throughout this journey. To Dr. Terry Church thank you for your thorough review. To my
dissertation advisor and supervisor Dr. Frances Richmond, I would like to thank for reeling me
back to reality when I started to go down several paths, for challenging me to think beyond my
comfort zone, and providing me the confidence in achieving both my professional and academic
goals. Your words of advice, inspiration, and shared experiences helped me to stay focused on
this research and grow exponentially in this field.
For the members who participated in my focus group, I would also like to thank you all
for your shared knowledge, insights, and advice. I would also like to acknowledge my
colleagues and mentors who I was fortunate enough to build strong relationships with, at both
Gilead Sciences and Kite Pharma, you have all supported me supported me throughout this
journey, including many others. Your encouragement and flexibility allowed me to pursue this
research and be part of this program. Further, I would like to acknowledge my industry peers;
Dr. Darren Brown, Dr. Carmilia Jimenez Ramirez and Ms. Bita Badiei, for believing in me and
supporting me throughout my professional career leading up to this doctoral degree, I am deeply
humbled and honored to have such mentors. Your input and insights strengthened this research.
For those peers and colleagues who helped provide responses, I look forward to sharing
the results and continuing to build to your expertise in this field of regulatory CMC strategy, just
as you have added to my knowledge. For my classmates in the doctoral cohort of 2018, I am

iv
deeply honored to be part of, I will cherish the camaraderie and will continue to look forward to
sharing many more experiences as we continue to expand our Trojan network.
To my family and friends, this academic journey has proven we really can accomplish
what we seek out to achieve, never give up when told you can’t do it, in the end hard work,
discipline, and perseverance pays off. To my partner, Ailen Abella, you have been here near the
beginning of this process and continued to cheer me on along the way. You have given me the
strength and helped me differentiate between what is important and true happiness.
Last but not least, to my brother, Long Luong, for his relentless support and continued
sacrifice opening the doors for me when what seemed to be the impossible, you have provided
me the freedom to achieve all the successes I have today, without you I definitely would not be
where I am. For that I will be eternally in debt to you. To the University of Southern California,
Fight On!

v
TABLE OF CONTENTS
Acknowledgments.......................................................................................................................... iii
List of Tables ............................................................................................................................... viii
List of Figures ................................................................................................................................ ix
Abstract .......................................................................................................................................... xi
Chapter 1. Overview ........................................................................................................................1
1.1 Introduction ................................................................................................................. 1
1.1.1 Biologics as Agents of Change ...................................................................... 5
1.2 Statement of the Problem ............................................................................................ 6
1.3 Purpose of the Study ................................................................................................... 8
1.4 Importance of the Study .............................................................................................. 8
1.5 Limitations, Delimitations, Assumptions .................................................................... 9
1.5.1 Limitations ..................................................................................................... 9
1.5.2 Delimitations ............................................................................................... 10
1.5.3 Assumptions ................................................................................................ 10
1.6 Organization of Thesis .............................................................................................. 11
1.7 Definitions and Acronyms ........................................................................................ 12
Chapter 2. Literature Review .........................................................................................................13
2.1 Introduction ............................................................................................................... 13
2.2 Evolution of Expectations for Pharmaceutical Quality ............................................. 14
2.2.1 History of Regulations governing Pharmaceutical Quality ......................... 14
2.2.2 Modernization of Regulatory CMC Landscape ........................................... 15
2.2.3 Chemistry and Manufacturing as a Focus ................................................... 21
2.2.4 Advancing CMC for Gene and Cell Therapies ............................................ 25
2.3 Shortening of Late-Stage Development Timelines ................................................... 32
2.3.1 Pathways for Drug Development ................................................................. 32
2.3.1.1 Orphan Drug Designation .............................................................. 34
2.3.1.2 Accelerated Approval ..................................................................... 35
2.3.1.3 Priority Review ............................................................................... 36
2.3.1.4 Rolling Review ................................................................................ 36
2.3.1.5 Fast Track Designation .................................................................. 36
2.3.1.6 Breakthrough Therapy Designation ............................................... 37
2.3.1.7 Regenerative Medicine Advanced Therapy .................................... 37
2.3.2 CMC Implications of Shortened Timelines ................................................. 39
2.4 Effects of Business Reorganization .......................................................................... 40
2.5 Research Approach and Framing the Study .............................................................. 45
2.5.1 Implementation Framework......................................................................... 47

vi
2.5.1.1 Exploration ..................................................................................... 47
2.5.1.2 Installation ...................................................................................... 48
2.5.1.3 Initial Implementation .................................................................... 48
2.5.1.4 Full Implementation........................................................................ 49
Chapter 3. Methodology ................................................................................................................51
3.1 Introduction ............................................................................................................... 51
3.2 Survey Development ................................................................................................. 51
3.3 Focus Group .............................................................................................................. 52
3.4 Dissemination of Survey ........................................................................................... 52
3.5 Survey Analysis ........................................................................................................ 53
Chapter 4. Results ..........................................................................................................................54
4.1 Survey Participation .................................................................................................. 54
4.2 Demographics ........................................................................................................... 54
4.3 Respondents Whose Company Integrated CMC Operations .................................... 58
4.3.1 Exploration .................................................................................................. 58
4.3.2 Installation ................................................................................................... 64
4.3.3 Initial Implementation ................................................................................. 70
4.3.4 Full Implementation .................................................................................... 79
4.3.5 Sustainability ............................................................................................... 82
4.4 Respondents Whose Company Remained as Independent CMC Operations ........... 88
4.5 Final Views of All Respondents on Overcoming CMC Hurdles .............................. 90
Chapter 5. Discussion ....................................................................................................................92
5.1 Introduction ............................................................................................................... 92
5.2 Methodological Considerations ................................................................................ 92
5.2.1 Delimitations ............................................................................................... 92
5.2.2 Limitations ................................................................................................... 95
5.3 Discussion of Results ................................................................................................ 98
5.3.1 Exploration .................................................................................................. 99
5.3.1.1 Due Diligence ................................................................................. 99
5.3.1.2 Organizational Culture ................................................................. 100
5.3.1.3 Decision Making ........................................................................... 101
5.3.2 Installation ................................................................................................. 103
5.3.2.1 Technology Transfer and Personnel Integration .......................... 103
5.3.2.2 Roles and Responsibilities ............................................................ 105
5.3.3 Initial Implementation ............................................................................... 107
5.3.3.1 Pilot Studies .................................................................................. 108
5.3.3.2 Disruptions and Delays ................................................................ 109
5.3.4 Full Implementation .................................................................................. 111
5.3.4.1 Standardizing and Improving CMC Operations ........................... 111

vii
5.3.5 Sustainability ............................................................................................. 114
5.4 Conclusions ............................................................................................................. 115
References ....................................................................................................................................118
Appendix A. Survey Questions....................................................................................................137
Appendix B. Survey Data ............................................................................................................159

viii
List of Tables
Table 1: Clinical Development ...................................................................................................4
Table 2: FDA Guidance and Considerations for Accelerating Regulatory CMC Strategies ....27
Table 3: Traditional Stages of Clinical Trials during Drug Development ................................33
Table 4: Expedited Programs for Serious Conditions ...............................................................34
Table 5: Implementation Framework: Overcoming the Rate Limiting Steps ...........................50
Table 6: Regulatory CMC Strategy Decision Making ..............................................................61
Table 7: Concerns of Integrations at Early Stages ....................................................................70
Table 8: Supporting Views for Ensuring Successful Integrations ............................................75
Table 9: Suggestions to the FDA for when CMC Operations are Integrated ...........................82
Table 10: Solutions to Overcome CMC Operational Integrations ..............................................84
Table 11: Advice to Organizations for Ensuring Successful Integrations ..................................87
Table 12: Responses - Pros and Cons of Not Merging CMC Operations ..................................88
Table 13: Overcoming hurdles for Timely Regulatory Submissions .........................................90

ix
List of Figures
Figure 1: Regulatory Pathways (351 vs 361) .............................................................................19
Figure 2: Gene and Cell Therapy Manufacturing Process and Testing .....................................28
Figure 3: Comparison of Traditional and Expedited Approval Timelines .................................38
Figure 4: Implementation Framework – GCT Technology Transfer Process ............................47
Figure 5: Drug Development Experience by Category ..............................................................55
Figure 6: Nature of Relationship underlying CMC Operational Integration .............................55
Figure 7: Years of Experience in Drug Development ................................................................56
Figure 8: Size of Company Represented by Respondents .........................................................56
Figure 9: Functional Department of Participants .......................................................................57
Figure 10: Current Position in Company .....................................................................................57
Figure 11: Distribution of Merging or Completely Independent CMC operations ......................58
Figure 12: Involvement in Due Diligence ....................................................................................58
Figure 13: Importance of Due Diligence Before Integrations: More Important ..........................59
Figure 14: Importance of Due Diligence Before Integrations: Less Important ...........................60
Figure 15: Importance of Restructuring .......................................................................................62
Figure 16: Areas of Greatest Concern when Merging CMC Activities .......................................63
Figure 17: Areas of Lesser Concern when Merging CMC Activities ..........................................63
Figure 18: Top Rated Concerns for FDA Approvals as Merging Began .....................................64
Figure 19: Additional Concerns for FDA Approvals as Merging Began ....................................65
Figure 20: Views of Difficulty when Aligning CMC Strategies .................................................67
Figure 21: Activities Most Commonly Shared during Organizational Integrations ....................68
Figure 22: Activities Less Commonly Shared during Organizational Integrations .....................69
Figure 23: Adequacy of Operational Changes to Meet FDA Expectations .................................70
Figure 24: Most Highly Rated Challenges as Operations Began to Merge .................................71
Figure 25: Challenges with Lower Rankings as Merging Operations Began ..............................72
Figure 26: Activities Meeting Expectations when Partnering Groups Align ...............................73
Figure 27: Areas More Frequently Not Meeting Expectations when Partnering Groups Align ..74
Figure 28: Views on Success of Integrations ...............................................................................75
Figure 29: Impact on Staff when Implementing Tech Transfers .................................................76
Figure 30: Implementation Effectiveness for Projects with New Teams .....................................77
Figure 31: Achieving Milestones when Implementing Projects ..................................................78
Figure 32: Delays with Regulatory Submissions .........................................................................79
Figure 33: Top Rated Challenges when Merging Operations ......................................................80
Figure 34: Additional Challenges when Merging Operations .....................................................80
Figure 35: Regulatory Oversight During Integrations .................................................................81
Figure 36: Decision Making for Developing Regulatory CMC Strategies ..................................82
Figure 37: Success of Regulatory Submissions for Drug Development Programs ......................84

x
Figure 38: Implementation of FDA Guidances ............................................................................85
Figure 39: Acceleration of Regulatory CMC Strategies ..............................................................86
Figure 40: Challenges when Implementing New Organizations .................................................87
Figure 41: Reflections on Preference for Integration or Separation ............................................90

xi
Abstract
Novel Gene and Cell Therapy (GCT) products offer important opportunities to treat rare and life-
threatening diseases and therefore become candidates for dramatically expedited development
and regulatory approval. However, the advantages of these expedited pathways can be
threatened when operational aspects of product management are disrupted by corporate
reorganizations after mergers and acquisitions. The combined effects of shortening and
disrupting the developmental path puts unprecedented pressure on the testing and manufacture of
these complex novel therapies. It can cause the activities associated with Chemistry,
Manufacturing, and Controls (CMC) to become the rate-limiting factor for drug approvals. This
exploratory study examined factors affecting CMC activities to reduce the hurdles for timely
CMC development. The study surveyed the views of CMC professionals with experience in
drug development, including mid to senior-level professionals working in both biotech and
pharmaceutical companies. An implementation framework was used to structure and frame the
research. Results suggested that aligning regulatory CMC strategies between the partners and
regulators pose many challenges. Amongst the most common were dissonant approaches for
incorporating regulatory guidances, conflicts with developing early-to-late-stage CMC strategies
to meet FDA expectations, and difficulties in preserving product knowledge as teams change as a
result of transitions. Results suggest that more direct communication and guidance from FDA on
the expectations and standards for development of these products would reduce uncertainty;
however, companies should also address vulnerable areas related to the retention of personnel
and the meshing of dissonant cultures to assure the success of CMC integrations.

1
Chapter 1. Overview
1.1 Introduction
One of the biggest challenges that biopharmaceutical companies have faced for more than
a century has been the need to manufacture a product of high and consistent quality. This area of
focus, often designated as “Chemistry, Manufacturing, and Controls,” has become progressively
more regulated since the beginning of the 20
th
century. In 1902, the Biologics Control Act was
enacted after 22 children died from tetanus that they acquired from a contaminated diphtheria
vaccine raised in a diseased horse (Schwieterman, 2006). This law, also known as the Virus-
Toxin Law, underscored the importance of having controls over the Chemistry and
Manufacturing (CMC) of biologics to ensure a safe and efficacious product. Under this law,
manufacturing facilities were required to undergo inspections; violating the provisions would be
punished by fine and/or imprisonment upon conviction.
However, this early law governing vaccine quality was insufficient to ensure all drug
safety. The need for broader regulation became a continuing theme for the next two decades as a
series of modest laws with limited enforcement capabilities were put into place. However, the
limitations of these laws became apparent in the 1930s when the U.S. was confronted by another
tragic failure of drug safety. In this case, 105 patients were poisoned with a newly introduced
antibiotic syrup called “Elixir of Sulfanilamide” that used the toxic solvent, diethylene glycol, as
its vehicle (Wax, 1995). The public outcry associated with both the product recall and the
subsequent insufficient legal outcomes underscored the need for a more stringent regulatory
framework. Congress then passed the Federal Food, Drug, and Cosmetic (FD&C) Act in 1938.
This law strengthened the role of the U.S. Food and Drug Administration to oversee and review
drugs prior to marketing. It also required manufacturers to demonstrate the safety of a drug

2
before it could be marketed, although the nature of that testing and quality management was still
relatively underdeveloped.
Throughout the ensuing century, scientific advances helped to turn the manufacturability
and testing of drugs into a much more sophisticated process, and the laws and regulations
coevolved to adjust. A key piece of legislation passed in 1962 was the Kefauver-Harris Drug
Amendment, driven by another crisis caused when a teratogen called thalidomide was introduced
into the European market (Meadows, 2006). The widespread congenital disabilities that were
observed following its use for the morning sickness of pregnancy came at the same time as FDA
was reviewing thalidomide for entry to the American market. The amendment allowed Congress
the opportunity to increase FDA’s regulatory authority. More rigorous regulations were
introduced in several areas: for evidence of product efficacy as well as safety; for informed
consent of subjects being tested with an experimental drug; for reporting of adverse events; and,
of particular relevance to this research, for the implementation of Good Manufacturing Practices
(GMPs) before the product could be marketed for its intended use (Meadows, 2006).
U.S. manufacturers and regulators take seriously the challenge to ensure that drug
development provides the safest and most advanced pharmaceutical product possible. To this
end, companies with new drug products now must provide FDA's Center for Drug Evaluation
and Research (CDER) with extensive evidence to demonstrate that their drugs are safe and
effective for their intended uses. A significant part of CMC submissions describes analytical and
manufacturing information about the new drug. The FDA takes nearly a year to review those
data and inspect the manufacturing facility before approving market entry. When drug
development and review times are combined, this stringent approach is both costly and lengthy,

3
averaging $2.6 billion and over a decade to market (Carroll, 2014). Such extended timelines
come at a cost to patients with serious conditions which could deprive them of critical therapies.
This concern prompted Congress, and by extension, FDA, to modify the approach taken
to shorten the drug development path for products that treat serious diseases or conditions.
Initially, these modifications were largely invisible to the CMC functions of the company
because the critical path was dominated by the long period of clinical trials. For example, this
path was not greatly affected by the new route for the “treatment use of investigational drugs,”
authorized in 1987, which allowed patients with life-threatening diseases and no alternative
treatment to use an investigational drug at the same time as supportive clinical trials were
underway. In 1992, FDA introduced an “accelerated approval pathway” to expedite the approval
of a critical drug by basing estimates of efficacy on surrogate endpoints rather than clinical
endpoints such as survival or clinical benefit; this shortened the trials somewhat but still required
the time-consuming recruitment of very large numbers of subjects. A new “priority review
program” shortened the time for review but did not affect the manufacturer’s activities toward
submission. All of these programs constructed overlapping opportunities to expedite drugs for
important unmet medical needs, as summarized in Table 1. However, they still gave
considerable time to address, in parallel, the increasing demands for CMC data.

4
Table 1: Clinical Development
Modified from (FDA, 2014a, FDA, 2020c, FDA, 2018a)
Designation Description
Fast Track
Accelerates the development and review of drugs to treat serious
conditions to fulfill an unmet medical need.
Breakthrough
Therapy
Permits more consultation, earlier submission, and faster review of
drugs demonstrating substantial improvement over available therapy.
Accelerated
Approval
Accepts a surrogate endpoint to facilitate approval of drugs treating
serious conditions that fill an unmet medical.
Priority Review
Tasks the FDA to review a drug marketing application within 6
months.
Regenerative
Medicine Advanced
Therapy (RMAT)
Supports the development and approval of a regenerative medicinal
product that addresses an unmet medical need related to a serious
condition.

In the last decade, however, this situation began to change as additional programs to
accelerate drug development began to affect the timelines available for CMC activities. The
Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) provided
additional expedited regulatory pathways, the “breakthrough therapy” and “Regenerative
Medicine Advanced Therapy (RMAT)” pathway, for new drugs and cell therapies demonstrating
substantial improvement over existing treatments for serious diseases at early clinical stages
(FDA, 2018e) (Puthumana et al., 2018). In both programs, the clinical testing phase is typically
much shorter than that for a conventionally developed drug. The conventional drug is expected
to progress through a series of clinical trials from Phase I to Phase III that typically require at
least 7 years and the participation of more than 1,000 patients. However, products participating
in the new programs break the typical rules. Their clinical trial period can be condensed to only
2-3 years and based on only a few hundred patients. This dramatic change has been particularly
influential in the development of novel biological products and puts additional time constraints
on CMC development and staff.

5
1.1.1 Biologics as Agents of Change
The first type of drug to be regulated was a vaccine. Vaccines are members of a larger
product class considered biologics, defined by the FDA as “Blood-derived products, vaccines, in
vivo diagnostic allergenic products, immunoglobulin products, products containing cells or
microorganisms, and most protein products (FDA, 2015a).”
Biologics have special status from a regulatory perspective. The Public Health Service
(PHS) Act of 1944 focused uniquely on assuring control over the purity and safety of biologics,
whose cell-based origins make them particularly vulnerable to contamination by infectious
communicable agents. Today, the diverse and growing families of biological products have
become particularly important therapeutically as companies redirect their attention from
developing small molecules to developing biologics with novel compositions (Gutierrez et al.,
2020). These biologics can be more difficult to manufacture, so CMC experts often need more
time to develop and validate their manufacturing processes and testing procedures. At the same
time, the astonishing effectiveness of some biologics makes them candidates for expedited
regulatory pathways. For example, three recent biologics based on CAR-T technologies,
KYMRIAH
®
(tisagenlecleucel), YESCARTA
®
(axicabtagene ciloleucel), and TECARTUS
TM
(brexucabtagene autoleucel), were approved after clinical trials with fewer than 110 patients
enrolled in less than 3 years (FDA, 2017b, FDA, 2017c, FDA, 2020j). Such a dramatic
shortening of the clinical path can put enormous pressure on the manufacturing and quality
divisions of companies as they try to put into place well-controlled and validated manufacturing
systems prior to the accelerated launch date.
The CMC challenges have become more problematic since the expansion of “Advanced
Therapies” such as gene and cell therapies (GCTs). More than 900 investigational new drug
(IND) applications have been lodged for such products (FDA, 2020d). FDA has been supporting

6
these companies by working closely with sponsors and finalizing guidances to address the
evolving landscape of modern manufacturing. Their efforts are supported by various forms of
formal regulatory and technical guidance. In November 2018, the ICH assembly endorsed the
proposal for a new quality guidance designated as ICH Q13: Continuous Manufacturing for Drug
Substances and Drug Products, aimed to improve product consistency and reduce the risk of drug
shortages (FDA, 2019c). In January 2020, FDA released five final guidances focused on gene
therapy manufacturing issues and clinical recommendations for product developers (Gray, 2020).
This concentrated activity reflects an underlying appreciation that biologics can be difficult to
manufacture consistently, so that process engineering and validation often take longer than for
synthetic small molecules. Thus, any additional perturbations or distractions along the CMC
pathway can have damaging effects on the timely submission of marketing applications for life-
changing products. One prevalent type of perturbation is felt when companies undergo merger
or acquisition just as manufacturing operations are being put into place and validations are
underway.
1.2 Statement of the Problem
Currently, biologics companies are faced with complicated manufacturing and validation
obstacles. Those issues often must be resolved within a compressed timeline as clinical trials
shorten. Added to this challenge is a third dimension, related to the fact that such products have
become acquisition targets. They are often developed by small companies that are acquired by
larger companies after they have been “derisked” by early evidence of efficacy and safety in the
clinical stage (Bain, 2011). The business model of larger pharma companies has evolved from
developing product pipelines in-house to forming strategic alliances for advancing novel
pharmaceutical technologies or acquiring pipeline products through mergers and acquisitions

7
(M&A). The pharmaceutical industry has more M&A activity than any other industry, both in
the number of deals and the amount of money (Bieri, 2018). This has significant implications for
the “due diligence” that must be carried out during the M&A process.
“Due diligence” is a term used to describe the preparations made by a company before
completing a business transaction in order to justify and set terms for a merger or purchase of
securities (Webster, 2020). Conventionally, this type of activity has focused on the financial and
commercial opportunities presented by the target acquisition. In the biotechnology and
pharmaceutical industries, however, these activities now must consider the risks associated with
development and regulatory activities of unmarketed assets. It is not clear whether the
integration activities associated with the complex and time-bound CMC requirements are
planned early, prior to or during the acquisition, and whether they pose problems after the
acquisition has occurred (Djukic, 2008). Even if acquisitions occur after the product has been
commercialized, team structures, manufacturing planning, validation, and documentation must
be revised to fit into a new organization with different procedures and company cultures.
We know that such challenges have affected the few recent biologics programs for which
information is available. For example, the technology for the first FDA-approved Chimeric
Antigen Receptor T-cell therapy (CAR-T) was originally developed by the University of
Pennsylvania, then transferred to Novartis as a collaboration to bring the therapy to market in
August 2017. Shortly after, in 2018, Novartis experienced post-approval CMC issues that
resulted in high failure rates related to deficiencies in product quality. Consequently, FDA
mandated that release specifications be revised when it became clear that regulatory CMC
strategies for pre-licensure manufacturing methods were not comparable to those of the

8
commercial manufacturing process, thereby risking product failures and decreased access to
these medicines (Davies, 2018).
What we know from the recent approvals is that CMC challenges threaten to become the
limiting factor to the successful and timely commercialization of complex biologics. However,
what we do not know is how companies are managing these challenges when their development
and commercialization efforts must be carried out in the disruptive environment of a concurrent
merger, acquisition, or joint venture.
1.3 Purpose of the Study
The purpose of this study was to examine the operational practices of manufacturers,
explore the current regulatory CMC framework, and identify challenges that limit the execution
of regulatory CMC strategies when companies co-develop novel biopharmaceutical technologies.
Industry perspectives were obtained by using an electronic survey platform (Qualtrics.com) to
solicit the participation of industry professionals at mid to senior levels whose functions related
to some aspect of CMC activities. This group was therefore delimited to manufacturing, quality,
regulatory, supply chain, analytical, and process development personnel working across small to
large pharmaceutical companies who had experienced a joint venture, merger, or acquisition
within the last decade. They were presented with a survey based on an implementation
framework originally developed by the National Implementation Research Network (NIRN)
(Bertram et al., 2015, Fixsen et al., 2005, Bertram et al., 2011).
1.4 Importance of the Study
Results of this study illuminated some “lessons learned” from attempting to implement
CMC strategies as two or more organizations came together to codevelop advanced therapy
products. Further, it gave some insight into areas of challenge that needed to be addressed to

9
deal with stressors imposed by shortened timelines when the products follow an accelerated
development path. Thus, results may be useful to CMC regulators, health authorities, and
scientists. This study will help to inform CMC regulators attempting to develop innovative
pathways for original marketing applications by suggesting alternative frameworks for electronic
submissions or validation strategies for important products developed under compressed
timelines (Algorri et al., 2020). It may assist scientists and strategists in industry obtaining
information about current and best practices in an environment where few precedents are
available. Understanding the challenges of implementing a robust and validated manufacturing
process can better equip those engaged in CMC functions with the insights of others as they
confront technical and operational integrations associated with business reorganizations.
Mitigating the pain points and creating forward-looking models for a flexible and adaptable
manufacturing process is key to advancing transformative medicines.
1.5 Limitations, Delimitations, Assumptions
1.5.1 Limitations
This research has certain limitations. The number of companies that have advanced GCT
products into late-stage development or commercialization is still relatively small, which
challenged my ability to recruit respondents. Nevertheless, it was possible to gain the responses
of 56 highly qualified individuals who met the criteria for inclusion. Further, experts
participating in the survey may lack experience in co-developing novel technologies and directly
working with therapies from developmental stages to commercialization, so individual
respondents sometimes could not answer all of the questions or may have guessed at answers.
Participants varied in their level of engagement with changes taking place in organizations
undergoing a merger, acquisition, or joint venture, and particularly with due diligence activities.

10
Thus, questions related to due diligence were answered by a smaller number of respondents.
This is the first survey known to me in an area of concern that is only now becoming prevalent
and lacks an extensive collection of literature on which to build. Thus, the questions may have
been limited in their ability to predict important areas to explore.
1.5.2 Delimitations
The regulatory landscape for CMC drug approval requirements and expectations varies
greatly across markets internationally. Therefore, the views of CMC professionals working in
the rest of the world also differ. For this reason, the current survey was delimited to the
experiences of those working in companies that market in the U.S. and work within the U.S.
regulatory framework. This study was further delimited to the practices and views of CMC
rather than other areas of industry affected by shortened and disrupted timelines, such as
marketing or clinical affairs. It was framed by an implementation approach, so it did not include
questions on other aspects such as the effects on hiring practices or detailed procedural aspects of
CMC. The research participants were delimited to CMC professionals who were engaged in
cross-functional departments such as process development, analytical sciences, quality
operations, and regulatory affairs to delimit the respondent sample to those who are involved
with assuring product quality and manufacturability. The surveyed population included
professionals who had at least two years of industry experience at mid to senior levels in biotech
and pharmaceutical companies of different sizes.
1.5.3 Assumptions
The study assumes that professionals responded truthfully and expressed views directly
related to their work-related experience on the subject matter. It further assumes that the
individuals completing the survey were qualified to respond to the questions posed in the survey.

11
1.6 Organization of Thesis
The dissertation comprised of five chapters. Chapter 1 is an overview of the current
challenges related to regulatory CMC strategies for advanced therapy products. Chapter 2
outlines the literature review findings, including the evolution of pharmaceutical quality, drug
and clinical development, operational integrations, and the research framework used to examine
the questions of interest. Chapter 3 defines the research methods, development of the survey,
focus group, and survey analysis. Chapter 4 reports and reviews the results of the study.
Chapter 5 discusses the significance and validity of the findings.

12
1.7 Definitions and Acronyms
Acronyms Definitions
ADC Antibody Drug Conjugate
ALL Acute Lymphoblastic Leukemia
BCA Biologics Control Act
BCMA B-Cell Maturation Antigen
BLA Biologic Licensing Application
BTD Breakthrough Therapy Designation
CAR-T Chimeric Antigen Receptor T-cell
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
CDMO Contract Development and Manufacturing Organization
CD3 Cluster of Differentiation 3
CFR Code of Federal Regulations
CJD Creutzfeldt-Jakob Disease
CMC Chemistry, Manufacturing, and Controls
CMO Contract Manufacturing Organization
CQA Critical Quality Attribute
CRL Complete Response Letter
CRO Clinical Research Organization.
CTL Contract Testing Lab
DLBCL Diffused Large B-Cell Lymphoma
eCTD Electronic Common Technical Document
EET Emerging Technology Team
FDA Food and Drug Administration
FDAMA Food and Drug Administration Modernization Act
FDASIA Food and Drug Administration Safety Innovation Act
FD&C Federal Food, Drug, and Cosmetic Act
FL Follicular Lymphoma
FOCR Friends of Cancer Research
GCT Gene and Cell Therapy
cGMP Current Good Manufacturing Practices
HCT/Ps Human Cells, Tissues, and Cellular and Tissue-Based Products
HCV Hepatitis C Virus
HIV Human immunodeficiency Virus
ICH International Council for Harmonization
IL-2 Interleukin-2
IND Investigational New Drug
IRs Information Requests
M&A Mergers and Acquisitions
mAbs Monoclonal Antibodies
NCI National Cancer Institute
NDA New Drug Application
NIRN National Implementation Research Network
ODA Orphan Drug Act
PD-1 Programmed Cell Death Protein 1
PD-L1 Programmed Death-Ligand 1
PDUFA Prescription Drug User Fee Act
PHS Public Health Service
PPQ Process Performance Qualification
R&D Research and Development
RMAT Regenerative Medicine Advanced Therapy
TSE Transmissible Spongiform Encephalopathy

13
Chapter 2. Literature Review
2.1 Introduction
Much of what we know about pharmaceutical development has stemmed from long
experience with synthetic drugs. The development path for such products has typically been
dominated by a lengthy period of clinical trials, needed to convince regulators that the product is
safe and effective in a target patient population. However, this model is far from adequate for
biological drugs based on cutting-edge technologies. For those products, development can be
dominated by novel challenges to characterize, manufacture and test the product, which is a
collection of activities that have come to be known as Chemistry, Manufacturing, and Controls
(CMC). Scientists responsible for CMC activities face at least three complicating challenges that
are unusual for other product types. First is the complexity of the therapy itself, which demands
extra effort at the early stages to define specifications and validation requirements that will
assure product quality. Second is the need to carry out these activities in an abbreviated period
of time because the clinical trial pathway for these life-saving “Advanced Therapies” has been
reduced substantially. Third are the logistical challenges inherent in attempting to conduct CMC
activities as companies integrate during partnerships and M&A ventures. When a merger or
acquisition takes place, the acquiring company can change not only the site at which business
must be done but also the nature and format of documentation, the structure of teams, and the
approach by which product milestones are set and reviewed, all of which slow developmental
progress (Dye et al., 2016). In the literature review that follows, the trends associated with these
three types of challenges will be traced as the first step in this research to understand better the
current experience and concerns of professionals responsible for the Chemistry, Manufacturing,
and Controls (CMC) of “Advanced Therapy” products as their companies experience changes in
business ownership or partnerships.

14
2.2 Evolution of Expectations for Pharmaceutical Quality
2.2.1 History of Regulations governing Pharmaceutical Quality
Concerns over the quality of commercialized drugs have been core to laws and
regulations governing drug development for more than a century. In 1901, contamination of
diphtheria antitoxin vaccine raised in a diseased horse led to tetanus outbreaks causing the death
of several children (Coleman, 2016). In response, the Biologics Control Act (BCA) of 1902 was
enacted. Also known as the Virus-Toxin Law, the BCA prohibited the sale, barter, or exchange
of any vaccines, serums, antitoxins, and analogous products in interstate or foreign commerce
(FDA, 2010). In 1906, the U.S. Congress expanded legal requirements beyond vaccines by
passing the Pure Food and Drug Act (FDA, 2019b) to prohibit misbranded and adulterated drugs,
drinks, and food. Oversight for enforcement was assigned to the Bureau of Chemistry within the
Department of Agriculture, which was reconfigured as the FDA in 1930 (FDA, 2018f).
Regulatory expectations expanded in 1937 with the introduction of the Federal Food,
Drug, and Cosmetic Act (FDA, 2018d), again motivated by concerns about insufficient
requirements and oversight. In this case, an antibiotic called sulfanilamide, developed by S.E.
Massengill Company was sold as a raspberry-flavored liquid “elixir” across the United States
(Akst, 2013). The drug was dissolved in diethylene glycol, a toxic liquid that poisoned 105
individuals before the crisis ended. The FD&C Act of 1938 required companies to submit a
formal application for marketing, called a New Drug Application (NDA), which FDA could
scrutinize to assure that the product was safe prior to commercialization. The narrow provisions
of this Act came into question in the 1960s when a drug called thalidomide entered the global
market and caused malformations in newborns. The U.S. largely escaped the adverse
consequences of this drug because its teratogenic effects were recognized before the product’s

15
NDA was fully reviewed by the FDA. Nonetheless, Congress took the opportunity to enhance
requirements by passing the Kefauver-Harris Amendment to the FD&C Act. Manufacturers
would now be required not only to demonstrate safety but also to provide evidence of product
efficacy, to assure the informed consent of subjects, to report adverse events, and to implement
Good Manufacturing Practices (GMPs) before the product could be marketed for its intended
use.
2.2.2 Modernization of Regulatory CMC Landscape
Amendments over the several decades following the initial passage of the FD&C Act laid
out certain important CMC requirements for all pharmaceutical products (FDA, 2018d). The
globalization of pharmaceutical commerce also drove more careful evaluation of product quality,
safety, and efficacy (FDA, 2019d). It created a need to harmonize laws, regulations, and
standards. As a result, the International Council for Harmonization of Technical Requirements
for Pharmaceuticals for Human Use (ICH), formerly known as The International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH), was formed in the 1990s with the goal of creating supranationally harmonized technical
and scientific requirements for a pharmaceutical quality consonant with the Good Manufacturing
Practices (GMP) requirements within each region. Because ICH members came not only from
industry but also from the regulatory agencies of the largest markets at that time, the organization
was well-structured to assure that the new guidances would be incorporated into the regulatory
thinking of key constituencies. Thus, they would furnish a singular, comprehensive approach for
sponsors seeking approval and market authorization of new products in different jurisdictions
(ICH, 2020). Since that time, ICH has evolved into a larger forum with more members and
observers. It has been responsible for the development of many valuable and well-accepted

16
technical approaches not only for quality but also for other aspects of drug development.
However, it takes a long time and multiple rounds of consensus building to develop guidances
through a series of formal ICH procedures prior to regulatory implementation of finalized
guidelines (Gupta et al., 2014). Not unexpectedly, the materials they develop lag behind
emerging science.
Additional activities at the national level also become important to ensure that the
chemical development and testing of drugs and biological products can keep pace with the rapid
evolution of novel technologies. In 2002, the FDA introduced the “Pharmaceutical Quality as
part of a 21st Century Initiative”, intended to modernize FDA's regulations related to the quality
of human drugs and certain types of biological products (FDA, 2015c). The initiative
encouraged industry to modernize quality management techniques for Current Good
Manufacturing Practices (cGMPs) using a risk-based approach based on the depth of product and
process understanding and monitored by the firm’s quality systems. As part of the risk-based
approach, process improvements for well-understood biologics would be managed under the
supervision of the sponsor’s internal change control procedures, whereas complicated and newly
developing manufacturing processes with less product knowledge would require heightened
regulatory oversight (FDA, 2015c). Because less understood and controlled process changes are
riskier than those typical for most well-characterized products, additional quality data for these
novel products would have to be shared with regulatory bodies. Regulatory agencies anticipated
that their regulatory review, compliance, and inspection policies could learn from the submission
data and evolve alongside of and take into account the modernized approaches based on state-of-
the-art pharmaceutical and manufacturing sciences (FDA, 2015c).

17
Biological products are harder to develop and manufacture consistently than synthetic
drugs. Throughout the course of their preclinical drug development and manufacturing, testing
and characterization become critical to understanding quality attributes such as the structure and
functional properties of biologics. These properties influence the manufacturability,
performance, and stability of the therapy, all of which must be under control if an investigational
biologic is to move forward into the clinic and subsequently gain regulatory approval.
Early biologics such as monoclonal antibodies were the first to test the traditional
regulatory CMC framework used for synthetic drugs. The techniques for developing monoclonal
antibodies were discovered by Milstein and Köhler in 1975 (Kohler and Milstein, 1975). By
1986, the first commercialized monoclonal antibody, Orthoclone OKT3
®
(Muromonab-CD3), by
Janssen (a subsidiary of Johnson & Johnson), was approved to prevent kidney transplant
rejection (Reichert, 2012). Since that time, monoclonal antibodies evolved from scientific
exotica into products so well understood that they gained the designation of “well-characterized
biologics” whose structure-activity relationships and “platform” manufacturing processes
became relatively routine. In fact, they were routine enough to justify their placement for review
and oversight into CDER rather than CBER, then designated for the oversight of “complex”
biologics. However, the lessons learned from those monoclonal antibodies could be applied to a
subsequent generation of modified monoclonal antibodies (mAbs), such as antibody fragments,
antibody-drug conjugates (ADCs), and bi- and multi-specific antibodies (Petrie, 2016).
Even as the manufacturing and quality expectations for “well-characterized” biologics
became refined, another wave of complex therapeutics began to emerge. One notable area of
progress stemmed from the work of Steven Rosenberg and colleagues at the National Cancer
Institute (NCI), who advanced the hypothesis that the T-cell growth factor cytokine, interleukin-

18
2 (IL-2), could be used to elicit an immune response against cancerous cells (Rosenberg et al.,
1985). In 1992, the results of IL-2 clinical studies led to the first approved immunotherapy to
treat metastatic renal cell carcinoma (Cavallo, 2018). These early advances paved the way for
treatments to modify the patients’ own (autologous) or donor (allogeneic) cells nearly
twenty-five years later. In such treatments, T cells are removed from a patient’s blood or
modified from donor cells. A gene is then introduced to the cells in vitro so that they express a
specific receptor, termed Chimeric Antigen Receptor (CAR), that is able to bind to cancerous
cells. These modified “CAR-T” cells are infused back into the patients to treat a specific,
targeted cancer type (NIH, 2019, Dai et al., 2019).
The rapid pace of change in Gene and Cell therapies (GCTs) has challenged legislators in
ways that were probably unimaginable more than a hundred years ago. According to the FDA,
these products now involve new classes of products:
Human gene therapy seeks to modify or manipulate the expression of a gene or to
alter the biological properties of living cells for therapeutic use. Cellular
immunotherapies, cancer vaccines, and other types of both autologous and
allogeneic cells for certain therapeutic indications, including hematopoietic stem
cells and adult and embryonic stem cells (FDA, 2019a).

However, the unique needs of biologics have been recognized for much longer than these
classes have existed. The Biologics Control Act (BCA) of 1902 focused uniquely on biologics
but was directed primarily at vaccines, serums, antitoxins, and analogous products. The spectra
of communicable disease transmission associated with these and later biologics, typically
injectable products that are difficult to sterilize, led the U.S. Congress to pass the Public Health
Services Act (PHSA) in 1944. This Act gave FDA the authority to make and enforce regulations
to prevent the transmission of diseases from foreign countries into the United States. However,

19
the deficiencies of that Act became abundantly clear by the early 1990s, when HIV transmission
was found to be passed through transplantation of human tissues.
FDA responded by strengthening the PHSA. Sections 361 and 351 of the Act became
focused on a group of products defined as Human Cells, Tissues, and Cellular and Tissue-Based
Products (HCT/Ps), and addressed specifically the need to prevent introduction, transmission, or
spread of communicable diseases through tissue transplantation (FDA, 2007). Products
categorized as low risk would be governed under Section 361 of the PHSA and would not
require pre-market FDA approval (FDA, 2006). In contrast, products categorized as high-risk
would be regulated as biological products under both Section 351 of the PHSA and the
applicable parts of the FD&C Act and would require premarket approval, as summarized in
Figure 1 (Lau, 2019, Silverman et al., 2019). Companies seeking to approve a product would
have to submit a Product License Application and an Establishment License Application; these
two documents were later combined into a single submission, called a Biologics License
Application (BLA) (FDA, 2022b)
Figure 1: Regulatory Pathways (351 vs 361)
Modified from (Silverman et al., 2019)

Commercialization
High Risk
Efficacy and potency
claims based on
clinical outcomes
Commercialization
Low Risk
No claims of efficacy
or potency due to
no clinical data
Section 351
HCT/P Pathway
Cell therapy pathway if:
• The criteria is not
met above (361)
Section 361
HCT/P Pathway
Cell therapy pathway if:
• Cells are minimally manipulated
• Intended for homologous use
• Cells not combined with other materials
• Only rely on metabolic activity of cell if
autologous
Preclinical Phase I Phase II Phase III
21 CFR Part 210 &211 – cGMP
21 CFR Part 1271 – Manufacturing
Arrangements

20
Still, in the 1990s, many cell therapies entering the market had features shared with 361
products even though they belonged to the 351 category. Initially, the most common products,
cord blood stem cells, were often derived from donors. For these types of products, FDA issued
its 2007 guidance titled “Eligibility Determination for Donors of Human Cells, Tissues, and
Cellular and Tissue-Based Products (HCT/Ps)” (FDA, 2007). The guidance gave specifics about
donor eligibility based on screening and testing for relevant communicable disease agents and
transmissible diseases, such as Human immunodeficiency virus (HIV); Hepatitis C virus (HCV);
Transmissible Spongiform Encephalopathy (TSE); and Creutzfeldt-Jakob disease (CJD). Shortly
thereafter, the processing of cell-based products was discussed in a 2008 draft guidance for FDA
reviewers and sponsors titled “Content and Review of Chemistry, Manufacturing, and Control
(CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications
(INDs)” (FDA, 2008). It provided instructions for the CMC content of IND submissions needed
to pursue clinical testing of potential BLA candidates.
Both guidances were directed not only to drug sponsors but also to FDA reviewers. For
reviewers, they outlined expectations on which their assessments should focus, taking into
consideration the manufacturing challenges associated with these types of biologics. The
identified challenges included the variability and complexity of intrinsic and extrinsic
components used to manufacture the final product. They called attention to not only the
autologous/allogeneic sourcing and quality of cells from patient to patient but also the potential
for contamination as the cells were processed (Dai et al., 2019). This challenge, identified as
early as the 1950s, still had not been solved effectively because the final product could not be
sterilized for fear of killing the living cells composing the product. Thus, starting materials and
materials from donors had to be tested to ensure that they carried no serious infectious agents.

21
2.2.3 Chemistry and Manufacturing as a Focus
Manufacturers determine Critical Quality Attributes (CQAs) based on clinical safety and
efficacy outcomes to define meaningful drug product specifications that will satisfy regulatory
requirements concerning “identity, purity, strength, potency, stability and safety” (Heidaran,
2017, Vatsan, 2017, Finn, 2018). One of the key attributes of a “controlled” manufacturing
process is its ability to yield a desired product or intermediate consistently. Companies must
therefore convince the regulators that their processes are “in control” by completing a variety of
validation tests of both the manufacturing processes producing the drug and the analytical
methods to assess the quality of the product (Gee, 2018). A robust and reproducible
manufacturing program can reduce the risk of product failures and consequent supply shortages.
For these reasons, operational controls and performance criteria for manufacturing are subjected
to rigorous scientific scrutiny when the CMC sections of a BLA are reviewed.
By the beginning of the 21
st
century, it was becoming clear that one group of products,
GCTs, would be particularly difficult to manufacture in the usual ways. For these products,
manufacturing was especially problematic because it was hard to “control.” Advice was first
sought from two relatively new guidance documents, “Process Validation: General Principles
and Practice Manufacturing Process Validation” (FDA, 2011b) and “Analytical Procedures and
Methods Validation for Drugs and Biologics” (FDA, 2015b). The first is directed at methods to
demonstrate that the manufacturing operations are in control by validating those processes. The
goal of validation is described as “The collection and evaluation of data, from the process design
stage through commercial production, which establishes scientific evidence that a process is
capable of consistently delivering quality product (FDA, 2011b).”

22
The second is directed at assuring the adequacy of analytic testing more specifically by
addressing the potential need not only to have defined methods but also to ensure the
science-based evolution of those methods over time. As stated,
Over the life cycle of a product, new information and risk assessments (e.g., a
better understanding of product CQAs or awareness of a new impurity) may
warrant the development and validation of a new or alternative analytical
method. New technologies may allow for greater understanding and/or
confidence when ensuring product quality (FDA, 2015b).

However, those guidances are rather generic. They do not specifically consider some of
the operational issues with which regulators and industry scientists must grapple as they attempt
to define what would be acceptable practice for GCTs. To address these challenges, FDA
released the final version of its guidance, “Emerging Technology Applications for
Pharmaceutical Innovation and Modernization,” in September 2017 (FDA, 2017a). As part of
that work, it also configured an Emerging Technology Team (ETT) with its home in CDER but
with multiple partners internally, including representation from FDA’s pharmaceutical quality
function, and externally with industry, to facilitate cross-functional quality assessments. These
teams were tasked with providing guidance for those who are manufacturing products with novel
features. Pharmaceutical companies were encouraged to submit questions and proposals about
specific emerging technologies prior to regulatory submission. Through the Emerging
Technology Program, FDA hoped to provide a vehicle that might encourage innovative
approaches to pharmaceutical manufacturing, including the use of continuous manufacturing as
well as high-throughput testing techniques to improve product quality throughout a product’s
lifecycle. Such innovative approaches are important not only to improve production speed and
consistency but also to reduce the risk of shortages that have often limited the availability of
hard-to-make and sterile products (Lee et al., 2015).

23
In July 2018, FDA continued to encourage innovation in the CMC domain by introducing
draft guidance titled “Quality Considerations for Continuous Manufacturing Guidance for
Industry” (FDA, 2019c). Continuous manufacturing describes “what's essentially an end-to-end
assembly line, through which raw materials are steadily fed and constructed into final products
(Pagliarulo, 2018).” The guidance, which was generic for all types of drugs but especially aimed
at traditional small molecules, described FDA’s current thinking on managing the quality of
drugs produced through continuous manufacturing and made recommendations for applicants in
pursuit of new drug applications (NDAs). It offered guidance on how to design monitoring and
controls for uninterrupted processes as well as how to set specifications for real-time release
testing. In doing so, the FDA redefined quality system expectations from a batch-to-batch
approach to a continuous process that would align with regulatory CMC validation requirements.
For biologic therapies, continuous bioprocessing is not a new concept (Schofield, 2018).
Many companies have attempted to establish such approaches to reduce the delays that often
occur when unit operations are conducted and documented in sequential batches. Commercial
operations such as Sanofi and WuXi Biologics have used its philosophy and methods to simplify
tech transfers, improve product quality, reduce the cost of goods, and enhance productivity as
they manufacture complex biologics and viral vectors used for gene expression in cell therapy
(Hill, 2020). In some instances, the implementation of continuous manufacturing methods has
been facilitated by partnering or even to acquiring companies with needed capabilities. One
particularly problematic area in the manufacturing process has been access to viral vector
starting materials. This need appears reflected by the acquisition of several Contract
Development and Manufacturing Organizations (CDMOs) in 2019 by manufacturers seeking
private access to starting materials and technological “know-how” (Lou, 2020). For example,

24
Thermo Fisher Scientific acquired Brammer Bio, Catalent Pharma Solutions acquired Paragon
Bioservices, and Astellas Pharma acquired Audentes Therapeutics.
Technology transfers from either smaller or academic establishments to larger facilities
or CDMOs may occur at any phase of the product’s life cycle (Jones, 2018). An area of concern
then becomes the comparability of products made when manufacturing approaches are modified.
In June 2005, FDA attempted to broaden its guidance regarding product comparability by issuing
“Q5E Comparability of Biotechnological / Biological Products Subject to Changes in Their
Manufacturing Process (FDA, 2005).”
Comparability becomes more critical as advanced therapies progress toward commercial
manufacture because this is the stage when FDA expects that more stringent controls will be put
into place. To assist with this challenge, FDA looked to the quality guidance, ICH Q10. In
2010, it published the “Guidance for Industry Q10 Pharmaceutical Quality System”, which
aimed to improve technology transfer within or between manufacturing and testing sites by
adopting the principles of that standard. ICH Q10 defines technology transfer as a stage of the
product development life cycle:
The goal of technology transfer activities is to transfer product and process
knowledge between development and manufacturing, and within or between
manufacturing sites to achieve product realization. This knowledge forms the
basis for the manufacturing process, control strategy, process validation
approach, and ongoing continual improvement (FDA, 2009).

When put into practice for well-characterized biologics, “expectation approaches”
compare the receiving site data to pre-defined acceptance criteria calculated from historical data
sets generated by the originating site. However, because GCT manufacturers may have special
needs, regulators responded by requesting a different standard for characterization and testing,
based on “equivalency approaches.” In this approach, GCTs can execute pre- and post-change

25
studies by dividing starting material tested at the originating and receiving sites concurrently
(Shen, 2017). This different standard reflects the way that regulatory CMC strategies are
coevolving with agency expectations to ensure successful agency approvals within the current
regulatory frameworks.
2.2.4 Advancing CMC for Gene and Cell Therapies
Pharmaceutical manufacturers have mostly viewed FDA’s attempts to collaborate as a
step forward (Cauchon et al., 2019). However, those collaboration attempts were largely driven
by CDER, so the 2017 and 2018 guidance documents did not address many of the issues
important for biological products under the oversight of CBER. Notably, they did not consider or
provide recommendations for certain aspects of continuous bioprocessing methods used to
manufacture biological products. For example, gene therapies rely on viral vectors as the
transfection vehicles for the genetic material; the manufacture of these vectors has depended
increasingly on continuous bioprocessing approaches to relieve the bottleneck that has been
posed by limitations on the supply of the needed vectors (Iyer et al., 2018, Merten et al., 2016,
McCarron et al., 2016, Sargent et al., 2018). In 2018, FDA recognized the need for risk-based
guidelines for continuous viral vector manufacturing to facilitate faster adoption of innovative
technologies (FDA, 2018c). Although continuous manufacturing is advancing to address the
viral vector supply gap, these risk-based approaches have not been fully adopted (Masri et al.,
2019, Lamperti, 2019).
FDA has recently attempted to support the specialized needs of GCT manufacturers with
other more focused guidance documents. In January 2020, FDA released final guidance, titled
“Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy
Investigational New Drug Applications (INDs)” (FDA, 2020e), to assist sponsors submitting

26
CMC materials related to drug substance and drug products described in Modules 2.3 and 3 of
the Common Technical Document (CTD) at the IND stage. A second guidance, titled “Testing
of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent
Retrovirus During Product Manufacture and Patient Follow-up” (FDA, 2020g), gave
recommendations and expectations for the manufacture of retroviral vector-based human gene
therapy products. A final guidance, “Human Gene Therapy for Rare Diseases” (FDA, 2020h),
addressed regulatory CMC strategies to accelerate timelines under pressure from the shortened
development programs of products with breakthrough designations for rare diseases (Table 2).
These final guidances replaced the outdated draft versions of these documents that had been
available as early as 2006 when the first few commercial GCT products were coming to market.
They now set the tone for how regulatory CMC requirements and best practices might be
expected to evolve in the future.

27
Table 2: FDA Guidance and Considerations for Accelerating Regulatory CMC
Strategies
Modified from (FDA, 2020h, FDA, 2011a)

Impact Regulatory CMC Strategy
Analytical Assays
Assess product concentration, potency, identity and purity as early as
possible in development, optimally before administration First in
Human (FIH) subject.
Changes to
Manufacturing
Process
Comparability assessment during Phase 1 studies provide evidence of
safety and effectiveness for licensure, by characterizing CQAs and
implementing CPPs, before initiating clinical studies.
Limited
Manufacturing Lots
Apply prior CQA knowledge from other similar products, leveraging
product characterization data from nonclinical studies, evaluating CPPs
during engineering runs, or multiple small versus large scale lots.
Product-related
variations
Establish assays for characterization of product-related variants and
impurities to determine product impurity profile variations for:
• Empty and wild-type viral particles in viral vectors.
• Genetically modified cell therapies due to intrinsic differences
among subject’s cells.
Potency
Assess functional activity, consistency and stability to provide evidence
of product comparability after changes to the manufacturing process.
• Evaluate multiple product characteristics before initiating
clinical studies, a potency test measuring relevant biological
activity qualified for suitability prior to conducting clinical
trials.

Regulatory CMC strategies continue to challenge manufacturers of advanced therapies as
they attempt to introduce more targeted and efficient approaches for drug development. Key
areas that require considerable time to “get right” include the selection of raw materials and
assurance of a reliable supply chain, development of appropriate test methods, validation, and
improvements in manufacturability and stability (Gee, 2018). Additional challenges relate to the
need for multiple manual steps to personalize the therapy for an individual patient. Figure 2
shows a representative manufacturing process workflow and associated validation requirements
for one of the most common of the advanced technologies, that for CAR-T cell production. As
complicated as this process appears, the difficulty increases when the primary apheresis material
which is removed from the sick patient, differs in amount and quality from one patient to another
(Fesnak, 2020, Dai et al., 2019). The inconsistency of starting material leads to inconsistency in

28
the expression of protein used to target the disease. Each batch then becomes unique, risking
failures in meeting the criteria of a singular target quality profile for different batches of the final
product.
Figure 2: Gene and Cell Therapy Manufacturing Process and Testing
Modified from (Roddie et al., 2019)

A deep discussion of the manufacturing operations of complex biologics is beyond the
scope of this dissertation, but one example can illustrate the inconsistencies with which the CMC
teams might have to cope. In a 10-patient study reported by Brentjens and coworkers, expansion
of transduced cells expressing a transgene of interest varied from only 23.6 times to as much as
385 times the count of the initial cell population even when the culture time was almost the same
(16-18 days). The rates of expansion reflect the unpredictable behavior of different sets of cells
growing under similar operating conditions. In that same study, the transduction step also
differed remarkably in its efficiency, from 4% to 70% when using retroviral vector transduction
Patient
Apheresis
T-Cell Selection
T-Cell Activation
T-Cell
Transduction
T-Cell Expansion
Formulation &
Cryopreservation
Process &
Analytical
Validation
Amplification
Expansion
Purification Fill & Finish
Viral Vector Manufacturing
Traditional
Regulatory CMC
Strategy
Phase I
• Qualification
Phase II
• Preliminary
Validation
Phase III
• Full Validation
Post Approval
• Product Life Cycle
Management
Accelerated
Regulatory CMC
Strategy
Phase I/II
• Full Validation
Post Approval
• Product Life Cycle
Management

29
and 6% to 45% when using lentiviral transduction (Vormittag et al., 2018, Brentjens et al., 2011,
Guo et al., 2016). These inherent variabilities make it difficult to compare products between
studies or even patients and thus make it difficult to validate methods and underlying causes. As
a result, the industry is still struggling with best practices. A stronger focus on regulatory CMC
strategies to advance viral vector production and CQA testing is still needed for CAR-T and
other gene-modified cell therapies (Glover et al., 2019).
All these specializations can be difficult for a regulatory agency to assess. The agency
cannot easily build on precedence with these novel technologies. Thus, during the FDA review
process, additional clarification for NDAs and BLAs must be sought frequently through
Information Requests (IRs) that they issue to sponsors. The approaches taken by the FDA are
spelled out in the 2001 guidance document, “Information Request and Discipline Review Letters
Under the Prescription Drug User Fee Act (PDUFA)” (FDA, 2001). Failure to provide
persuasive information in response to these requests can result in a Complete Response Letter
(CRL) from the Agency, in which deficiencies are identified that make the application “not
approvable” in its current state. These documents are valuable to other developers or researchers
because they can shed light on the areas of special difficulties. A report by AgencyIQ recently
showed that CMC-related IRs accounted for more than half of total IRs received across five
different sponsors and types of GCTs analyzed: Imlygic, Kymriah, Luxturna, Yescarta, and
Zolgensma. Among the most common issues were testing (55%), validation (15%), and
manufacturing (13%) (Tadesse, 2020). Findings also highlighted questions related to
transportation and shipping, which are areas that are not generally problematic for traditional
biologics and/or pharmaceuticals. They underline added challenges that are posed in moving

30
highly fragile living tissues under strict environmental controls from place to place (Myles,
2021).
How do manufacturers deal with the rapidly evolving practices in CMC for GCTs? Two
opportunities appear to be widely used. First, academic and regulatory professionals participate
in global CMC strategy forums that are typically held annually. Key areas related to
biopharmaceutical development are 1) Process Performance Qualification (PPQ) requirements,
2) unique manufacturability challenges for functional areas, such as cell-culture, purification,
analytical, stability, and formulation, and 3) challenges of assuring compliance with GMP and
other quality requirements when stellar clinical results are predicted to reduce the length of
late-stage development (CASSS). Nevertheless, companies are often loath to disclose their lessons
learned or implementation strategies to keep that proprietary information confidential.
The second way that insight is gained is through early engagement with the FDA (Au et
al., 2012). Input from FDA reviewers is especially valuable, not only because those reviewers
are gaining significant experience as they study the dossiers of competitors but also because they
are prohibited from sharing the material facts of the discussions amongst competitors. FDA also
adds to its internal expertise by using external scientific and clinical experts, patient groups, and
other key stakeholders through various mechanisms, such as scientific workshops and advisory
committees. Prospective IND applicants have been encouraged to communicate early and
frequently with the agency through informal interactions and formal pre-IND meetings (Chen,
2017). Such interactions can de-risk CMC strategies and establish a collaborative relationship
prior to initiating clinical studies.
However, even when the sponsor and agency are aligned, product failures do occur. CMC
process variability remains a significant manufacturing challenge that can limit the BLA

31
approval (Iyer et al., 2018). The experience with one of the first CAR-T products,
KHYMRIAH
®
(Tisagenlecleucel), illustrates how managing product quality remains
problematic. In a multinational study in which Tisagenlecleucel was used to treat pediatric and
young adult B-ALL, 7 of the 92 enrolled and leukapheresed patients did not receive treatment
because product quality was deficient. The lengthy manufacturing process is also detrimental to
the success of some products. For CAR-T therapies, 14 to 21 days are needed to produce the
modified cells. During that time, the patient’s disease may progress. In a different clinical study
in which Tisagenlecleucel was used to treat relapsed or refractory Diffused Large B-Cell
Lymphoma (DLBCL) and Follicular Lymphoma (FL), 13% of patients did not receive modified
cells because their disease had advanced too quickly (Maude et al., 2018).
Challenges with manufacturing did not stop after the development stage but extended
after commercialization. KHYMRIAH
®
was still experiencing CMC issues post-approval, as
disclosed by Novartis CEO Vasant Narasimhan in his Q2 2018 earnings call (Novartis, 2015).
He identified that Novartis had “seen some variability in their product specifications” when
comparing their commercially marketed product lots to those used during their ELIANA clinical
trials. Indeed, the fact that the manufacturing success rate for KHYMRIAH
®
during clinical
development already hovered on average of 93%, as opposed to a 99% success rate for
YESCARTA, led FDA to mandate a revision to the release specifications related to cell viability,
a critical issue that appeared to underlie the variability (Davies, 2018). These examples
underline the fragility of the manufacturing process for GCT therapies, that can increase their
vulnerability to factors that might perturb their production.

32
2.3 Shortening of Late-Stage Development Timelines
A second challenge for the CMC refinement of GCTs presents when those activities must
be enacted very quickly (Boyle, 2020). The shorter time frame is forced on the CMC experts
when the clinical trial phase is shortened. Such a situation is particularly common for GCTs
because they are often approved under accelerated pathways designed to speed their market
access for serious diseases. These effects become clear when comparing the traditional pathway
of drug development to expedited programs for therapies with special promise, discussed below.
2.3.1 Pathways for Drug Development
Decades of experience with synthetic drugs have produced a picture of drug development
whose time to market is generally determined by the long periods of animal and human testing
needed to prove safety and efficacy. In this developmental strategy, a leading molecular
candidate is first screened in animal models to understand its pharmacological and toxicological
profile. Lengthy human studies are then conducted to give “substantial evidence” of safety and
efficacy in man (Junod, 2008). Those human studies generally proceed in three stages of clinical
trials of increasing size and length (Table 3). Current estimates suggest that the full clinical trial
package for most drugs will take at least seven years to complete (Dye et al., 2016, Kepplinger,
2015, PhRMA, 2015, PhRMA, 2016).

33
Table 3: Traditional Stages of Clinical Trials during Drug Development
Modified from (Anderson, 2020)
Clinical
Trial
Population Time Purpose Additional Studies
Phase I
20 to 100
healthy
volunteers
1.5 Years
Establish safety
profile
Safety, absorption,
metabolism, and
excretion.
Phase II
100 to 500
patient
volunteers
2 Years
Assess effectiveness
in a specific condition
or disease
Active drug compared to
placebo (inactive) or
other active drug to
determine effectiveness.
Continued review of
safety and side effects.
Phase III
1000 to
5000
patients
3.5 Years
Monitor in clinics and
hospitals to determine
effectiveness and
identify further side
effects
Types and age ranges of
patients are evaluated.
Dose ranges of the drug
in combination with other
treatments.

Ways to accelerate this long development cycle have been subject to much attention since
the 1990s to ensure that patients with serious diseases and limited treatment options can gain
access to promising novel drugs. As a result, several programs are now available to reduce the
length of the clinical trials or regulatory review for drugs that can treat serious or life-threatening
conditions. These include providing a shortened pathway for orphan drugs; an accelerated
approval pathway; a program of priority review; a systematic rolling review; a fast-track process;
and most recently, an aggressive pair of programs, the “breakthrough therapy” and “regenerative
medicine advanced therapy” programs. These are summarized in Table 4 (FDA, 2020c, FDA,
2018a, FDA, 2014a, Meekings et al., 2012) and described below.

34
Table 4: Expedited Programs for Serious Conditions
Modified from (FDA, 2014a, FDA, 2020c, FDA, 2018a, Meekings et al., 2012)
Program Qualifying Criteria Benefits
Orphan Drug
Designation
A drug intended to treat, prevent or diagnose a rare
disease or condition affecting fewer than 200,000
persons in the United States.
Seven-year market exclusivity.

Tax credits, R&D grants,
waived fees and protocol assistance
Accelerated
Approval
A drug that treats a serious condition, generally
provides a meaningful advantage over available
therapies, and demonstrates an effect on a surrogate
endpoint that is reasonably likely to predict clinical
benefit or on a clinical endpoint that can be
measured earlier than irreversible morbidity or
mortality or other clinical benefit.
Approval based on an effect on a
surrogate endpoint or an
intermediate clinical endpoint that is
reasonably likely to predict a drug’s
clinical benefit.
Priority
Review
An application (original or efficacy supplement) for
a drug that treats a serious condition and if
approved would provide a significant improvement
in safety or effectiveness.
Shorter period for review of
marketing application (6 months
compared with the 10-month
standard review)
Rolling
Review
After preliminary evaluation of clinical data and
determination that the drug may be effective.
Submission of completed sections
of the BLA or NDA for review,
rather than waiting until the entire
application is completed before it
can be reviewed.
Fast Track
Designation
A drug intended to treat a serious condition by
which nonclinical or clinical data demonstrates the
potential to address unmet medical need.
Frequent interaction opportunities
with FDA to expedite development
and review.

Eligibility for priority rolling
review.
Breakthrough
Therapy
Designation
A drug intended to treat a serious condition and
preliminary clinical evidence indicates that the drug
may demonstrate substantial improvement over
available therapy on a clinically significant
endpoint.
Intensive guidance on efficient drug
development. FDA organizational
commitment.

Eligibility for priority rolling
review.
Regenerative
Medicine
Advanced
Therapy
Designation
A drug is a regenerative medicine therapy intended
to treat, modify, reverse, or cure a serious condition,
and preliminary clinical evidence indicates that the
drug has the potential to address unmet medical
needs for such disease or condition.
Includes all breakthrough therapy
designation features, including early
interactions to discuss any potential
surrogate or intermediate endpoints.

Addresses potential ways to support
accelerated approval and satisfy
post-approval requirements.
Eligibility for priority rolling
review.
2.3.1.1 Orphan Drug Designation
In 1983, the Orphan Drug Act (ODA) was enacted to encourage development of drugs
for the treatment of neglected or rare diseases, defined as populations with fewer than 200,000

35
patients a year in the U.S. (Herder, 2017). The National Institutes of Health (NIH) reported that
nearly 7,000 rare diseases affect more than 25 million Americans (Bouwman et al., 2020). Many
new GCTs are particularly important because they target rare diseases for which no therapeutic
options yet exist (Geigert, 2019). In 2018, Peter Marks, Director of CBER, estimated that
roughly 70% of GCT INDs were designated to target rare diseases. This trend was mirrored by
the rapid increase in requests for orphan drug designations over the last few years (Auchincloss
and Health, 2020).
Designation as an “orphan drug” confers advantages by decreasing the need for long
clinical trials and awarding the sponsor with a “priority review” voucher which can be retained
or sold to a competitor. This notable voucher opportunity speeds up the review process of a
subsequent potential blockbuster drug from 10 to 6 months. This shortening can allow the
product to reach the market more quickly and position it as “first in class,” an advantage that can
give a company a larger market share with respect to later competitors even after 10 years (Cha
and Yu, 2014). The voucher can also be sold at a high price to another company so that the
purchasing company can use it to secure priority review. After the orphan drug is approved,
sponsors may also be eligible for seven years of marketing exclusivity as long as the “same
drug” has not been approved already for the same use or indication (FDA, 2022d).
2.3.1.2 Accelerated Approval
The “accelerated approval” pathway, introduced in 1992, was designed to expedite access
to novel therapeutics by allowing the manufacturer to use a surrogate rather than clinical
endpoint to provide evidence of efficacy (Vaggelas and Seimetz, 2019). The surrogate endpoint
is a measurable or visual marker or indicator that may predict a clinical benefit by accelerating
the drug approval process. This is important because some clinical outcomes, such as death, may

36
not occur until many years after treatment has begun. Thus, it allows a more rapid approval that
would otherwise be possible.
2.3.1.3 Priority Review
In the same year, the Prescription Drug User Fee Act (PDUFA) authorized the “priority
review” program. This program gave FDA the ability to prioritize the review of marketing
applications for serious conditions so that it could approve them in a timeframe of 6 rather than
the 10 months that have been usual for traditional drugs.
2.3.1.4 Rolling Review
The Food and Drug Administration Modernization Act of 1997 (FDAMA) continued to
address unmet medical needs by introducing a "rolling review" and by encouraging frequent
communication between FDA and sponsor. Typically, FDA reviewers do not begin to consider a
marketing application until the entire application is submitted to the FDA. In a rolling review,
however, completed sections of the BLA or NDA are evaluated in stages, as the content becomes
finalized, rather than waiting until the clinical trials or other time-limiting studies have been
completed.
2.3.1.5 Fast Track Designation
The same FDAMA allowed FDA to create a “fast track” program that would expedite the
development, evaluation, and marketing of new therapies that address an unmet medical need for
serious and life-threatening medical conditions (Darrow et al., 2014). To evaluate whether a
medical condition is “serious,” FDA considers such factors as the impact of the product on
survival, day-to-day function, or likelihood of disease progression if left untreated. The criterion
of “unmet medical need” is fulfilled if no suitable treatment exists or if the existing therapies that
do exist are less efficacious than the new product. As a benefit, frequent and early interactions

37
with the FDA are used during the progression of drug development and review process to assure
that arising questions and issues are resolved quickly, leading to earlier drug approval and access
to patients (FDA, 2018b).
2.3.1.6 Breakthrough Therapy Designation
All the programs that were introduced by 2000 could be utilized by manufacturers in
concert, if appropriate. However, the Food and Drug Administration Safety and Innovation Act
(FDASIA) of 2012 authorized FDA to integrate and extend these separate programs (FDA,
2018e). The Breakthrough Therapy Designation (BTD) program was therefore introduced to
expedite both the development and review of early phase drug candidates that satisfied the
definition of Section 506(a) of the FD&C Act:
. . . if the drug is intended, alone or in combination with 1 or more other drugs, to
treat a serious or life-threatening disease or condition and preliminary clinical
evidence indicates that the drug may demonstrate substantial improvement over
existing therapies on 1 or more clinically significant endpoints, such as
substantial treatment effects observed early in clinical development. (FDA,
2014b)

Breakthrough therapy designation has been effective at accelerating clinical development
timelines because it allows promising treatments for serious or life-threatening diseases to enter
the market much earlier than was possible in the past. FDA published a listing of approvals for
breakthrough therapy-designated drugs at the end of 2020 that included 179 by CDER and 11 by
CBER (FDA, 2020a, FDA, 2020b).
2.3.1.7 Regenerative Medicine Advanced Therapy
If the product is based on a regenerative technology, a second option, the Regenerative
Medicine Advanced Therapy (RMAT) program, was introduced as an alternative regulatory
pathway for the approval of novel biological products such as GCTs and other HCT/Ps. An

38
RMAT designation offers all the benefits available through fast track and breakthrough therapy
designation programs. It streamlines the approval of regenerative medicine products by
encouraging flexibility in clinical trial design, authorizing the use of real-world evidence, and
giving more attention to the choice of clinical endpoints and outcome assessments.
The availability of accelerated pathways has had a dramatic effect on the timelines of
clinical studies. As illustrated in Figure 3, Phase I/II/III clinical trials supporting traditional
NDA submissions typically take six to seven years. In contrast, Phase I/II studies for Gene and
Cell Therapy BLAs are estimated to take only three to four years.
Figure 3: Comparison of Traditional and Expedited Approval Timelines
Modified from (Anderson, 2020)

Three examples illustrate how GCT products have been able to take advantage of
breakthrough therapy designation. In August 2017, the first FDA-approved CAR T-cell gene
therapy product, KYMRIAH
®
(tisagenlecleucel), was developed and commercialized by
Novartis (FDA, 2017b). Subsequently, FDA approved two additional CAR T-cell gene therapy
products from Kite Pharma (a subsidiary of Gilead Sciences): YESCARTA
®
(axicabtagene
ciloleucel) in October 2017 and TECARTUS
TM
(brexucabtagene autoleucel) in July 2020 (FDA,
2017c, FDA, 2020j). In all three cases, cells of patients with cancer are collected, genetically
Phase I/II
3 to 4 Years
Pre-IND
BLA Submission
20 to 100
Patients
0.5 to 2 Year
Post Approval Lifecycle
Clinical Trials FDA Review
BTD/RMAT Approval
Phase I Phase III Phase II
6 to 7 Years
Pre-IND
NDA Submission
20 to 100
Patients
100 to 500
Patients
1,000 to 5,000
Patients
2 to 5 Years
Post Approval Lifecycle
Clinical Trials FDA Review
Traditional NDA Approval

39
modified, and infused back to kill cancer cells. The clinical trials that based the approvals of all
three products involved fewer than 110 patients and lasted less than 3 years.
2.3.2 CMC Implications of Shortened Timelines
The dramatic shortening of the clinical trial period, sometimes to only a couple of years,
has had substantial implications for departments responsible for these CMC activities. The time
available for robust validation studies is reduced, and fewer manufacturing lots are needed to
support clinical studies. This situation makes it difficult to ensure mature manufacturing and
testing programs, especially when the GCT products target rare diseases (FDA, 2020f). The
pressure of time magnifies stresses already present, as discussed above in Section 2.2, to
modernize analytic and stability testing and manufacturing procedures. Manufacturing and
quality divisions now often find themselves to be the bottleneck that hampers the availability of
commercial-grade products. For example, in 2019, FDA rejected a BLA for Enzyvant’s VT-802,
a tissue therapy aimed at treating rare congenital athymia, primarily because of manufacturing
concerns (Scott, 2020).
Other submissions to FDA have already illustrated the types of problems caused by the
shortened timelines. One of these examples was provided by Celgene and Juno Therapeutics
(subsidiaries of Bristol Myers Squibb Company), in collaboration with Bluebird Bio, when they
submitted a BLA for the breakthrough therapy-designated idecabtagene vicleucel, a B-Cell
Maturation Antigen (BCMA) directed CAR T-cell immunotherapy for the treatment of multiple
myeloma in adult patients. The clinical trial program relied on a pivotal phase II KarMMa study,
initiated in December 2018, that enrolled fewer than 200 participants and was completed in less
than 2 years (Squibb, 2019, NIH, 2020). FDA responded to their BLA with a “refuse to file”
letter, in which it specifically requested further information in CMC Module 3 related to the

40
validation and control of both lentiviral vector and drug product manufacturing processes
(Squibb, 2020a). The sponsor resubmitted the expanded application at the end of July 2020 and
received acceptance for priority review two months after at the end of September 2020, with
FDA targeting approval by the end of March 2021 (Squibb, 2020b).
2.4 Effects of Business Reorganization
Much has been written recently about the stresses on regulatory CMC departments as
they cope with specialized manufacturing challenges in a timeline dictated by unusually short
clinical trials. However, another challenge has received less attention. This challenge relates to
the need to modify CMC approaches when the department is forced to modify its procedures and
practices when businesses are restructured. The pharmaceutical industry is highly dynamic and
interconnected; it is a “poster child” for complex business models created by joint ventures,
collaborations, partnerships, and Mergers and Acquisitions (M&A). The pharmaceutical
industry is, in fact, one of the most active business sectors in both the size and number of M&A
deals (Alvaro et al., 2020). In part, these deals are driven by the risky and expensive nature of
drug product development, in which small companies shepherd the drug through early stages,
and large companies then acquire the rights to that drug after proof of efficacy and safety has
begun to emerge (Evens and Kaitin, 2015, Burns et al., 2012).
By some estimates, new drugs today can cost more than 2 billion dollars to develop
(DiMasi et al., 2016). These expenses then follow the drug into the post-approval period, when
the extraordinary costs of sales and promotional activities add to other types of costly
post-market product maintenance, including drug manufacture, distribution, and
pharmacovigilance across global markets. Most small companies developing advanced therapies
have limited experience with late-stage drug development and insufficient financial resources to

41
oversee such cost-intensive programs (Vaggelas and Seimetz, 2019, Jekunen, 2014). Further
progress then depends on the experience and resources of larger and more experienced
companies with a mature clinical trial team and a robust sales and distribution network. It is only
at this point that large companies, which are usually publicly traded, are sufficiently confident
that the results have been sufficiently “derisked” to gain approval of a skittish and risk-averse
Board of Governors. However, acquisitions at this point become useful for both partners. For
the acquirer, product portfolios can be replenished on schedules that allow new products under
patent protection to replace older ones losing market advantage or patent protection (Siebert and
Tian, 2020). For the acquired company, integration brings the resources that otherwise would
prevent a smaller firm from successfully advancing its product into the commercial environment
(Bain, 2011).
It might seem from first glance that many advanced therapies are poor acquisitions. In
the past, acquisitions of synthetic drugs and then mAbs were typically seen as more valuable
than those of novel biologics. Traditional drug programs favored products that treat chronic
conditions in large patient populations with previously unmet medical needs; these types of
products could guarantee consistently high sales over time. However, disruptive GCT products
have been recognized more recently as valuable investments because they can take advantage of
several financially advantageous opportunities (Kapoor et al., 2017, Mavilio, 2017).
First, high prices can be charged for products that provide one-time treatments for
difficult-to-manage disorders, particularly cancer. According to a report by “Global Gene
Therapy Market Opportunity & Clinical Trials Insight 2026", cancer indications account for half
of gene therapy trials globally to address an estimated market opportunity of greater than $8
Billion USD (Report, 2020). By 2018, 69 autologous GCT market authorizations were approved

42
globally, mostly for oncological treatments (Shukla et al., 2019). Amongst the commercialized
products were three autologous CAR-T products described above, whose prices ranged from
$373,000 USD (YESCARTA
®
& TECARTUS
TM
)

to $475,000 USD (KYMRIAH
®
) per
treatment (Gilead, 2017, Carroll, 2020, Sagonowsky, 2017).
Second, the accelerated approval routes available to GCTs identified above have reduced
the development costs and encouraged more products to enter development programs. This is
reflected in the large numbers, more than 900 INDs, associated with investigational drugs using
novel technologies and targeting previously intractable indications (FDA, 2020d). Furthermore,
four years after Congress passed the 21st Century Cures Act in 2016, more than 50 sponsors
have been granted RMAT designations, a clear indication that companies are taking advantage of
such opportunities (FDA, 2020c, Sietsema and Lambert, 2020).
Third, most of the products under development are well-positioned to take advantage of
orphan drug benefits with special financial and regulatory options designed by governments to
increase the commercial attractiveness of developing these challenging types of products. With
lower research and development costs, expedited regulatory reviews, and exclusivity,
rare-disease-targeting orphan drugs are amongst the most expensive and profitable drugs on the
market globally (Herder, 2017).
All these factors appear to be driving a remarkable increase in joint ventures and
acquisitions related to GCTs. From 2010 to 2016, pharmaceutical companies entered into more
than 50 collaborations and investments to advance GCTs (Kapoor et al., 2017). Many took the
form of acquisitions in which the acquirer gained the entire GCT pipeline of the target company,
including its CMC technologies and process manufacturing capabilities. However, even when
they pursued more modest collaborations, integration of CMC operations typically resulted as

43
technology was transferred from the unit in which it was first developed to a new receiving
facility to consolidate manufacturing processes, control strategy, process validation, and product
lifecycle management.
Historically, big pharma companies spent a great deal of time investigating a target
company by performing due diligence before pursuing partnerships or M&A deals. These
investigations were often conducted on drugs in late-stage, Phase III trials or after regulatory
submissions when much data had become available. Late-stage evaluations reduce the risks
associated with re-executing additional studies to support regulatory CMC requirements from an
immature company with underdeveloped processes and quality systems. However, it can be
more difficult to estimate risk in companies developing GCTs because they move so quickly
toward their commercial goals. Some of the first GCT acquisitions in the early 2000s were
disappointing because the acquired products eventually proved to have poor safety profiles and
lower than expected return on investments. In response, fewer such deals were made in the years
immediately thereafter (Kapoor et al., 2017). The novel technologies of today have a much
better track record, so investors are again gambling on them, even if the acquired company is at
an early developmental phase and has limited manufacturing experience (Kong et al., 2017).
Acquisitions of GCTs can be risky because the fundamental phase-appropriate CMC
requirements associated with that product are not well understood. Despite this incomplete
understanding, manufacturing operations must evolve quickly from an idiosyncratic set of
processes conducted under limited quality control for small numbers of patients to a highly
controlled manufacturing and quality system capable of supplying a much larger patient group
across multiple production facilities (Seimetz et al., 2019). At the time of acquisition, small
companies may have underdeveloped CMC capabilities and quality systems. Even if the

44
acquired company has sophisticated CMC capabilities (an unusual situation at best), the acquirer
must decide how to put its stamp on several aspects of day-to-day operations, from team changes
to documentation and IT integration, for example. With an insufficient understanding of
manufacturing and testing requirements, companies are frequently challenged to assure the
reproducibility and manufacturability of an acquired therapeutic. These technology transfer
problems can disrupt R&D and manufacturing operations and damage morale.
Evidence for challenges during the transition from one company to another can be
recognized from the experiences of both biologics and GCTs that were recently brought to
market. For example, FDA approved a first-in-class Antibody Drug Conjugate (ADC) in
December 2019 based on results of a clinical trial that enrolled 125 patients with locally
advanced or metastatic urothelial cancer previously treated of PD-1 or PD-L1 inhibitor and
platinum-based chemotherapy. PadcevTM (enfortumab vedotin-ejfv) experienced multiple
technology transfers during its development as CDMOs, and Contract Testing Labs (CTLs) were
engaged in expanding production capabilities. Its base molecule, a proprietary monoclonal
antibody developed by the start-up, Agensys Inc., was acquired by a large pharmaceutical
company, Astellas Pharma, in 2007, in collaboration with Seagen Inc., to take advantage of its
proprietary Antibody Drug Conjugate (ADC) technology. The production of both the antibody
and its highly toxic drug conjugate required innovative technologies, unique CQA testing,
complex final product validations, and manufacturing requirements with progressive regulatory
oversight (Gladd, 2015). Handling such potent and toxic agents required special safety
procedures managed within a complex network of production facilities with highly specialized
operations. Consequently, as partnerships and collaborations developed over time, the acquirer

45
encountered long lead times caused by issues with the conjugation processes of ADCs; this, in
turn, delayed production and distribution of drug product.
Additional evidence comes from the experiences of the two FDA-approved Chimeric
Antigen Receptor T-cell therapies, already described in earlier sections. Khymriah
®

(tisagenlecleucel) was the first approved CAR-T developed by the University of Pennsylvania
(UPenn) and transferred to Novartis in 2017 to treat acute lymphoblasticleukemia (ALL).
YESCARTA
®
(axicabtagene ciloleucel) technology was developed by National Cancer Institute
(NCI), then transferred to Kite Pharma, and acquired by Gilead Sciences in 2017 for treatment of
large B-cell lymphoma. Both therapies required extensive technology and manufacturing
changes as the companies moved from a flexible operation at a single academic institution to a
highly controlled network of multiple collection, manufacturing and treatment sites (Seimetz et
al., 2019, Levine et al., 2017, Tyagarajan et al., 2020). Initial scale-out challenges from the
original research-based approach included: 1) the need to standardize and characterize the
manufacturing process and testing of product; 2) the need to validate automated manufacturing
solutions as opposed to manual processes; 3) the need to resolve the complex logistics of
managing collection centers, manufacturing facilities, and patient treatment institutions during
the transition from phase I/II clinical trials to pivotal global trials.
2.5 Research Approach and Framing the Study
As discussed above, FDA views and recommendations for advancing drug development
have matured over the years. FDA encourages early evaluation of product quality and its
appropriate validation requirements prior to market authorization. It expects that developers will
have a thorough understanding of its product and manufacturing processes at an early stage, even
when very little is known about the drug candidate. FDA further urges frequent regulatory

46
engagement to discuss how to deal with compressed CMC timeliness as described in recently
issued guidances.
What those regulations and guidances do not do, however, is offer insight into the
exploration and implementation activities that companies have carried out to assure that those
operations are integrated successfully across merging business organizations and collaborating
partners. Thus, companies struggle to recognize and deal with the drivers, outputs, and outcomes
that affect these activities. One approach to gaining insight to the challenges and approaches has
been through expert forums. For example, at a 2019 conference held in Washington D.C.,
Friends of Cancer Research (FOCR) and the Parker Institute for Cancer Immunotherapy (PICI)
discussed efforts to form collaborations that could promote and accelerate the development of
innovative GCTs (Eastman, 2019, FCR, 2019, Stewart et al., 2020). Their discussions at these
shared forums mainly focused on high-level perspectives related to the application of FDA
guidances or the development of regulatory CMC strategies. They seldom touch specifically on
the associated challenges of assuring successful CMC strategies when working with
collaborative partners or operational integrations after a merger or acquisition.
The literature review provided anecdotal evidence suggesting reasons why industry had
difficulties in assuring a robust CMC program for novel biologics. In this research, a more
systematic approach was used to gain insight into the experiences, practices, and lessons learned
by companies of various sizes as they realign their corporate structures. To carry out this project,
an implementation framework was selected to examine the progress of implementation along a
series of sequential stages, each of which may have its own challenges.

47
2.5.1 Implementation Framework
The basis of implementation science and its framework was developed by Fixsen and
colleagues of the National Implementation Research Network (NIRN) (Bertram et al., 2015,
Fixsen et al., 2005, Bertram et al., 2011). They described implementation as an iterative process
that requires two to four years to move through stages that they identify as exploration,
installation, initial implementation, and full implementation, as shown in Figure 4. Although the
stages of the implementation framework are sequential, the activities can be bidirectional to
improve the subsequent stage and gradually build a sustainable system.
Figure 4: Implementation Framework – GCT Technology Transfer Process
Modified from (Bertram et al., 2015, Bertram et al., 2011, Tyagarajan et al., 2020)

2.5.1.1 Exploration
In this stage, organizations develop regulatory CMC strategies by educating personnel
about the current regulatory landscape and CMC considerations fundamental to drug
development. This is done by training in various forums such as educational workshops, review
Exploration
Consider implementation
drivers
Assess needs:
▪ FDA guidances and
regulations
(validations and CQAs)
Examine intervention
components:
▪ Observe process at
originating site,
process mapping and
data mining
Installation
Prepare implementation
drivers
Acquire resources and
prepare organizations:
▪ Side by side training of
CMC operations
Prepare organization:
▪ Initial test runs split
comparability runs
Initial
Implementation
Manage change and
assess fidelity
Adjust implement drivers:
▪ Demonstrating
product comparability
improvement cycles:
▪ Clinical and
commercial
manufacturing
Full
Implementation
Further improve fidelity
and systems
Monitor implementation
drivers:
▪ Routine reviews of
process capabilities
Achieve fidelity:
▪ Robustness of
organizational
outcomes
Pre-Transfer Transfer Post-Transfer
Sustainability (2 to 4 Years)

48
of regulatory documents, and analysis of materials such as white papers or journal articles
detailing past experiences with marketed products. During exploration, CMC stakeholders
identify late-stage regulatory requisites as companies co-develop technologies and integrate
operations. By evaluating such practices, CMC operations decide whether a change is needed,
recognize barriers, and seek opportunities to progress to the installation step.
2.5.1.2 Installation
The activities and skills necessary to support the changes associated with the newly
configured organization must be assessed and strengthened where necessary through talent
acquisition and training. During installation, resources are identified and secured to give a solid
foundation for the needed activities prior to implementation. Such activities include identifying
key CMC stakeholders with roles and responsibilities for establishing critical aspects of
manufacturing infrastructure, product quality, and validation across product development
lifecycle. It may also include, for example, the addition of needed equipment, site
refurbishment, or other physical and software needs to align two systems into one.
2.5.1.3 Initial Implementation
To be successful, new initiatives profit from opportunities to pilot those approaches.
Initial implementation of regulatory CMC strategies may include performing early-to-late-stage
gap analyses and due diligence to certify that phase-appropriate validation initiatives are in place
before integrating the new approaches into CMC operations. Because BTD and RMAT trials
have compressed timelines, the regulatory CMC strategies must converge on a standardized
process appropriate not only to the new corporate environment but also the evolving operational
landscape related to novel manufacturing approaches. Initial implementation also requires that
practitioners understand the effects of change on personnel. At this stage, excitement and

49
anticipation of new practices may be dampened by the fear of change, leading to an awkward
period of high expectations, challenges, and frustrations (Bertram et al., 2011). The initial
implementation stage is the time in which the team can evaluate its new skills and practices at
the same time as confronting tensions that might initially develop in response to changes in
organizational culture.
2.5.1.4 Full Implementation
Full implementation is the final stage of implementation in which the newly configured
company solidifies its practices into its business operations. At this stage, the program
components must be well supported, policies must be integrated, and procedures must be
implemented fully. Successful implementation is most likely to occur when CMC professionals
have a supportive leadership and culture to assure a robust system for partnerships. The goal of
this stage is to ensure that evidence-based programs will become routinized and sustainable
(Fixsen et al., 2005).
In the following research, the implementation framework was used to structure the
boundaries and content of the survey. A list of questions is presented in Table 5, providing
preliminary insight into the way that the survey explored the challenges faced when departments
are forced to adjust their CMC procedures and practices as a result of corporate restructuring.
These questions changed considerably as survey development proceeded, as described in
Chapter 3.

50
Table 5: Implementation Framework: Overcoming the Rate Limiting Steps
Stage Questions
Exploration
• Which regulations and guidances are consulted when organizations undergo
M&As and technical operation integrations in order to satisfy FDA
expectations? Are they useful?
• Who is on the team to plan the merged CMC approaches?
• Were CMC challenges included in the due diligence activities and
considerations of site or departmental changes?
Installation
• Who decides how to standardize its day-to day operations, from team
changes to documentation, and infrastructure?
• Who leads regulatory CMC strategies, for technical operations, regulatory
affairs, and training personnel during integrations? Is this shared or does
one company dominate?
• Have predicted implementation timelines been developed? Have costing
estimates been developed?
• What considerations affect the decision to begin implementation?
• How does the sponsor decide at what point regulatory CMC strategies for
drug development will be introduced and who leads the initiatives?
Initial
Implementation
• Did the team members have relevant expertise to execute pilot studies such
as; managing product development and validating CMC operations?
• How did the early integration affect morale and retention of key staff?
• How successful were the pilot studies in implementing the harmonized
CMC processes, quality systems, SOPs, and filing strategies?
• Were there any constraining factors; were enough resources made available
to implement the plan effectively and did it take longer than anticipated?
Full
Implementation
• Were the procedures for regulatory CMC evidence-based protocols and
standard eCTD initiatives with similar modalities to aid partners successful?
• Are metrics in place to measure the effectiveness of CMC operations when
drug developers collaborate and integrate operations?
• Were the processes sustainable for drug development programs and did they
result in successful submissions or marketing authorizations? If not, why?

51
Chapter 3. Methodology
3.1 Introduction
This study evaluated the views and experiences of mid-level and senior CMC
professionals working in industry who have expertise in developing regulatory CMC strategies
for biologics and/or GCTs. It explored how CMC professionals used current FDA guidances for
developing regulatory CMC strategies, how they approached their restructuring requirements,
and whether their experiences reveal hurdles to overcome or opportunities to guide policy or
operational changes for others. The study included five steps: completing a literature review and
analysis of CMC regulations and experience for advanced therapy products, described in
Chapter 2. developing a survey tool for participants; critiquing the survey by a focus group of
experts; disseminating the survey to potential respondents; and analyzing the results.
3.2 Survey Development
A draft survey was developed based on the implementation framework as described in
Chapter 2 using the electronic survey platform produced by Qualtrics (Qualtrics.com). The
electronic survey was viewed to be the most appropriate tool for gathering data from a large
number of geographically separated participants and processing responses into a database
efficiently (Sue and Ritter, 2012, Saleh and Bista, 2017). The survey had 38 questions about
regulatory CMC strategies that survey participants could elect to answer. Questions range from
multiple-choice, yes/no, scaled choices, and other forms of closed-ended questions.
Additionally, open-ended questions were introduced so that respondents could provide open-text
information. Questions were grouped by six main themes: (1) Demographics of the respondents;
(2) Exploration; (3) Installation; (4) Initial Implementation; (5) Final Implementation (6)
Sustainability.

52
3.3 Focus Group
A focus group was identified prior to finalizing and disseminating the survey. The
purpose of the focus group was to provide suggestions, considerations, and feedback to identify
gaps in areas relevant to the final survey. The focus group included 7 participants from
academia and industry, whose selection was based on their experiences with regulatory CMC
strategies and with accelerated drug development for advanced therapy products. All
participants in the focus group were provided with a copy of the survey prior to an online
meeting held using a video conferencing platform (zoom.com) through the University of
Southern California to accommodate the requirements of COVID-19 restrictions. The abstract,
Chapter 1, and list of survey questions were sent to the focus group prior to the meeting,
scheduled for approximately 60 to 90 minutes. Following the focus group, the survey was
revised to incorporate the feedback provided by the participants in the focus group.
3.4 Dissemination of Survey
The ability to disseminate the survey correctly was validated by sending the survey to
three participants who ensured the emails arrived, the content and questions were formatted
correctly, and questions could be answered as intended. The survey was then distributed
electronically to CMC and regulatory affairs professionals working in U.S.-based
biopharmaceutical industries of varying sizes. The survey gained responses from 44 respondents
who had at least two years of drug development experience at mid to senior levels. Some of the
participants were contacted prior to survey dissemination, explaining the scope of the
dissertation and the purpose of the research. They were also asked to forward the
correspondence to colleagues who were qualified to take the survey. The survey was anonymous

53
and voluntary, with no financial incentive to encourage participation. Follow-up emails were
sent out to participants who had not completed the survey two weeks after receipt.
3.5 Survey Analysis
After the survey responses were collected, the survey was closed, and results were
described and analyzed with simple statistical tools. For open-ended questions, written
descriptions from participants were grouped according to topics or themes.

54
Chapter 4. Results
4.1 Survey Participation
This study was initiated by sending individual survey links to 124 participants using the
distribution capabilities of Qualtrics software. Three of these failed to be delivered; others may
have been redirected by spam filters so were not seen by the target recipient, but this number
cannot be estimated. Sixty-six of the remaining 121 potential participants opened the survey, for
a response rate of 55% (66/121). Of the 66 respondents, 85% (56/66) started the survey by
answering at least one question, and 52 completed the survey, for a completion rate of 79%
(52/66). Most of the drop-offs occurred at the end of the demographics section [question 1 (4%,
2/52) and question 2 (10%, 5/52); Error! Reference source not found.]. Ten participants
(approximately 15%) who opened the survey failed to answer any of the questions.
4.2 Demographics
Most respondents identified that they would be sharing their work experience in biologics
(e.g. mAbs and vaccines) (45%, 25/56) or advanced therapies (e.g. gene and cell therapies)
(43%, 24/56), as shown in Figure 5. Very few identified that their responses would relate to
experience in small molecules / synthetic peptides (5%, 3/56) or that they had no CMC
experience (4%, 2/56). Two respondents selected “other,” clarified by one as experience with
both mAbs and ATMPs (2%, 1/56) and the other with antibody-drug conjugates (2%, 1/56).

55
Figure 5: Drug Development Experience by Category
When thinking about the case on which you will base your CMC feedback, which of the
following best describes that company? (n=56)

When asked about the type of CMC operational integrations on which subsequent
answers would be based, half of the respondents identified a collaboration, partnership, or joint
venture (43%, 23/53), as shown in Figure 6. The other half gained their experience through an
acquisition, as part of either the acquired (25%, 13/53) or acquiring party (23%, 12/53). A few
did not have direct experience with operational integrations (9%, 5/53).
Figure 6: Nature of Relationship underlying CMC Operational Integration
When thinking about the case on which you will base your CMC feedback, which of the
following best describes the type of operational integrations in which you have been involved?
(n=53)

Respondents were asked about their length of experience with drug development
(Figure 7). Most (78%, 35/45) had more than 10 years of experience, and about 18% (8/45) had
6 to 10 years of experience. Only one (2%) had 2 to 5 years of experience, and one (2%) had
less than 2 years of experience.
2
2
3
24
25
0 5 10 15 20 25
No CMC experience
Other
Small / Synthetic Molecules
Advanced Therapies
Biologics
Number of Respondents
5
12
13
23
0 5 10 15 20 25
None of the Above
Acquisition as Acquirer
Acquisition as Acquired
Collaboration / Partnership
Number of Respondents

56
Figure 7: Years of Experience in Drug Development
How many years of drug development experience do you have? (n=45)

Respondents were distributed quite evenly across companies of varying sizes; 35%
(16/46) were in companies with greater than 5,000 employees, 30% (14/46) with less than 200
employees, 26% (12/46) with 501 to 5,000 employees, and 9% (4/46) with 201 to 500 employees
(Figure 8).
Figure 8: Size of Company Represented by Respondents
How many people does your company employ? (n=46)

Most respondents worked either in analytical / process development (48%, 22/46) or
quality control/manufacturing (20%, 9/46), as shown in Figure 9. The others worked in
regulatory affairs - CMC (11%, 5/46), quality assurance / compliance (4%, 2/46), or materials
management / supply chain (2%, 1/46). Fifteen percent (7/46) selected “other,” which they
identified as technical operations (13%, 6/46) or program management (2%,1/46).
1
1
8
35
0 5 10 15 20 25 30 35 40
< 2 Years
2 to 5 Years
6 to 10 Years
> 10 Years
Number of Respondents
4
12
14
16
0 5 10 15 20
201 to 500
501 to 5000
< 200
> 5000
Number of Respondents

57
Figure 9: Functional Department of Participants
Which department best describes your functional area? (n=46)

Most frequently, respondents were senior directors or directors (52%, 24/46), as shown in
Figure 10. Fewer were managers or senior managers (20%, 9/46), scientists or researchers (13%,
6/46), vice presidents or executives (7%, 3/46), and associates or analysts (2%, 1/46). The
remaining 7% (3/46) selected the category of “other,” identified as president/founder (1/46),
validation engineer (1/46), and associate director (1/46), respectively.
Figure 10: Current Position in Company
Which best describes your current position? (n=46)

About half of the respondents reported that CMC operations of the companies remained
separated (47%, 20/43) despite the new organization or collaborative venture (Figure 11). About
half reported that the operations had merged (53%, 23/43).
1
2
5
7
9
22
0 5 10 15 20 25
Materials / Supply Management
Quality Assurance / Compliance
Regulatory Affairs CMC
Other
Quality Control / Manufacturing
Analytical / Process Development
Number of Respondents
1
3
3
6
9
24
0 5 10 15 20 25
Analyst / Associate
Vice President / Executive
Other
Scientist / Researcher
Manager / Sr. Manager
Director / Sr. Director
Number of Respondents

58
Figure 11: Distribution of Merging or Completely Independent CMC operations
Did your collaboration/acquisition/merger keep the CMC operations of the two groups
completely independent? (n=43)

4.3 Respondents Whose Company Integrated CMC Operations
4.3.1 Exploration
Most respondents (15/22) were not involved in due diligence activities, but about
one-third (7/22) had been involved (Figure 12).
Figure 12: Involvement in Due Diligence
Were you involved in due diligence activities for the merger/acquisition? (n=22)

Those seven respondents were asked to rate the level of importance paid during due
diligence to certain aspects of CMC operations (Figure 13). Nearly all (V+S:86%, 6/7) identified
that the need to train staff was very (V) or somewhat (S) important rather than not (N) important.
Sufficiency of manufacturing site infrastructure (V+S:83%, 5/6), plans for CMC validations
(V+S:83%, 5/6), and sufficiency of documentation to capture the development history of the
acquired product (V+S:71%, 5/7) were also rated as very or somewhat important by most. Only
in the latter case was a single individual unsure how to respond. (Need to train staff: V:43%, 3/7;
20
23
0 5 10 15 20 25
Yes
No
Number of Respondents
7
15
0 2 4 6 8 10 12 14 16
Yes
No
Number of Respondents

59
S:43%, 3/7; N:14%, 1/7; Manufacturing infrastructure: V:50%, 3/6; S:33%, 2/6; N:17%, 1/6;
Plans for CMC validations: V:17%, 1/6; S:67%, 4/6; N:17%, 1/6; Development history: V:14%,
1/7; S:57%, 4/7; N:14%, 1/7; Unsure: 14%, 1/7)
Figure 13: Importance of Due Diligence Before Integrations: More Important
When due diligence was conducted as part of the integration, how much importance do you think
was placed on assessing the following aspects of CMC operations? (n=7)

Other choices with which these respondents were presented had somewhat similar ratings
of importance. Ratings of very or somewhat important were more common for gap analysis for
CMC strategies (V+S:67%, 4/6); sufficiency of SOPs (V+S:71%, 5/7); and staffing adequacy
(V+S:71%, 5/7) as shown in Figure 14. None were undecided. Respondents were split on their
views regarding the importance of differences in company culture. Half found it to be very
important, but the other half as not important; one respondent was not sure. (Cultural
differences: V:43%, 3/7; S:0%, 0/7, N:43%, 3/7; CMC strategy gap analysis: V:50%, 3/6;
S:17%, 1/6; N:33%, 2/6; Sufficiency of SOPs: V:14%, 1/7; S:57%, 4/7; N:29%, 2/7; Staffing
adequacy: V:43%, 3/7; S:29%, 2/7; N:29%, 2/7)
0
0
1
0
1
1
1
1
4
2
4
3
1
3
1
3
0 1 1 2 2 3 3 4 4 5
Plans for CMC validations
Manufacturing infrastructure
Development history
Need to train staff
Very Important Somewhat Important Not Important Not Sure

60
Figure 14: Importance of Due Diligence Before Integrations: Less Important
When due diligence was conducted as part of the integration, how much importance do you think
was placed on assessing the following aspects of CMC operations? (n=7)

Respondents were asked to rate whether the parent company or collaborating partner had
more input to decision making in four categories (Table 6); their responses were also used to
construct a weighted score in which a weight of (-6, -5, -4, -3, -2, (0), 2, 3, 4, 5, 6) is assigned to
the scale of (0 to 10), then each response is multiplied by the number of respondents and the sum
resulted in a weighted score. The parent company had a greater role in decisions regarding the
planning of CMC milestones and meeting with FDA to align expectations, reflected by highly
positive weighted scores (WS) of 34 and 23, respectively. However, both the parent and
collaborating company appeared to have an equal role in decisions about assuring adequate
resources (WS:8) and encouraging innovation (WS:2).
0
0
0
1
2
2
2
3
1
4
2
0
3
1
3
3
0 1 1 2 2 3 3 4 4 5
CMC strategy gap analysis
Sufficiency of SOPs
Staffing adequacy
Culture differences
Very Important Somewhat Important Not Important Not Sure

61
Table 6: Regulatory CMC Strategy Decision Making
How well matched are your companies in the following areas when it comes to decision making?
Scale
Collaborating
Company
Similar Parent
Company
Weighted
Score (WS)
0 1 2 3 4 5 6 7 8 9 10

Planning CMC milestones 0 0 2 0 2 1 2 1 3 3 2 34
Meeting with FDA to align
expectations
0 0 1 1 1 2 2 3 1 3 0 23
Assuring adequate resources 0 1 2 3 2 1 4 3 0 1 2 8
Encouraging innovation 2 1 3 2 0 2 1 5 0 4 0 2
Calculation of the weighted score assigns a weight to each response. Based on a scale from [collaborating company
(0)] assigned a weight of (-6) to [parent company (10)] assigned a weight of (6) and [similar (5)] was assigned a
weight of (0) as the center point defined as; -6, -5, -4, -3, -2, (0), 2, 3, 4, 5, 6. Then the number of respondents was
multiplied by of the assigned weight. The sum of the ten from each category resulted in negative or positive results,
where a higher weighted score indicates a favorable response as parent (positive) or collaborating (negative).

Respondents were asked to rank the importance of four areas that senior executives may
have considered when planning the new organizational structure (Figure 15). The distribution of
scores was supplemented with a weighted average for each choice, in which most important was
assigned the value of 1 and not important was assigned a value of 4. “Retaining key talent” had
both the highest number of scores as “most important” [(M):60%, 12/20; Important (I):20%,
4/20; Somewhat important (S):15%, 3/20; Least important (L):5%, 1/20] and the most impactful
weighted average of (1.2). “Redefining roles and responsibilities” had the second most
impactful weighted average of (1.8) because respondents more commonly identified the choice
as important rather than most important (M:25%, 5/20; I:55%, 11/20; S:20%, 4/20; L:0% 0/20).
The other two choices were ranked lower overall. “Reducing staff redundancy” was ranked by
almost half as least important and had a weighted average of 3.3. (M:10%, 2/20; I:15%, 3/20;
S:35%, 7/20; L:40%, 8/20) ranked as the least important. “Integrating culture” was ranked by

62
slightly more than half as least important (M:5%, 1/20; I:10%, 2/20; S:20%, 6/20; L:55%, 11/20)
but had a similar weighted average of 3.4.
Figure 15: Importance of Restructuring
When senior executives planned restructuring that merged CMC groups, which was most
important when considering the following? Please rank from (1 - Most Important) to (4 - Least
Important) (n=20)

Respondents with experience in preparing operational CMC activities were asked to rate
their concerns with six additional aspects using a choice of three options from very to not
concerned (Figure 16). Two choices, meeting timelines (V+S:96%, 21/22) and retaining
employees (V+S:91%, 20/22), were scored by almost all as very or somewhat concerning.
“Ensuring successful knowledge transfer” was also ranked highly (V+S:86%, 19/22). (Meeting
timelines: V:50%, 11/22; S:45%, 10/22; N:5%, 1/22; Retaining employees: V:32%, 7/22; S:59%,
13/22; N:9%, 3/22; Knowledge transfer: V:41%, 9/22; S:45%, 10/22; N:14%, 3/22)
11
0
8
1
6
4
7
3
2
11
3
4
1
5
2
12
0 2 4 6 8 10 12 14
Integrating culture
Redefining roles and responsibilities
Reducing staff redundancy
Retaining talent
1- Most Important 2 - Important 3 - Somewhat Important 4 - Least Important

63
Figure 16: Areas of Greatest Concern when Merging CMC Activities
When your department prepared to merge operational CMC activities, how concerned were you
with the following aspects? (n=22)

Concerns for the remaining choices had lower ratings: aligning SOPs (V+S:59%, 13/22);
assigning roles, responsibilities and accountabilities (V+S:68%, 15/22); meeting regulatory
expectations (V+S:77%, 17/22) (Figure 17). (Aligning SOPs: V:23%, 5/22; S:36%, 8/22; N:
41%, 9/22; Assigning roles and responsibilities: V:36%, 8/22; S:32%, 7/22; N: 32%, 7/20;
Satisfying regulatory expectations: V:14%, 3/22; S:64%, 14/22; N:23%, 5/22).
Figure 17: Areas of Lesser Concern when Merging CMC Activities
When your department prepared to merge operational CMC activities, how concerned were you
with the following aspects? (n=22)

0
0
0
2
3
1
13
10
10
7
9
11
0 2 4 6 8 10 12 14
Retaining employees
Knowledge transfer
Meeting timelines
Very Concerned Somewhat Concerned Not Concerned Not Sure
0
0
0
9
7
5
8
7
14
5
8
3
0 2 4 6 8 10 12 14 16
Aligning SOPs
Roles and responsibilities
Regulatory expectations
Very Concerned Somewhat Concerned Not Concerned Not Sure

64
4.3.2 Installation
Respondents were asked to rate concerns related to areas that might delay FDA approvals
as their organizations began to integrate operations (Figure 18). As during exploration, almost
all were very or somewhat concerned about retaining employees (V+S:91%, 20/22). A smaller
majority identified that they were very or somewhat concerned about validating manufacturing
processes (V+S:85%, 17/20), aligning documentation (V+S:82%, 18/22), meshing regulatory
CMC strategies (V+S:73%, 16/22) and integrating quality systems (V+S:75%, 15/20). Only 1-3
individuals were not sure how to respond for each choice. (Retaining employees: V:27%, 6/22;
S:64%, 14/22; N:9%, 2/22; Validating manufacturing processes: V:15%, 3/20; S:70%, 14/20;
N:10%, 2/20; Aligning documentation: V:23%, 5/22; S:59%, 13/22; N:14%, 3/22; Meshing
regulatory CMC strategies: V:18%, 4/22; S:55%, 12/22; N:18%, 4/22; Integrating quality
systems: V:30%, 6/20; S:45%, 9/20; N:20%, 4/20)
Figure 18: Top Rated Concerns for FDA Approvals as Merging Began
As your organization began integrating operations, how concerned were you that challenges in
the following areas might delay FDA approvals? (n=22)

1
2
1
0
1
2
4
4
2
3
14
12
9
14
13
3
4
6
6
5
0 2 4 6 8 10 12 14 16
Manufacturing validations
Meshing CMC strategies
Integrating quality systems
Retaining employees
Aligning documentation
Very Concerned Somewhat Concerned Not Concerned Not Sure

65
Other types of activities were also seen to concern many respondents. More than two
thirds were very or somewhat concerned about validating analytical test procedures (V+S:77%,
17/22), transferring technologies (V+S:75%, 15/20), setting product specifications (V+S:68%,
15/22), integrating company culture (V+S:71%, 15/21) and passing site inspections (V+S:71%,
15/21) (Figure 19). In only one case did one respondent identify that he or she was not sure how
to respond. (Validating analytical test procedures: V:14%, 3/22; S:64%, 14/22, N:23%, 5/22;
Transferring technologies: V:25%, 5/20; S:50%, 10/20; N: 25%, 5/20; Setting product
specifications: V:18%, 4/22; S:50%; 11/22, N: 27%, 6/22; Integrating company culture: V:29%,
6/21; S:43%; 9/21, N:29%, 6/21; Passing site inspections: V:14%, 3/21; S:57% 12/21; N:29%,
6/21)
Figure 19: Additional Concerns for FDA Approvals as Merging Began
As your organization began integrating operations, how concerned were you that challenges in
the following areas might delay FDA approvals? (n=22)

Respondents who were involved in the specifics of CMC alignment were asked to rate
the degree of difficulty with five aspects of this alignment on a three-point scale, specified as
0
1
0
0
0
6
6
5
5
6
12
11
14
10
9
3
4
3
5
6
0 2 4 6 8 10 12 14 16
Passing site inspections
Setting specifications
Analytical validations
Transferring technologies
Integrating culture
Very Concerned Somewhat Concerned Not Concerned Not Sure

66
Most difficult (M), Difficult (D), and Easy (E), with weightings of 1-3 respectively (Figure 20).
The distribution of scores was supplemented with a weighted average for each choice, in which
most difficult was assigned the value of 1 and easy was assigned a value of 3. Assignments of
the “Most difficult” rating were split across different choices. “Planning to demonstrate product
comparability” was seen by a few as most difficult (M:14%, 3/22), by more than half as difficult
(D:55%, 12/22), and by a few as easy (E:18%, 4/22) with the most impactful weighted average
of 1.8. Similarly, “CMC strategies for submissions” was seen as most difficult by a few
(M:14%, 3/22), as difficult by half (D:50%, 11/22), and as easy by a quarter (E:27%, 6/22) with
an weighted average of 2.0. The remaining aspects had similar weighted averages. “Setting
phase appropriate validation requirements” was seen to be most difficult by a few (M:14%,
3/22), as difficult by less than half (D:41%, 9/22), and as easy by about one-third (E:36%, 8/22)
with a weighted average of 2.1. “Choosing/working with suppliers” was seen as most difficult
by a few (M:9%, 2/22), as difficult by about a third (D:36%, 8/22), and as easy by nearly a half
(E:41%, 9/22) with a weighted average of 2.1. The least difficult for most was “Following
regulatory guidances,” that was never selected as most difficult; it was seen as difficult by about
a third (D:36%, 8/22) and as easy by a majority (E:59%, 13/22) and had a weighted average of
2.5. A few (1 to 3) individuals were not sure how to respond to a given a choice.

67
Figure 20: Views of Difficulty when Aligning CMC Strategies
Once the CMC and Quality departments had been reconfigured, how easy was it to align the
following aspects of CMC strategy with the new partner? (n=22)

Respondents were asked to rate their interactions with others in the partnering company
as they began to work together on a 3-point scale of agree (A), disagree (D), and neither agree
nor disagree (N) (Figure 21). Asked whether both parties led the planning initiatives, most
respondents agreed (59%, 13/22) rather than disagreed (27%, 6/22); a few (14%, 3/22) neither
agreed nor disagreed. Similarly, when asked if both were involved in determining when
implementation would begin, most agreed (55%, 12/22) rather than disagreed (D:23%, 5/22) or
neither agreed nor disagreed (N:9%, 2/22). When asked if both organizations had sufficient
input to phase appropriate validation requirements, somewhat fewer agreed (A: 45%, 10/22) but
still outnumbered those who disagreed (D:23%, 5/22) or neither agreed nor disagreed (N:23%,
5/22). From 0-3 individuals were unable to answer for each of the different choices.
1
2
2
3
3
0
3
3
3
2
8
9
11
12
8
13
8
6
4
9
0 2 4 6 8 10 12 14
Following regulatory guidances
Phase appropriate validations
Agreeing on CMC strategies
Demonstrating comparability
Choosing/working with suppliers
Easy Difficult Most Difficult Not Sure

68
Figure 21: Activities Most Commonly Shared during Organizational Integrations
When the organizational teams began to work together, please rate whether you agree with the
following statements. (n=22)

Respondents agreed less frequently with other statements. They were split (A:36%, 8/22
versus D:32%, 7/22) when asked if both organizations had sufficient input to CMC gap analyses;
a few neither agreed nor disagreed (N:18%, 4/22) (Figure 22). Similarly, a split was seen
between respondents who agreed and disagreed when asked whether the organizations had
dissonant approaches when incorporating ICH and FDA guidances (A:27%, 6/22 versus D:32%,
7/22) or when asked if both organizations understood their roles (A:27%, 6/22 versus D:32%,
7/22). However, for both questions, a third of respondents neither agreed nor disagreed (32%,
7/22 for each choice). Notably, the majority (D:45%, 10/22 versus A:23%, 5/22) disagreed that
both organizations shared sufficiently in decisions about day-to-day operations; nearly a quarter
neither agreed nor disagreed (N:23%,5/22). Very few individuals (from 2 to 3) were not able to
answer.
2
3
0
5
5
6
5
2
3
10
12
13
0 2 4 6 8 10 12 14
Both organizations had sufficient input to phase
appropriate validation initiatives
Both organizations determined when
implementation would begin
Members from both partners led planning
initiatives
Agree Neither Agree nor Disagree Disagree Cannot Answer

69
Figure 22: Activities Less Commonly Shared during Organizational Integrations
When the organizational teams began to work together, please rate whether you agree with the
following statements. (n=22)

Respondents were asked whether they were satisfied that operational changes were
adequate to meet FDA expectations as the manufacturing operations began to partner but before
they had implemented tech transfers (Figure 23). About two-thirds indicated that they were very
satisfied (V) or satisfied (S) rather than not satisfied (N) with revisions to quality systems
procedures (V+S:67%, 14/21) and with updates to the manufacturing infrastructure (V+S:62%,
13/21). About half were very satisfied or satisfied with the side-by-side training (V+S:48%,
10/21). However, only a minority were satisfied that sufficient staffing was made available to
meet FDA expectations (V+S:29%, 6/21). Compared to previous questions, more respondents
(from 3 to 6) were not able to answer. (Revised quality systems: V:5%, 1/21; S:62%, 13/21;
N:5%, 1/21; Updated manufacturing infrastructure: V:5%, 1/21; S:57%, 12/21; N:10%, 2/21;
Completed side by side training: V:0%, 0/21; S:48%, 10/21; N:24%, 5/21; Sufficient staffing:
V:0%, 0/21; S:29%, 6/21; N: 57%, 12/21)
2
2
3
2
7
7
7
10
7
7
4
5
6
6
8
5
0 2 4 6 8 10 12
The organizations had dissonant approaches
incorporating ICH and FDA guidances
Both organizations understood their roles
Both organizations had sufficient input to CMC
gap analyses
Both organizations shared sufficiently in
decisions about day-to-day operations
Agree Neither Agree nor Disagree Disagree Cannot Answer

70
Figure 23: Adequacy of Operational Changes to Meet FDA Expectations
As the manufacturing operations began to partner prior to implementing tech transfers, please
indicate your level of satisfaction to ensure that operational changes were adequate to meet FDA
expectations. (n=21)

Respondents whose CMC operations had been merged were asked to provide further
comments that they felt would be related to the early stages of CMC operational integrations
(Table 7).
Table 7: Concerns of Integrations at Early Stages
If you have other concerns related to the early stages of CMC operational integrations, please
specify.
Category Comments
Personnel
The availability of resources at the parent company to take on the work resulting from the
acquisition was very inadequate.
There was disagreement or dissatisfaction with the newly combined companies, some of
the talent retained didn't want to stay and some of the people dismissed ended up being
more knowledgeable than those let go. There was quite a bit of knowledge loss during the
transition period because some key talent was dismissed and those in what were purported
to be "key" roles were retained, yet those individuals didn't have good understanding of
the technical details of their role.
Process governance Lack of integration planning or expectations.
Roles and responsibilities
Aligning point of contacts toward suppliers and CDMO was not satisfactory, also person
in plant responsibilities were not clear.
4.3.3 Initial Implementation
Respondents who identified that their CMC groups had integrated rated the degree of
challenge associated with several specific activities related to early stages of that merger
6
6
6
3
2
1
5
12
12
13
10
6
1
1
0
0
0 2 4 6 8 10 12 14
Updated manufacturing infrastructure
Revised quality systems
Completed side by side training
Sufficient staffing was made available
Very Satisfied Satisfied Not Satisfied Cannot Answer

71
(Figure 24). Almost all (V+S:95%, 21/22) identified that retaining employees was very or
somewhat challenging rather than not challenging. Assuring knowledge transfer between parties
(V+S:86%, 19/22), satisfying regulatory expectations (V+S:77%, 17/22), documenting quality
systems (V+S:77%, 17/22), and assuring manufacturing success rates (V+S:68%, 15/22) were
also viewed by most as very or somewhat challenging. Very few individuals, ranging from 0 to
1, were not sure how to respond to each category. (Retaining employees: V:46%, 10/22; S:50%,
11/22; N:5%, 1/22; Knowledge Transfer: V:46%, 10/22; S:41%, 9/22; N:9%, 2/22; Satisfying
regulations: V:14%, 3/22; S:64%, 14/22; N:14%, 3/22; Quality systems: V:9%, 2/22; S:68%,
15/22; N:9%, 14/22; Manufacturing success: V:14%, 3/22; S:55%, 12/22; N:18%, 4/22)
Figure 24: Most Highly Rated Challenges as Operations Began to Merge
How challenging were the following CMC activities as your partnership/merger proceeded?
(n=22)

Other choices had lower ratings (Figure 25). Only about half reported that working under
budget constraints (V+S:46%, 10/22), maintaining product quality (V+S:50%, 11/22), and
assuring batch lot reproducibility (V+S:55%, 12/22) were very or somewhat challenging.
Relatively few individuals (0 to 3 for each choice) were not sure how to respond. (Budget
3
1
0
3
2
4
2
1
2
3
12
9
11
15
14
3
10
10
2
3
0 2 4 6 8 10 12 14 16
Manufacturing success
Knowledge transfer
Retaining employees
Quality systems
Satisfying regulations
Very Challenging Somewhat Challenging Not Challenging Not Sure

72
constraints: V:14%, 3/22; S:32%, 7/22; N:50%, 11/22; Product quality: V:9%, 2/22; S:41%,
9/22; N:36%, 8/22; Batch reproducibility: V:9%, 2/22; S:46% 10/22; N:32%, 7/22)
Figure 25: Challenges with Lower Rankings as Merging Operations Began
How challenging were the following CMC activities as your partnership/merger proceeded?
(n=22)

After integration, respondents were asked to rate levels of agreement when aligning
activities with the partnering group (Figure 26). The majority (E:68%, 15/22) indicated that
training was as expected (E). None of the respondents (B:0%, 0/22) agreed this choice was
better than expected (B), and very few (W:14%, 3/22) said that it was worse than expected (W).
Nearly as many had ratings of better or as expected for activities related to regulatory CMC
filing strategies (B:5%, 1/22; E:68%, 15/22), meeting consistent product quality results (B:9%,
2/22; E:68%, 15/22), funding (B:14%, 3/22; E:59, 13/22), and maintaining manufacturing
success rates (B:14%, 3/22; E:55%, 12/22). The percentage of “worse than expected” ratings
were below 20% in all these cases. Very few respondents (2 to 4) identified that a given
question was not applicable. (Agreeing on regulatory CMC filing strategies: B:5%, 1/22; E:68%,
15/22; W:18%, 4/22; Consistent product quality: B:9%, 2/22; E:68%, 15/22; W: 14%, 3/22;
Funding: B:14%, 3/22; E:59 13/22; W:14%, 3/22; Maintaining manufacturing success rates:
B:14%, 3/22; E:55%, 12/22; W:18%, 4/22)
1
3
3
11
7
8
7
10
9
3
2
2
0 2 4 6 8 10 12
Budget constraints
Batch reproducibility
Product quality
Very Challenging Somewhat Challenging Not Challenging Not Sure

73
Figure 26: Activities Meeting Expectations when Partnering Groups Align
Please indicate whether you agree with the following statements regarding the alignment of the
partnering groups. (n=22)

The frequency of “worse than expected” responses relative to more positive ratings
appeared to increase in three other questions (Figure 27). “Communicating across sites” and
“Aligning documentation” had similar rankings, with only one respondent identifying that the
experience was better than expected, about half identifying that it was as expected (E:55%, 12/22
for each), and more than one-third that it was worse than expected (W:36%, 8/22 and W:32%,
7/22 respectively). Further, more than half indicated that sharing knowledge across sites was
worse than expected (W:55%, 12/22). Only 1-2 respondents identified a choice as not applicable.
(Communicating across sites: B:5%, 1/22; E:55%, 12/22; W:36%, 8/22; Aligning
documentation: B:5%, 1/22; E:55%, 12/22; W:32%, 7/22; Sharing knowledge across sites:
B:5%, 1/22; E:36%, 8/22; W:55%, 12/22)
2
3
4
2
3
3
4
3
4
3
15
12
15
15
13
2
3
0
1
3
0 2 4 6 8 10 12 14 16
Meeting consistent product quality test results
Maintaining manufacturing success rates
Sufficiency of training
Agreeing on regulatory CMC filing strategies
Sufficiency of funding
Better than Expected As Expected Worse than Expected Not Applicable

74
Figure 27: Areas More Frequently Not Meeting Expectations when Partnering Groups
Align
Please indicate whether you agree with the following statements regarding the alignment of the
partnering groups. (n=22)

Respondents working in operational integrations were asked to rate their level of success
as they carried out their first studies as a new partnership/team (Figure 28). About two-thirds
indicated that they were very successful (V) or somewhat successful (S) rather than not
successful (N) when it came to integrating CMC technical operations (V+S:73%, 16/22),
regulatory CMC strategies (V+S:73%, 16/22), quality systems (V+S:68%, 15/22) and
documentation/SOPs (V+S:68%, 15/22). The majority rated training as very successful or
somewhat successful (V+S:59%, 13/22). Of the 22 respondents, 4 to 7 respondents in each of
the categories were unable to respond. (CMC Technical Operations: V:23%, 5/22; S:50%,
11/22; N:9%, 2/22; Regulatory CMC strategies: V:23%, 5/22; S:50%, 11/22; N:14%, 3/22;
Quality Systems: V:18%, 4/22; S:50%, 11/22; N:14%, 3/22; Documentation/SOPs: V:18%, 4/22;
S:50%, 11/22; N:9%, 2/22; Training: V:18%, 4/22; S:41%, 9/22; N:9%, 2/22)
2
1
1
7
12
8
12
8
12
1
1
1
0 2 4 6 8 10 12 14
Aligning documentation
Sharing knowledge across sites
Communicating across sites
Better than Expected As Expected Worse than Expected Not Applicable

75
Figure 28: Views on Success of Integrations
In your view, how successful were operational integrations in the following areas as you carried
out the first studies as a new partnership/team? (n=22)

Respondents involved with integrating CMC operations at early stages were asked to
comment on what they could have done differently to ensure success (Table 8).
Table 8: Supporting Views for Ensuring Successful Integrations
When making initial changes to begin CMC operational integrations, what in retrospect
do you think could have been done differently to ensure a successful program?
Category Comments
Personnel
The company made some poor decisions related to dismissing staff. Many of the Sr leaders at the site
were dismissed as part of the acquisition and they retained most of the strategic understanding of the
decisions that were made. Many of the people retained knew what decisions were made but they
didn't have a clear understanding of "why" the decision was made.
Plan to retain key talent early in the process. Communicate often and clearly.
Dedicate resources from the parent company to integrate the CMC operational integrations instead of
just adding the workload on top of the existing resource constraints.
Roles and
responsibilities
Roles & responsibilities, definitions, timeline/milestone targets alignment.
Overlap in roles and responsibilities, although inefficient, could have been more valuable in
knowledge sharing and teamwork during the initial time period.
Plan what integration looks like, roles and responsibilities
A high-level overview/roadmap of the current and future states (IT, quality systems, suppliers,
manufacturing/testing sites, etc.) with regular status updates would be ideal to align the two
organizations on a path to an integrated company. Piecemeal communication, or lack thereof makes
merging feel disjointed, lowers morale, and hastens key departures.
General
comments
Still in the early stages.
It has been going well.
7
5
4
3
4
2
2
3
3
2
9
11
11
11
11
4
4
4
5
5
0 2 4 6 8 10 12
Training
Documentation / SOPs
Quality Systems
Regulatory CMC strategies
CMC Technical Operations
Very Successful Somewhat Successful Not Successful Not Sure

76
Respondents were asked to rate the effects that operational integrations had on CMC
staffing and morale in early stages (Figure 29). More respondents agreed (A:59%, 18/22) than
disagreed (D:18%, 4/22) that staffing was insufficient; a few neither agreed nor disagreed
(N:14%, 3/22). Nearly as many agreed that key personnel had left (A:50%, 11/22). Somewhat
fewer agreed that staff morale decreased (A:41%, 9/22), projects were delayed by staffing
shortfalls (A:41%, 9/22), and trust in leadership decreased (A:36%, 8/22), but these rankings
were still higher than the number who disagreed. Very few individuals (from 1 to 3) were not
sure how to answer. (Key personnel left: A:50%, 11/22; D:14%, 3/22; N:27%, 6/22; Staff
morale decreased: A:41%, 9/22; D:14%, 3/22; N:32%, 7/22; Projects were delayed by staffing
shortfalls: A:41%, 9/22; D: 27%, 6/22; N: 27%, 6/22 and Trust in leadership decreased: A:36%,
8/22; D: 27%, 6/22; N: 32%, 7/22)
Figure 29: Impact on Staff when Implementing Tech Transfers
How did the operational integration affect CMC staff during the earliest tech transfers? (n=22)

Respondents were also asked about the effectiveness of their new teams during their
initial implementations (Figure 30). “Effectiveness at technology transfers” was regarded as
effective or very effective by about three quarters (V+S:73%, 16/22), and only one respondent
3
2
1
2
1
3
3
6
3
6
7
6
7
4
6
9
11
8
13
9
0 2 4 6 8 10 12 14
Staff morale decreased
Key personnel left
Trust in leadership decreased
Staffing was insufficient
Projects delayed by staffing shortfalls
Agree Neither Agree nor Disagree Disagree Not Sure

77
regarded it as ineffective. Nearly as many rated the teams as very or somewhat effective during
operational integrations (V+S:73%, 16/22) and transfer of product knowledge (V+S:68%,
15/22). However, a higher number regarded these activities as ineffective (N:18%, 4/22 and
N:23%, 5/22 respectively). A few individuals (from 2 to 5) were not sure how to answer.
(Technology transfers: V:18%, 4/22; S:55%, 12/22; N:5%, 1/22; Operational integrations:
V:18%, 4/22; S:55%, 12/22; N:18%, 4/22; Transfer of product knowledge: V:18%, 4/22; S:50%,
11/22; N:23%, 5/22)
Figure 30: Implementation Effectiveness for Projects with New Teams
As new teams were developed, how effective was the new team in implementing the initial plans
effectively? (n=22)

The same respondents were asked to identify the duration of delays associated with
targeted milestones in different areas (Figure 31). Activities related to technology transfer
appeared to be most delayed; 55% (12/22) identified delays from one to twelve months; only
14% (3/22) reported no delays. Significant delays were also associated with the transfer of
product knowledge (50%, 11/22) and with operational integrations (41%, 9/22); no delays were
reported by only a few (18%, 4/22 for each). However, several individuals in each category
(from 6 to 9) were not able to answer. (Technology transfers: 1-3Mo:41%, 9/22; 3-12Mo:14%,
2
5
2
5
1
4
11
12
12
4
4
4
0 2 4 6 8 10 12 14
Transfer of Product Knowledge
Technology Transfers
Operational Integrations
Very Effective Somewhat Effective Not Effective Not Sure

78
3/22; >1YR:0%, 0/22; ND:14%, 3/22; Transfer of product knowledge: 1-3Mo:27%, 6/22; 3-
12Mo:23%, 5/22; >1YR:5%, 1/22; ND:18%, 4/22; Operational integrations: 1-3Mo:32%, 7/22;
3-12Mo:9%, 2/22; >1YR:0%, 0/22; ND:18%, 4/22).
Figure 31: Achieving Milestones when Implementing Projects
When implementing the initial activities, did you have delays in achieve the targeted milestones?
If yes, how long was the delay? (n=22)

Respondents were asked to identify delays with regulatory submissions when faced with
certain problems associated with restructuring (Figure 32). About half of the respondents agreed
that insufficient project management resulted in some delays (45%, 10/22), whereas a quarter
disagreed (27%, 6/22). Nearly as many agreed that disagreements within leadership resulted in
some delays (41%, 9/22); about a quarter disagreed. However, relatively few, 18% (4/22),
agreed that delays were seen due to culture clashes, and half (50%, 11/22) saw no delays. Four
respondents also indicated that delays occurred for other reasons, but they did not specify these
other causes. Many individuals (from 6 to 7) were not sure how to answer. (Disagreements
within leadership: S:41%, 9/22; N:27%, 6/22; R:0%, 0/22; Culture clashes: S:18%, 4/22; N:50%,
11/22; R:0%, 0/22 and Other: S:36%, 4/22; N:9%, 1/22; R:0%, 0/22).
9
7
6
4
3
4
7
9
6
2
3
5
0
0
1
0 1 2 3 4 5 6 7 8 9 10
Operational Integrations
Technology Transfers
Transfer of Product Knowledge
>1 year 3-12 Months 1-3 Months No Delay Cannot Answer

79
Figure 32: Delays with Regulatory Submissions
Did the following problems that might be associated with restructuring cause issues that delayed
your regulatory submissions? (n=22)

4.3.4 Full Implementation
Respondents who identified that their CMC groups had integrated more fully were asked
to rate the degree of challenge associated with specific activities. The three areas rated as most
challenging are identified in Figure 32. Almost all (V+S:96%, 22/23) identified that aligning
culture was very (V) or somewhat (S) challenging rather than not (N) challenging. Nearly as
many identified that training staff (V+S:87%, 20/23) and aligning operational expectations
(V+S:87%, 20/23) were very or somewhat challenging. Very few individuals (0 to 1) were not
sure how to respond. (Aligning culture: V:52%, 12/23; S:44%, 10/23; N:4%, 1/23; Training
staff: V:13%, 3/23; S:74%, 17/23; N:9%, 2/23; Aligning culture: V:43%, 10/23; S:43%, 10/23;
N:13%, 3/23).
6
6
7
7
0
0
0
0
4
10
4
9
1
6
11
6
0 2 4 6 8 10 12
Other
Insufficient project management
Culture clashes
Disagreements within leadership
No Delays Some Delays Refuse to File Cannot Answer

80
Figure 33: Top Rated Challenges when Merging Operations
Overall, how would you rate the degree of challenge associated with each of the following
activities throughout the process of integrating two (or more) CMC groups? (n=23)

Other areas of challenge typically ranked lower. Nonetheless, more than half identified
that updating SOPs (V+S:54%, 12/22), generating reproducible data (V+S:65%, 15/23), and
aligning expectations with FDA requirements (V+S:61%, 14/23) were very or somewhat
challenging (Figure 34). The other quarter to third reported that these areas were not
challenging. Very few (1 to 3) were not sure how to respond to different options. (Updating
SOPs: V:9%, 2/22; S:45%, 10/22; N:36%, 8/22; Reproducing data: V:13%, 3/23; S:52%, 12/23;
N: 30%, 7/23; Aligning FDA: V:13%, 3/23; S:48%, 11/23; N: 26%, 6/23).
Figure 34: Additional Challenges when Merging Operations
Overall, how would you rate the degree of challenge associated with each of the following
activities throughout the process of integrating CMC groups? (n=23)

0
0
1
1
3
2
10
10
17
12
10
3
0 2 4 6 8 10 12 14 16 18 20
Aligning culture
Aligning operations
Training staff
Very Challenging Somewhat Challenging Not Challenging Not Sure
3
1
2
6
7
8
11
12
10
3
3
2
0 2 4 6 8 10 12 14
Aligning FDA requirements
Reproducing data
Updating SOPs
Very Challenging Somewhat Challenging Not Challenging Not Sure

81
Respondents were asked to rate their levels of agreement related to certain types of
regulatory assistance or oversight (Figure 35). More respondents agreed than disagreed that
FDA should require manufacturing inspections for commercialized products after a merger or
acquisition (36%, 8/22 versus 5%, 1/22); however, nearly half neither agreed nor disagreed
(45%, 10/22). More disagreed (27%, 6/22) than agreed (18%, 4/22) that insufficient FDA
guidance was available on assuring product comparability after a merger or acquisition; the
remaining 40% (9/22) neither agreed nor disagreed. Only 3 individuals were not sure how to
answer each of the questions.
Figure 35: Regulatory Oversight During Integrations
Please indicate your level of agreement with the following statements related to regulatory
oversight during your operational integrations. (n=22)

Respondents whose CMC operations were fully integrated were asked to provide
suggestions on what FDA might do better to provide support when companies undergo
operational integrations (Table 9).
3
3
6
1
9
10
4
8
0 2 4 6 8 10 12
Insufficient FDA guidance on assuring product
comparability after a merger or acquisition
FDA should require manufacturing inspections
after a merger or acquisition
Agree Neither Agree nor Disagree Disagree Not Sure

82
Table 9: Suggestions to the FDA for when CMC Operations are Integrated
Please provide comments on what else FDA might do better to provide support for CMC
operations as two departments are meshed.
Comments
A review of the quality systems that have changed as a result of the merger. If previous inspections focused on Company X,
which was then merged with Company Y, a review of any changes to quality systems with respect to the programs affected by
the merger should be executed to ensure product safety.
I don't necessarily believe that the FDA needs to perform an inspection directly after the integration, but perhaps at the next
biannual inspection they should do a more thorough dive into the operations and quality systems of the new (combined)
organization.
Allow more/repeat meetings, e.g., if End of Phase (EOP 1) meeting already happen prior to merger, should allow a follow-up
EOP1 meeting post- merger. Approaches changes across organizations and leadership so difficult to execute something you
were not part of.
Consistent response regardless changes of company size and culture after merger
Regular meetings to support CMC operational integration
No comment

Respondents with collaboration experience were asked if they felt the acquired or
supporting organization should have more decision-making opportunities for developing
regulatory CMC strategies (Figure 36). The majority, 64% (14/22), agreed, and only 14% (3/22)
disagreed. The remaining 23% (5/22) were not sure how to answer.
Figure 36: Decision Making for Developing Regulatory CMC Strategies
When working in a collaboration, partnership or joint venture, do you think the supporting
organization working with the sponsor should have more decision-making opportunities for
developing Regulatory CMC strategies? (n=22)

4.3.5 Sustainability
Respondents with experience with regulatory submissions were asked to rate levels of
success in satisfying FDA requirements after operational integrations had been completed
5
3
14
0 2 4 6 8 10 12 14 16
Not Sure
No
Yes
Number of Respondents

83
(Figure 37). When asked about each of the types of submissions that might be made, about half
of new INDs were successful with delays (With:50%, 11/22), and only two (WithOut:9%, 2/22)
were successful without delays. Nearly as many identified that clearance of IND amendments
was successful with delays (W:45%, 10/22), and fewer were approved without delays (WO:23%,
5/22). Relatively few marketing applications were approved either with or without delays
(W:27%, 6/22; WO:9%, 2/22). Similarly, relatively few marketing applications supplements or
post approval commitments were approved with or without delays (Marketing supplements:
W:14%, 3/22, WO:14%, 3/22; Post approval commitments: W:14%, 3/22; WO:14%, 3/22). One
respondent also identified “other, with delays” but did not specify the activity that was
successful. Many individuals (7 to 16) were unable to answer these questions. (Clearance of
IND amendments: W:45%, 10/22; WO:23%, 5/22; N:0%, 0/22; Marketing application approvals:
W:27%, 6/22; WO:9%, 2/22; N:0%, 0/22; Marketing application supplements: W:14%, 3/22;
WO:14%, 3/22; N:0%, 0/22 and Post approval commitments: W:14%, 3/22; WO:14%, 3/22;
N:0%, 0/22)

84
Figure 37: Success of Regulatory Submissions for Drug Development Programs
Were regulatory submissions for drug development programs successful in satisfying FDA
requirements after operational integrations had been completed?

Respondents were asked to comment on potential solutions to overcome the challenges of
operational integration (Table 10).
Table 10: Solutions to Overcome CMC Operational Integrations
In your new way of conducting CMC operations, do you have any other challenges not discussed
above for which you might propose a better solution?
Comments
No major disconnects between sites regarding functions.
Each site has a dedicated functional area or areas, but the decision-making cores are dispersed throughout multiple sites

Respondents were asked how early they began to implement four activities suggested in
FDA’s guidance, “Human Gene Therapy for Rare Diseases,” to accelerate CMC activities in the
face of shortened clinical timelines for BLA submissions (Figure 38). Suggestions to implement
early Process Performance Qualification (PPQ) at Phase I were reported to be implemented fully
7
16
16
14
7
9
0
0
0
0
0
0
1
3
3
6
10
11
0
3
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2
5
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0 2 4 6 8 10 12 14 16
Other
Post approval commitments
Marketing application supplements
Marketing application approvals
Clearance of IND amendments
Clearance of new INDs
Successful without Delays Successful with Delays Not Successful Cannot Answer

85
by only two respondents (F:10%, 2/21) and somewhat implemented by only 4 (S:19%, 4/21). Of
the rest, over a third (N:38%, 8/21) did not implement the suggestion, and a third (CN:33%,
7/21) could not answer. Similarly, only 3 (F:14%, 3/21) fully implemented and none of the
respondents partially implemented late-stage manufacturing process validations at Phase I; over
a third (N:38%, 8/21) did not implement them, and almost half (CN:48%, 10/21) could not
answer. A few fully (F:5%, 1/21) or somewhat (S:24%, 5/21) implemented implement testing
validations (including potency) at Phase I; instead, nearly a third (N:29%, 6/21) did not, and
almost half (CN:43%, 9/21) could not answer. One respondent fully implemented (F:5%, 1/21)
and a few somewhat implemented (S:29%, 6/21) approaches to leverage contents from marketed
products by using “Simplified IND or cross-referencing shared CTD sections”; two respondents
did not implement these approaches (N:10%, 2/21) and more than half (CN:57%, 12/21) could
not answer.
Figure 38: Implementation of FDA Guidances
In 2020, FDA issued guidance “Human Gene Therapy for Rare Diseases” to accelerate CMC
activities in order to address shortened clinical timelines for BLA submissions. Please rate
your level of implementation of the following when considering regulatory CMC strategies.
(n=21)

12
7
10
9
2
8
8
6
6
4
0
5
1
2
3
1
0 2 4 6 8 10 12 14
Leveraged contents from marketed products by
“Simplified IND or cross-referencing shared CTD
sections”
Completed early Process Performance
Qualification PPQ at Phase I
Conducted late stage manufacturing process
validations at Phase I
Conducted testing validations (including potency)
at Phase I
Fully Implemented Somewhat Implemented Did Not Implement Cannot Answer

86
Respondents were asked how the realignments impacted decision-making for
accelerating regulatory CMC strategies (Figure 39). A third (32%, 6/19) identified some
adoption of FDA guidance to accelerate CMC activities, and nearly as many (26%, 5/19) aligned
with FDA guidance. The remaining few (11%, 2/19) did not consider the FDA guidance, and
close to a third (32%, 6/19) were not sure.
Figure 39: Acceleration of Regulatory CMC Strategies
How did working with another company impact decision making for accelerating regulatory
CMC strategies? (n=19)

Respondents who had fully implemented activities in a new CMC operational
organization were asked to rate four challenges identified in Figure 40. Almost all identified that
retaining employees was very or somewhat challenging (V+S:75%, 15/20), and none (E:0%,
0/20) that it was not challenging. Similarly, half (V+S:55%, 11/20) identified that meeting
sponsor and partner expectations, demonstrating product consistency to satisfy FDA expectations
(S:55%, 11/20), and defining regulatory CMC strategies to meet FDA expectations (S:50%,
10/20) were very or somewhat challenging. Nearly a quarter (5 to 6) in each category were not
sure how to respond. (Meeting sponsor/ partner expectations: V:5%, 1/20; S:50%, 10/20;
N:15%, 3/20; Demonstrating product consistency: V:10%, 2/20; S:45%, 9/20; N:15%, 3/20 and
Defining regulatory CMC strategies: V:5%, 1/20; S:45%, 9/20; N:25%, 5/20)
6
2
5
6
0 1 2 3 4 5 6 7
Not Sure
Did not consider FDA guidance
Aligned FDA guidance
Some adoption of FDA
Number of Respondents

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Figure 40: Challenges when Implementing New Organizations
Did you have challenges in the following areas even after fully implementing a new CMC
operational organization? (n=20)

Respondents were asked to provide advice to others who might be entering a new
partnership/merger/acquisition (Table 11). Of 6 responses, 4 were concerned with
retention/addition of staff, and the other two dealt with organizational structure.
Table 11: Advice to Organizations for Ensuring Successful Integrations
What advice might you give to organizations entering a new partnership/merger/acquisition to
assure successful integration?
Category Comments
Personnel
Retain more staff to find out what information they have. Perhaps a slower integration (I know it isn't
likely given that the bean counters who wanted the merger in the first place did so by being able to
"reduce redundancy" in the staff as a part of the merger). There has been a lot of knowledge loss during
mergers that I've been involved with. Most frequently it is because key staff are let go early in the
process.
Place more emphasis on the importance of retaining employees
Assign dedicated resources for the new program to allow for a sudden increase in workload.
Prioritize values that an organization need to retain that should be consistent from top managements
through front line members for PMI.
Roles and
responsibilities
Make sure you have a means and willingness to share product and technology know-how.
Prioritize/outline the future organizational structure with clear roles and responsibilities before
integration so employees and projects don't get lost in the mix

6
5
6
5
3
5
3
0
9
9
10
8
2
1
1
7
0 2 4 6 8 10 12
Demonstrating product consistency to satisfy FDA
expectations
Defining regulatory CMC strategies to meet FDA
expectations
Meeting sponsor and partner expectations
Retaining employees
Very Challenging Somewhat Challenging Not Challenging Not Sure

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4.4 Respondents Whose Company Remained as Independent CMC Operations
Respondents who worked in companies in which the CMC activities remained separate
were not asked in the same detail about their changed activities because such changes were likely
to be modest. However, they were asked instead to provide feedback on pros and cons of not
integrating with the partner company (Table 12).
Table 12: Responses - Pros and Cons of Not Merging CMC Operations
What in your opinion are the pros and cons of not merging CMC operations and working as
isolated organizations?
Category Comments
Roles and
responsibilities
Company X acquired company Y. Company X has loads of CMC experience, but they had
zero experience in the advanced/cell therapy arena. Company Y really had the expertise in
this area and were allowed to maintain leadership in CMC with some but minimal
intervention. Company Y is always able to seek advice and guidance from company X CMC,
but company X looks to company Y as the leaders since we have more experience.
Pros: Already familiar with our own company approach and templates, operations were
already streamlined to a certain extent, only 1 set of reviewers to appease
• Pros: - retention of key individuals w historical knowledge of the project (business
continuity)
• Cons: - alignment of objectives not as clear - access to historical information by the
acquirer is rendered difficult - harder to evolve the culture of the acquired toward that of
the acquirer.
Conclusion: the uniformization and merger of the CMC operation is inevitable in the medium
to longer term. Maintaining a separate CMC org makes sense in the case of i) the acquired is
a mature organization w track record of compliant and operational excellence ii) the area of
operation is sufficiently distinct (i.e. biologics vs cell therapy)
• Pros: (1) It takes a fairly long time to merge CMC operations and that delays the
development of the new cell based therapy (2) It is also a fairly expensive process and in
this case both parties were university/hospital based research institutes (3) From a GMP
standpoint we were able to treat the collaborator in Germany as a supplier so we were
able to audit them as a supplier.
• Cons: (1) in our case the one collaborator was in Germany and we were in Canada, so
we had to deal with the differences in the GMP regulations between the two
jurisdictions on a case by case basis. If we had merged the two systems at the start all of
that would have already been done.
Even though the CMC teams were independent (2 separate companies), many of the projects
I've worked on had shared accountability for the certain CMC operations. For example, in
one collaboration, the PD/AD/MSAT responsibilities are shared 50/50 with our partnering
company so they attended every meeting, reviewed every protocol and report document, and
shared equal decision-making power.
• Pros: For QA and compliance oversight, including batch release and stability, my
company was solely responsible for those aspects. The pros of shared accountabilities
and decision making are that both teams are on the same page, have access to the same
information at the same time, and can build team rapport through frequent interactions.
This dynamic works quite well if the underlying company cultures are similar.
• Cons: The cons of this type of structure, where two independent organizations
collaborate, is that it usually takes some time to align the way the two organizations
work and communicate with each other. Each company has its own other projects and
priorities, and it can be challenging to align project deliverables, timelines, and
priorities. If the company cultures are highly dissimilar, additional effort is needed to

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achieve alignment, and this can cause a certain amount of frustration. Collaborating as
two separate entities also can be challenging if the two companies have different levels
of experience when it comes to phase-appropriateness, quality culture, compliance, and
regulatory expectations.
• Pros: May leverage most mature CMC Ops organization to develop strategy for
"newcomers" or less experienced organization.
• Cons: Diverging regulatory approaches and decisions on how to file new submissions or
variations Risk to supply if regulatory landscape for change management is not clearly
understood for all jurisdictions where the product is marketed.
Personnel
The ability to focus directly on the deliverable at hand such as tech transfer/scale up without
additional pre-clinical/clinical data keeps information to the respective CMC party licensing
the product/technology was beneficial. It kept nice to have information at the higher strategic
level. Strategy meetings to confirm directional decisions are still held and communicated as
appropriate.
• Pros: remaining nimble, employees remain content, low disruption of activities.
• Cons: redundancy in costs, missing opportunities to leverage expertise and knowledge,
employees from acquired company may feel uncertainty in their future.
Process
governance
I am not sure how to answer this question. I believe in regard to the collaboration of company
X/Y relationship there were a lot of processes between the 2 organizations that did not align
so I am unsure in this particular case if both could work as isolated organizations. It was a
collaborated effort between the 2 parties.
Companies that I have worked for have independent operations for about 2-3 years then
merge to the bigger company systems. Some systems are better than others but at the end of
the day, the acquired company will follow the operations of the acquiring company.
The two merging organizations may have different product portfolios, and, in such cases, it
becomes even more critical to retain product-specific CMC expertise.
The organization we collaborated with had several mAbs, but no cell therapy experience. We
did not merge CMC operations. We transitioned it to the partner company, as they bought
majority share.
• Pros: leveraging different resources and know how (e.g. PAI, reg-CMC).
• Cons: communication, decision making (governance), information sharing,
accountability.
Organizational
structure
The speed at the rate of organization was one of the more frustrating aspect. The cons of
being an isolated organization is the lack of visibility. This created a culture of fear among
some groups and a need to please the parent company by pushing projects that will ultimately
not succeed.
Different organizations may have different backgrounds/expertise that would not blend well
post-merger.
• Pros: Clear functionality and responsibility

The same respondents were asked whether they believed that their CMC operational
organizations should have been integrated (Figure 41). The majority preferred to have an
independent organization (64%, 14/22), but about a third (32%, 7/22) thought that a merged
structure would have been preferable; one individual (5%, 1/22) chose other and suggested that
the companies “offer CMC packages such as IND filing.”

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Figure 41: Reflections on Preference for Integration or Separation
In retrospect how do you feel your CMC operational organizations should have integrated?

4.5 Final Views of All Respondents on Overcoming CMC Hurdles
Respondents were asked to provide feedback on overcoming their biggest CMC hurdles
when working to assure timely submissions to the FDA (Table 13).
Table 13: Overcoming hurdles for Timely Regulatory Submissions
Based on your experience, what are the biggest CMC hurdles to overcome for timely
submissions to regulatory agencies?
Category Comments
Regulatory
CMC strategies
Breakthrough therapy designation has led to jumping from a few Phase 1 batches to an expectation of
Phase 3 readiness in too short an amount of time. Updating a Phase 1 manufacturing processes to a
commercial process requires extensive process and product comparability and characterization that take
more time than the clinical timelines, leaving the CMC timeline as the bottleneck.
Focus and strong leadership with vision and executable path to commercialization.
It depends on phase of development. For early phase development, it would be CMC data availability
related to safety. For BLA submission, it would be commercial readiness.
1. All the data available - sound data
2. An experienced regulatory group which lead the integration of all the building block in a coherent and
cohesive manner
3. A sound and robust storyboard - with a narrative that is more than here is just the data
4. Trained and experienced functional authors
5. Solid suite of reviewed/audited source documents
One of the biggest challenges that I have experienced is the conflicting strategies to implement "Phase
appropriate" CMC activities while attempting to shorten the time to marketing approval.
1. Thus far analytical development, contracted timelines, and new modalities (e.g. critical components)
so not sure what the Agency is looking for.
There are many, on top of list are: 1) defined comparability strategy, 2) setting meaningful product
specifications, 3) integrating control strategies across organizations and CDMOs, 4) experienced SMEs
in writing regulatory documents is scarce
With cell based therapies I think it would be things like: - cell line validation - batch to batch variation
- dealing with the short shelf life of the cell therapy and things like sterility testing - requirements for
adventitious agent testing often differs from country to country - validation of shipping conditions and
preparation at the site - screening requirements for donors often differs from country to country
Strong data package
Supplying sufficient stability data
Meeting regulatory requirements.
Establishing specifications
1
7
14
0 2 4 6 8 10 12 14
Other
Merged organizations
Maintained independent organization
Numer of Respondents

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Process
governance
I've worked mainly at companies that have adequate funding, so funding is excluded from my list but
I'm sure it is a major factor. If funding is adequate, the biggest CMC hurdles have been improper project
planning and management, and poor team assembly skills or lack of suitable human resources.
Pandemic was a big hurdle in the middle of us trying to get process validation runs completed in another
country and to get the drug shipped and approved in another country
Organized and accurate data archiving system. The most challenging thing for us is to determine exactly
what data has gone into what filing, where is that data archived for data verification purposes. As time
goes on, more data is generated that often supplants older data and we need to decide if/when that data
should be shared, if/when we will update filings.
Collecting data in time to allow enough time to write the CTD sections of the submission.
Lack of convergence on general requirements to approve new licenses or variations.
GMP production timeline.
Personnel
Manpower…. I have experienced really aggressive timelines for submissions and management is so
keen on the deadline not considering factors that can affect possible delays. They just want you to work
multiple roles to meet the deadline. I have seen this with expansion projects/construction.
All companies have personnel turnover, which results in loss of historical knowledge about why specific
data was used rather than other. I wish we had a reference program (like Endnote) for data, which
identified the exact reports data came from and the ability to explain why “this” data from “that” report,
etc. Knowledge and data management is challenging for all companies…
Roles and
responsibilities
I believe experience and communication are one of the biggest factors in the group. The lack of
communication between groups have led to the company missing some serious milestones. This was
driven by certain groups hiding their progress with the rest of the team. They misled the company that
the target deadlines were on track.
Having a team that is aligned operational & regulatory. Either the operations staff doesn't get input from
their regulatory counterparts or the regulatory organization assumes that the operations side "knows"
what regulatory knows and will make appropriate decision. There needs to be VERY GOOD
communication between the two sides to hash out the path forward, especially when things go wrong on
the operations side.
Organizations that act as a CMO need to have better policies and procedures to manage customer
requirements that are not in alignment with internal processes. For example, if a customer wants to use a
particular grade of material that is not approved by internal supplier quality, there should be a process
for how to handle customer requested materials that do not align with internal requirements. I would
also recommend submitting IND independently of working in a partnership if there are too many
differences in timelines between the 2 parties or the processes are completely different between the 2
parties. For example, parent company was on a completely different schedule than collaborating partner,
we were ready to manufacture at much higher volume but there was hardly any demand or clarity on
when we would get the material we needed from our partner to continue production. If a partnership or
CMO situation occurs, provide enough support for the project. For example, if you have a complicated
process do not make things more difficult by limiting technology such as ERP / MRP functions. We had
a very complicated chain of Identity process which could have been smoother if we had all the ERP
functions in oracle that other sites had access to.
The level of risk each company (sponsor, CMO, and any partnership involvement) must be aligned. I.e.
milestones for payment and work done, must not be so strict to inhibit progress towards a timely
submission. This often requires making decisions based on incomplete data sets which must be
exercised often to build comfort at making those decisions and set the culture at all levels of
management.
Alignment across sites and division of responsibilities
Lack of harmonization
Project management, conflicting/redundant internal governing bodies

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Chapter 5. Discussion
5.1 Introduction
Personalized medicines such as gene and cell therapies will transform the
biopharmaceutical industry but will also introduce novel challenges. Much has been written
about operational CMC challenges associated with the inherent variability in sourcing the
starting materials, testing the product, and fine-tuning the manufacturing processes used to make
such medicines. Discussed less frequently are the strategic CMC challenges when faced with
shortened timelines for FDA approvals during a merger, acquisition, and/or joint venture.
Through this study, I have supplemented that scanty literature by exploring the nature and impact
of those challenges.
5.2 Methodological Considerations
5.2.1 Delimitations
Careful attention had to be paid to this exploratory study to assure that delimitations were
placed on its scope and reach. The regulatory requirements and expectations related to CMC
drug approval vary greatly across markets internationally (Ahluwalia et al., 2021). To avoid the
blurring that might occur if respondents reported on diverse experiences in those different
countries, the target pool of participants was delimited to those employed by companies that
work within the U.S. regulatory framework. This focus seemed to make the most sense as a
starting point because the U.S. clinical trials of GCTs comprise the largest share of such
activities globally (ARM, 2021). Also, the U.S. requirements are amongst the most rigorous in
the world. Thus, U.S. regulatory systems often provide a benchmark and model for the oversight
of GCTs in other geographies calling for regulatory convergence for both the European
Medicines Agency and the World Health Organization (Drago et al., 2021).

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This research is delimited in time as well. It examines views related to the regulations
and practices governing GCTs over the last decade. Because these therapies are so novel, their
development was restricted mainly to the basic research environment prior to this period.
Further, most of the regulatory guidances for gene and cell therapy products have only been
introduced in the last five years (FDA, 2022a, Lapteva et al., 2020). It is also likely that the
current environment will change markedly in the future. The more than 200 clinical trials on
GCT therapies currently in progress (Brennan, 2020) will undoubtedly result in new insights and
approaches that will change the regulatory expectations in the future. Thus, the results presented
here cannot predict the regulatory CMC environment prospectively because CMC regulations
almost certainly will change as technologies advance and best practices become hardened into
requirements.
This study was delimited further to practices and views related to CMC rather than other
areas of industry affected by shortened and disrupted timelines, such as those associated with
safety or efficacy concerns that might be identified during clinical development (Yang et al.,
2022). CMC challenges constrain CMC experts working under the pressures of accelerated
clinical trial pathways by shortening the time available to “get right” the sourcing, development
of methods, and validation needed to assure consistent manufacturing processes (Gee, 2018).
However, those same CMC constraints impact the work of others, including the sponsors or
biopharmaceutical partners with whom they are collaborating. Thus, the scope was relaxed to
permit the responses of a wider cross-section of job functions. Different CMC experts may
participate in only certain aspects of CMC activities and might not be able to answer all the
questions related to specific types of activities, such as participation in due diligence, for
example. Nonetheless, it was important to delimit the surveyed population to CMC

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professionals who were engaged in regulatory aspects of CMC, such as process development,
analytical sciences, quality operations, and CMC regulatory affairs.
To assure that responses would be sufficiently insightful, the surveyed population was
further restricted to professionals who had at least two years of industry experience at mid to
senior levels within biotech/pharmaceutical companies of different sizes. This group of experts
is relatively small and hard to identify, but appropriate expertise was needed to ensure that a
deep understanding could be gained from their specialized experiences. This objective was
achieved and reflected in the profiles of the respondents. More than half had senior positions at
or above the Director level across a broad range of CMC functional areas. Nearly 90% had direct
experience with gene and cell therapies as well as similarly complex biologics such as
monoclonal antibodies. As part of their professional responsibilities, it was assumed that this
sample would be well-versed in the current U.S. regulations. Thus, the surveyed participants
would be well-positioned to provide insight into the adequacy of the regulations as well as the
challenges with the CMC management.
Another delimitation was placed on the study by choosing a singular framework to
determine the scope of the study. The implementation framework used to focus the survey
assured that a particular set of challenges could then be studied systematically and in some detail.
In the past, implementation frameworks have been used in medicine, psychology, and education
to evaluate evidence-based approaches and applications as those initiatives transition from
research to practice (Fixsen et al., 2005, Fixsen et al., 2009, Soicher et al., 2020). As a result,
however, the survey does not include questions on other aspects, such as the effects of merging
operations on hiring practices or detailed procedural aspects of CMC.

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5.2.2 Limitations
Several potential limitations were identified that might threaten the validity of this
research, but none more than the need to engage in a sufficient group of CMC experts with
experience in the narrow field on which this study was focused (Zuidgeest et al., 2011). Two
aspects were of particular concern. One was the relatively small number and size of many
companies in this field (Development, 2020). The other was the ability to find and engage
respondents who were co-developing advanced therapies and integrating CMC operations.
Mergers and joint ventures are known to be common between companies that are developing
advanced therapies (Alvaro et al., 2020, Weintraub, 2021). However, many of these companies
do not have a single commercialized product, and so can be hard to identify. As of February
2020, only nine cell or gene therapy products had been approved in the United States; however,
three hundred sixty-two (362) are still in clinical development and could have experts who have
faced the kinds of challenges explored here (Development, 2020). Thus, individuals who
manage their regulatory CMC strategies are difficult to find by using conventional methods such
as mining the regulatory and commercial documents publicly available to find their expertise.
In addition, CMC experts from small companies often do not present at seminars and
conferences where it might be possible to meet them in person. Often, in early stages, they are
reluctant to share their technologies and experiences with others to preserve competitive
advantage and intellectual property rights (Hanna et al., 2001). Instead, it was necessary to use a
variety of purposive approaches, including personal contacts, snowball methods, and analysis of
regulatory contacts in clinicaltrials.gov or the professional database, LinkedIn. These methods,
which have proven successful for others (Naderifar et al., 2017, Leighton et al., 2021), were able
to yield an initial distribution list of 124 individuals, felt to be sufficient for an exploratory study.
Further, over three-quarters of these individuals had more than 10 years of experience in relevant

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job functions. However, this does not guarantee that I was able to sample evenly from eligible
companies because companies at earlier stages of product development are likely to be
underrepresented in most databases and membership lists. Further some individuals may be
missed if they do not have the professional descriptors in their LinkedIn profiles that match the
search terms used to find potential participants.
Additional concerns included the likelihood that some potential participants might not
participate. First, the targeted participants may not have received the invitation. Electronic
survey invitations can be filtered by companies to safeguard security and reduce phishing
intrusions (Saleh and Bista, 2017). Further, the individual may no longer use the email address
to which the invitation was sent. The type of employees targeted here are in high demand and
often move from one company to another. It is rare that a company would forward the emails of
the former employee to a new email address after employment terminates. Research has also
shown that most individuals have more than one email address; alternate email addresses may be
inactive or unattended for extended periods (Saleh and Bista, 2017).
Second, not all potential participants who receive an invitation will accept it. Some
potential participants might consider themselves unqualified to complete the survey. Others are
very busy in their professional roles, so may be unavailable or distracted. Even if the potential
participant has the time, he or she may only choose to respond to a survey if the research is
aligned with their current interests and is not prohibited by their employer (Baruch, 1999). In
most cases, individuals surveyed here were employed by companies where intellectual property
needs to remain confidential, so that may sway their decision to decline for fear of disclosing
proprietary information. Despite these possible limitations to participation, a 55% response rate
was obtained. This rate is similar to average response rates of 53%, typical for academic studies,

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and is consistent with historical trends for academic research (Baruch and Holtom, 2008, Saleh
and Bista, 2017).
Not only is it important to recruit qualified respondents, but also to ensure that the
individuals do not drop out of the survey prematurely. Several approaches were used to improve
the likelihood that respondents would complete the survey. These included restricting the
number of questions, using rating scales rather than requiring text responses for most questions,
and paying careful attention to the face validity by using focus group (Moy and Murphy, 2016,
Liu and Wronski, 2018, PRC, 2022). In addition, the survey was administered through an
efficient electronic dissemination tool that permitted respondents to complete the survey at their
convenience and provided tardy respondents with reminders. These approaches appeared to
contribute to a completion rate of 79%, a rate surprisingly high given the often-difficult nature of
the questions that were asked of these specialists.
One aspect that was unexpected at the beginning of this study, however, was the
relatively high proportion of respondents in companies that merged their business operations but
not their CMC operations. From the extensive discussions of mergers amongst these types of
companies in the business literature, one might think that the ventures would be more likely to
merge their CMC operations to reduce production costs (Gascón et al., 2017, Madsen and Wu,
2016). However, about half of the mergers or joint ventures were constructed in such a way that
CMC operations remained separate. This provided an opportunity to compare the viewpoints of
the two subgroups. However, it did result in fewer participants who could report on the
challenges faced by newly merged CMC operations. As suggested by Litman and colleagues,
quality is often determined not by the absolute number of participants but by the homogeneity
and quality of the data that they provide (Marshall and Rossman, 2014, PRC, 2022, Moss and

98
Litman, 2022). In this case, the participants were all professionals with a strong familiarity with
the strengths and weaknesses of collaborations, mergers, or acquisitions. Therefore, having more
than 20 answers to questions was considered sufficient to reach a point of saturation where little
added insight was considered to be likely (Saunders et al., 2018). In fact, it might have been
difficult to find many more respondents with the required experience, given the relatively small
numbers of companies with commercialized or well-developed GCT therapies.
5.3 Discussion of Results
The current study is certainly not the first to focus attention on how to develop CMC
strategies that can accelerate manufacturing. As discussed in Chapter 2, CMC delays have been
recognized by health authorities globally as a hurdle that can limit access to much-needed and
transformational medical products. Organizations such as FDA and EMA have collected
extensive information as they review regulatory submissions for a range of drugs that they can
use to inform CMC requirements for breakthrough products. Academicians and industry experts
have also conducted research related to the improvement of CMC methods for gene and cell
therapies (Dye, 2014, Dye et al., 2015, Dye et al., 2016, Heidaran, 2017, Vatsan, 2017, Shen,
2017, Cauchon et al., 2019, Geigert, 2019, Lennard, 2019, CASSS, Levy, 2020, Boyle, 2020,
Gutierrez et al., 2020). However, this previous work dealt primarily with products already well-
advanced in their development cycles and was directed at the specifics of manufacturing and
testing methods. That research identified several impediments to manufacturability but did not
provide specific insight into the unique challenges associated with companies collaborating
across more than one CMC group. The results of this survey shed light on this set of concerns by
looking step by step, from exploration, through installation, to implementation, at the way that

99
companies reorganize their CMC operations as they merge or enter a collaborative venture. The
following discussion considers the findings by following this same stepwise path.
5.3.1 Exploration
The goal of exploration is to investigate options and determine operational readiness for a
new collaborative venture. During this phase, the partnering companies will identify cost and
resource needs, apportion some aspects of responsibility, and modify their regulatory strategy to
meet the requirements and expectations of the FDA. The first part of this process is often
carried out even before two companies announce a significant new collaboration or acquisition,
as they conduct their due diligence (Rhodes et al., 2003).
5.3.1.1 Due Diligence
During this stage, the partnering or merging companies will determine whether resources
are sufficient to move a promising product toward commercialization. An important requirement
is to assure that cGMP-grade product can be produced in sufficient quantities. In some cases the
joint ventures are even put into place specifically to assure that the product can be manufactured
successfully by creating synergies and efficiencies that capitalize on existing capabilities of the
two partners (Werling et al., 2009, Kessel and Frank, 2007, Schweizer, 2005, Shepherd, 2018).
Thus, one might expect that due diligence activities would focus on the relative roles and
production capabilities of each partner to blend them effectively. However, it can be difficult to
explore the capabilities of a potential partner before the contracts have even been executed.
Negotiations at this stage may be fragile (Garcia, 2007), so diligence activities are closely held to
preserve some level of confidentiality. Many individuals at the negotiating companies may then
be unaware that negotiations are taking place. Nevertheless, a third of respondents in this survey

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had been involved in due diligence activities prior to integrating CMC operations and could
therefore provide insight into the nature of that process.
One aspect of due diligence that appeared to be important to most respondents was the
assessment of manufacturing capabilities, underlining the centrality of manufacturing as part of
many alliances. It is reflected in the findings that most respondents ranked the assessment of
manufacturing infrastructure and CMC validations as important to their due diligence teams.
That is not to say that the two activities were ranked equally. In this relatively small sample,
manufacturing infrastructure was more often viewed as “very important” and plans for
validations as “somewhat important.” The difference is consistent with previous reports that
identify a focus of due diligence on the sufficiency of infrastructure and staffing as an immediate
concern (Data-Room, 2021). Planning steps for logistical activities such as validation, while
important, might be regarded by the due diligence teams as activities that could be left until the
installation phase, after contracts have been signed.
5.3.1.2 Organizational Culture
Another area that is known to be important when two companies merge is the
compatibility of their cultures. Incompatible culture can be a key driver that will cause valuable
individuals to leave their positions after a merger or acquisition has been announced (Fernandes
and Miller, 2009). It is considered by many as a differentiator when attracting and retaining
talent, especially when the company is undergoing a merger or has acquired a smaller firm
(Gildner and Radford, 2018). It is, therefore, dangerous to ignore the importance of culture in an
environment in which it is difficult to attract specialized talent. However, Bain identified that
culture is often not an area of focus during due diligence (Bain, 2011). Her observations are
consistent with a dichotomy seen in the results; about half of respondents who were involved in

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due diligence reported that culture was very important to the due diligence teams, but a similar
number found that it was not important.
The modest focus on culture does not mean, however, that companies are insensitive to
the need to attract and retain talent. A compelling observation was the high level of importance
assigned to the training and retention of personnel, even at the stage of due diligence; “retaining
key talent” as well as “redefining roles and responsibilities and reducing staff redundancy” were
ranked as the top concerns. Similar concerns about shortfalls in capable expertise have been
expressed recently in other specialized areas of drug development, such as biocompatibility
(Yartzoff, 2022). Further, results in this study are consistent with the broader observations of
educators that an insufficient talent pipeline exists for individuals with regulatory capabilities
(Richmond and Church, 2020). Finding individuals with a specialized knowledge of CMC as
well as a working knowledge of advanced therapies is doubly difficult and makes the task of
replacing lost talent more challenging (Lynch, 2019, Randstad, 2021).
5.3.1.3 Decision Making
Once a collaborative relationship has been established, attention typically turns to
assessing whether the partnering organizations have enough resources and a clear division of
labor for their important near-term projects. The impression is often gained from the literature
that the acquiring company will “call the shots” in that new collaboration, merger, or acquisition
(Schweizer, 2005). In this study, respondents mostly agreed that the larger or acquiring
company took the lead for certain types of operations. For example, it was typically reported to
play the dominant role in “meeting with FDA to align expectations” and “planning CMC
milestones.” Such an allocation of responsibility is not unexpected; as previously identified by
Grabowski and colleagues, the acquiring company generally has considerably more experience

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with regulatory activities and interactions (Grabowski and Kyle, 2008). Further, acquired
biotechnology companies with the “know-how” to develop novel technologies typically depend
on the resources from the larger pharmaceutical company to ensure needed manufacturing
infrastructure at a commercial scale. The smaller companies also need the distribution networks
and sales forces already developed by the larger partner to manage the hurdles associated with
commercialization (Tsai and Erickson, 2006, Shepherd, 2018). Additionally, a dominant role
seems appropriate for activities that will require a significant investment of funds, as noted by
Danzon (Danzon et al., 2007).
However, the acquiring or parent company may not dominate other types of activities,
such as deciding how to distribute resources or encourage innovation. For these activities, the
two parties appeared to have more equal roles. Acquisitions or partnerships frequently happen
when a smaller company with specialized intellectual property and innovative products can fill
the pipeline of a larger organization. Their specialized expertise, identified by Rafferty as
“knowledge keeps,” can make the acquired company a better judge of what is going to be needed
to execute CMC activities effectively and efficiently (Rafferty, 2007, FDA, 2022b). This kind of
relationship has been described in some detail by analyses of the acquisition of Genentech by
Roche, for example. At the time of acquisition, Roche vowed to give Genentech more
independence and flexibility in its decision-making because “Genentech’s creative culture and
rigorous science have been seen as essential to its ongoing success in producing novel
medicines” (Hayden, 2009). Genentech’s integration exemplifies a “preservation approach”
characterized by high autonomy and low interdependence of the acquired company. That type of
more limited integration can preserve the smaller company’s innovative way of doing business
(Haspeslagh and Jemison, 1991).

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5.3.2 Installation
Once contracts have been signed and a decision has been made to go forward, the newly
integrated organization moves to the stage of installation. The installation stage is critical to
secure and develop the resources needed to establish an effective approach that will prepare the
newly configured organization for implementation (Bertram et al., 2015). At this stage, staff and
leaders become more knowledgeable about the CMC requirements and work together in the
planning process. Manufacturing specifications and process capabilities are defined. Product
knowledge must then be disseminated to key CMC stakeholders across sites, so decisions will be
made about the roles and responsibilities with the respective collaborating partners (Kelly et al.,
2020).
5.3.2.1 Technology Transfer and Personnel Integration
Staffing decisions become particularly important during installation because the two
organizations may now have two individuals but only need one to carry out a particular job
function. To reduce these redundancies, some individuals may be laid off, and others may find
that their roles will change. In the provocative view of Cullen, “When companies enter into a
merger, employee loyalty is of the lowest priority in their considerations” (Cullen, 2015).
During the transition, employees of the acquired company typically experience uncertainty about
their current role in the newly combined company. They may even have unrealistic expectations
of the integration process by expressing inappropriate optimism or pessimism. At the same time,
employees of the acquiring company may feel uncertain about their new roles and exhibit a
range of positive or negative reactions (Rafferty, 2007). Most acquiring companies understand
that employees may choose to pursue opportunities outside the organization after a new
organizational structure is announced. It should come as no surprise to find that concerns about

104
“retaining employees” and “integrating company culture” appeared in this survey to increase as
the integrated CMC groups began to work together and the theoretical challenges of merging
cultures become real.
A large cultural gap often exists between acquiring and acquired companies in the
biotechnology industry. Small companies have often used entrepreneurial skills to progress
organically to the point of acquisition (Nahavandi and Malekzadeh, 1988, Barney, 1986).
However, the acquiring company, which is often a large multinational organization, may have a
more structured and bureaucratic system (Schweizer, 2005). A shift in culture toward that of a
large company can damage the entrepreneurial spirit and flexible nature of the smaller one.
Employees from the small company may find that the new restrictions are uncomfortable and
may leave, taking with them some of the “know-how and knowledge transfer” of specialized
technologies on which further development may depend (Kogut and Zander, 1992). Such
challenges were seen, for example, when Sandoz (Novartis) acquired a smaller company,
Genetic Therapy (GTI):
Nearly everybody (of the senior management at GTI) left, because they (Novartis)
no longer looked for a local management team. We were used to make common
decisions, taking much more risk and common responsibility. And they no longer
looked at the local management to really do that so much. (Schweizer, 2005)
Retaining key talent is an integral part of preserving the “know-how and knowledge
transfer” as manufacturing groups work to operationalize tech transfers. However, this challenge
appears to be addressed insufficiently by many companies represented in this research;
respondents in this study were frequently dissatisfied with the new staffing arrangements that
were considered “inadequate.” Such problems can occur because the new organization tries to
rationalize costs by reducing the workforce. For example, Schweizer identified that a
consolidation of Novartis and SyStemix in 2000 reduced staffing by 50% (Schweizer, 2005).

105
However, losses can be compounded when personnel leave in larger numbers than had been
anticipated by the staffing consolidation. As stated by two respondents.
There was disagreement or dissatisfaction with the newly combined companies,
some of the talent retained didn't want to stay and some of the people dismissed
ended up being more knowledgeable than those let go. There was quite a bit of
knowledge loss during the transition period because some key talent was
dismissed and those in what were purported to be "key" roles were retained, yet
those individuals didn't have good understanding of the technical details of their
role.(Schweizer, 2005)

The availability of resources at the parent company to take on the work resulting
from the acquisition was very inadequate.(Schweizer, 2005)
5.3.2.2 Roles and Responsibilities
It is important not only to retain individuals during the installation phase but also to
redefine their roles (Rose, 2021). To avoid delays and inefficiencies drug developers must
define clearly the allocation of responsibilities related to development and regulatory activities
and then ensure that these changes are communicated to colleagues, potential partners, and
health authorities (Tsokas et al.). This also seemed to be an area of weakness in the companies
surveyed here. Half of the respondents in this survey did not understand their roles within the
organizations and agreed that the “organizations had dissonant approaches when incorporating
ICH and FDA guidances.” Nevertheless, both strategic and tactical roles and responsibilities
must be clearly understood because these layers of activity are critical to ensuring success of the
program (Föller, 2002).
The types of partnerships studied here are usually developed to facilitate marketing
approval for a new product. Regulatory approval for an advanced therapy is known to be
difficult. Thus, it was not surprising to find that some activities related to meeting FDA
expectations were challenging for these companies. It was interesting to see the areas in which
problems were and were not seen. For example, most respondents seemed comfortable with the

106
clarity of the multiple regulations and guidances that FDA has published to inform the
development process. However, they faced difficulties when “developing CMC strategies for
submissions” and “setting phase appropriate validation requirements.” Their observations were
consistent with the view previously expressed by Gee that CMC can be the largest hurdle to gene
therapy approvals (Gee, 2018). FDA guidances to support early phase CMC activities are
relatively limited, so when operations merge, companies often attempt to implement their early-
to late-stage approaches without a clear understanding of FDA expectations (News-Medical,
2020, FDA, 2022c). Designing early- to late-stage regulatory strategies is vital to the success of
product development, yet balancing multiple factors that affect that strategy cannot be
accomplished with a one-size-fits-all model.
Planning how to demonstrate process and product comparability was another area of
significant challenges for the respondents in this study. These difficulties are consistent with
recent findings by Yang and colleagues, who examined the relative frequency of CMC-related
disruptions for GCTs in companies in phase III clinical trials between 2016 and 2021. They
noted that the most common causes of CMC regulatory deficiencies were problems
demonstrating comparability for clinical and commercial supply before or during those phase III
studies. (Yang et al., 2022).
Comparability assessments assume considerable importance when companies restructure
because they must be performed to justify changes or additions of manufacturing sites or
scale-up or -out of production to enhance productivity (Tate et al., 2017). If planning at this
phase is muddied by the merger of two entities with different levels of understanding, needed
testing may not be done, or mistakes may occur that delay the regulatory approval process. One
example of this problem can be seen from the experience of Bristol Myers Squibb after it

107
purchased Celgene and acquired a CAR-T-cell immunotherapy that had already been in co-
development with Bluebird Bio. The commercial launch of its CAR-T product, Abecma
TM
, was
delayed by almost a year when FDA issued a “refuse to file” letter requesting supplemental
information about the validations and controls for both its lentiviral-vector and drug-product
manufacturing processes (Bratulic, 2020, Dearment, 2020, Keown, 2021). This failure followed
previous delays in BLA approval for Bluebird Bio when FDA identified that it had provided
insufficient CMC data to prove “analytical comparability” as it transitioned from clinical-grade
to commercial-grade manufacturing of gene therapy, LentiGlobin™ (Tong, 2020).
Most respondents in this survey also found that “planning to demonstrate product
comparability” was the “most difficult” activity when aligning CMC strategies with the new
partner. Good planning depends on having appropriate processes and capable people. The
observations appear to underline the fact that insufficiencies in either processes or people can be
detrimental as groups integrate. Together they suggest that newly merged teams must not only
have a clear understanding of what regulators expect but also be able to build on the early stage
“know-how” of the partner that developed the novel technology to define the roles and
responsibilities for the implementing teams.
5.3.3 Initial Implementation
During initial implementation, the newly integrated organization attempts to use recently
learned skills and practices before fully integrating them into practice (AIRN, 2022). At this
stage, teams make their initial attempts, often described as pilot studies, to assess the
manufacturability of their product under the changed conditions. In this highly dynamic phase,
different approaches may be attempted to improve the process or to address areas that require

108
further development before the technology transfer is complete, to support the needed scale-up of
clinical and commercial manufacturing.
5.3.3.1 Pilot Studies
An area of importance during early implementation are pilot studies of operational
procedures and validation testing to gain more knowledge about the newly acquired technologies
(Junker et al., 2006). As one example, Fraser noted that Genentech experimented with methods
to scale up cell cultures for expansion in pilot studies, first with just a few cells in a test tube,
then expanded to trillions of cells, before transfer into several large 1,000-liter tanks. These bulk
products could then be tested for their critical quality attributes (Fraser, 2016). However, he
quoted two Genentech scientists who observed that much could go wrong in these early studies.
“There are a lot of challenges going from small-scale to large-scale production, and cell
cultures in particular have many variables that can go wrong.” (Fraser, 2016)
“Sometimes the cells just don’t grow, the cultures get contaminated, or we have to figure
out the best ways to feed the cells to keep them happy.” (Fraser, 2016)
Part of the challenge of early implementation is assuring that personnel become familiar
with new procedures. This was an aspect of implementation that did not seem to trouble many of
the respondents. In fact, most identified that training was “as expected” during initial
implementation. However, their views seem to be at odds with observations by most of the same
respondents that “sharing knowledge across sites” was worse than expected, and one-third
identified that “communicating across sites” was worse than expected. The consequences of this
problem were captured well by the comment of one respondent who linked the lack of
communication and difficulties with retaining talent. “Piecemeal communication, or lack thereof
makes merging feel disjointed, lowers morale, and hastens key departures”.

109
Another respondent suggested that the premature loss of knowledgeable personnel made
it difficult to move forward during the early implementation. “Overlap in roles and
responsibilities, although inefficient, could have been more valuable in knowledge sharing and
teamwork during the initial time period.”
Transparent communication and information sharing are often considered to be critical to
limit the mistrust that can be caused by errors in implementing joint activities. The observations
here resonate with the findings of researchers in the consulting firm Watson Wyatt, who found
that most top executives from 190 companies globally rated “communication, retention of key
talent, and integration of corporate cultures” as “critical” activities in integrations. They further
recognized that these activities became more vulnerable with increasing numbers of
collaborators and target acquisitions (Kay and Shelton, 2000). Results also corroborate previous
findings that managing communication plays a critical role in the process of change (Schuler and
Jackson, 2001).
5.3.3.2 Disruptions and Delays
Results from this study were helpful to identify factors that were seen to be responsible
for delays in regulatory progress. For example, nearly half of the respondents identified that
disagreements within the leadership team were another cause of delays. Their views were
consistent with those of Schuler and colleagues, who concluded after surveying 123 pharma
companies that absent or unclear leadership was an important factor that could cause uncertainty,
lack of direction, stalled product development, and postponement of important decisions
(Schuler and Jackson, 2001). Surprisingly, however, relatively few respondents implicated
“culture clashes,” even though many had acknowledged its indirect effect on personnel retention.
This finding differs from the conclusions of Weghoeft that culture integration was a main cause

110
of failures during mergers and acquisitions because of its ability to affect the retention of key
talent (Weghoeft, 2021).
A significant problem that appeared to persist as implementation evolved was a
continuing challenge of assembling and maintaining functional teams. The beginning stages of
operational integration can be the point when some teams work together for the first time. When
problems arise during this critical phase, key stakeholders who chose initially to stay with the
merged organization may reassess their participation. Most respondents identified that “retaining
employees” continued to be very or somewhat challenging. More than half of the respondents
agreed that “staffing was insufficient,” and nearly as many agreed that “key personnel had left”
in the early stages of implementation. Because key talent is often lost at this stage, it stands to
reason that most respondents would find that “assuring knowledge transfer between parties” and
“satisfying regulatory expectations” were very or somewhat challenging. These results are
reflected in the comments of Table 8 from two respondents related to maintaining know-how and
transferring knowledge, respectively:
The company made some poor decisions related to dismissing staff. Many of the
Sr leaders at the site were dismissed as part of the acquisition and they retained
most of the strategic understanding of the decisions that were made. Many of the
people retained knew what decisions were made but they didn't have a clear
understanding of "why" the decision was made.

Dedicate resources from the parent company to integrate the CMC operational
integrations instead of just adding the workload on top of the existing resource
constraints.

Challenges with communication and knowledge exchange also appear to be a reason why
respondents identified that activities related to “technology transfer” and “transfer of product
knowledge” were most delayed by the reorganization, from 1-12 months or more. Results here
are consistent with the delays seen when Breyanzi
®
, a cancer cell therapy, was first developed at

111
Juno Therapeutics and then transferred to Celgene. In 2017, Juno Therapeutics targeted FDA
approval of the drug by 2018, but regulatory delays held up its progress as the sequential
acquisition caused the development program to be transferred first to Celgene and then to Bristol
Myers-Squibb (Pagliarulo and Fidler, 2021). FDA eventually accepted the company’s BLA in
August 2020, but the approval was further delayed by challenges to the acceptance criteria for its
initial commercial drug-product specifications. The product finally achieved its approval in
February 2021, nearly three years after commercialization had been projected (Sagonowsky,
2021, FDA, 2020i).
5.3.4 Full Implementation
During full implementation, innovation occurs as new methods become integrated into
the organization’s practices and procedures. Over time, innovation becomes a standardized
practice, and a new state of “business as usual” takes its place (Faggin, 1985). At this stage,
routine practices and data reviews are subject to quality oversight, and improvement cycles
occur. Further, this is a time in which staffing may increase, and more routine personnel
turnover takes place (NIRN, 2022). The time it takes to move from initial to full implementation
will vary depending upon the complexity of new programs, the availability of resources, and the
pace with which integrated operations can be developed.
5.3.4.1 Standardizing and Improving CMC Operations
In this continuously evolving phase, organizations adopt standardized practices and
lessons learned from pilot studies to assure sustainable delivery of clinical and marketed
products. However, significant issues with culture clashes and maintaining critical technical
knowledge appeared to occur even at this late stage for many companies. It comes as no surprise
that most respondents continued to identify “aligning culture” and “training staff” as very or

112
somewhat challenging well into full implementation, as teams continued to struggle with
“aligning operational expectations.” It is not unusual for teams to find it difficult to implement
necessary training as key talent continues to depart or transfer to other areas of responsibility;
part of successful implementation is having a clear strategy for ensuring operational expectations
are met in the face of personnel turnover (2022). This can be especially important for newly
evolving technologies where the goal to routinize CMC operations is never fully possible; even
during this phase, improvements to quasi-standardized practices and procedures are often
needed.
Because companies must fine-tune regulatory CMC strategies well into the
implementation phase, good decision-making capabilities are important to assure the success of
regulatory approvals. More than half of the respondents in this survey continued to identify that
“aligning expectations with FDA requirements” was very or somewhat challenging. As
previously identified by Grabowski and colleagues and discussed above, most regulatory
expertise resides in the parent company, which then plays a larger role in strategy development
(Grabowski and Kyle, 2008). However, most respondents had views that agreed with one
individual who “felt the acquired or supporting organization should have more decision-making
opportunities for developing regulatory CMC strategies.” These results are consistent with
findings reported by Smith and colleagues, who examined the transactions and investments made
by approximately 50 large pharma companies for therapeutics in CAR-T, gene therapy, cell
therapy, and gene editing sector between 2010 and 2016. They found that the smaller partner
can bring both development and commercial expertise to the table in an ideal partnership (Smith
et al., 2018). Given these results, companies would appear wise to include the smaller company

113
in important decisions as the two companies attempt to put into place their regulatory CMC
strategies.
The ability to predict and respond to regulatory requirements is also challenged by the
evolving nature of those requirements. Guidance documents that represent FDA's current
thinking are not inviolate; sponsors can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations (FDA, 2022e). In this study, most of the
respondents agreed that the available FDA guidances were mostly sufficient to inform
expectations regarding product comparability after a merger or acquisition. However, some
reservations were expressed about the level of oversight exercised by the regulators after a
merger or partnership has taken place. Respondents here more commonly agreed than disagreed
that “FDA should require manufacturing inspections for commercialized products after a merger
or acquisition.” Together these results resonate with comments in Table 9 from one respondent
related to site inspections of a newly combined organization and what FDA can do better.
I don't necessarily believe that the FDA needs to perform an inspection directly
after the integration, but perhaps at the next biannual inspection they should do a
more thorough dive into the operations and quality systems of the new (combined)
organization.

Such oversight is, of course, important from a patient safety perspective. However, it
could also reduce the likelihood of unpleasant surprises that have been seen in the past when
FDA inspections associated with marketing review threaten to derail commercialization.
Deficiencies found during manufacturing site inspections can then result in refuse-to-file letters,
complete response letters, or Form 483 issues that would delay product approvals (Yang et al.,
2022).

114
Respondents also provided suggestions on what FDA might do better to support
companies undergoing operational integrations. As noted in Table 9, one respondent commented
that FDA could be more engaged by reviewing pre- and post-merger activities.
A review of the quality systems that have changed as a result of the merger. If
previous inspections focused on Company X, which was then merged with
Company Y, a review of any changes to quality systems with respect to the
programs affected by the merger should be executed to ensure product safety.

Another suggested that FDA might be more engaged by allowing companies to repeat
meetings that took place with the agency in the past so that the post-merger leadership could be
fully informed about regulatory expectations.
Allow more/repeat meetings, e.g., if End of Phase (EOP 1) meeting already
happen prior to merger, should allow a follow-up EOP1 meeting post- merger.
Approaches changes across organizations and leadership so difficult to execute
something you were not part of.

All these observations seem to suggest that companies would welcome more rather than
less engagement with regulators soon after integration has taken place to assure that integrations
do not face problems that ultimately could drag down the ability to market the product and to
keep patients safe.
5.3.5 Sustainability
Fixsen’s Implementation Framework suggests that sustainability is an ongoing goal of all
stages in the implementation cascade that typically can be achieved within 2 to 4 years after
establishing a fully implemented, evidence-based program (Fixsen et al., 2005). However, for
advanced therapies, what defines sustainability is difficult to determine. The regulatory CMC
strategies put into place prior to commercialization continue to evolve even after
commercialization and scale-up, and these changes could present new hurdles (Elverum and
Whitman, 2020). If some level of sustainability is to be achieved, it will be dependent on having

115
effective systems to manage changing regulatory requirements and CMC practices, especially
practices to assure comparability of the changed products. This hurdle is not yet well managed;
nearly half of respondents here, for example, identified that “demonstrating product consistency
to satisfy FDA expectations” was very or somewhat challenging even after integrations were
well advanced. Their views are consistent with the results of Yang and colleagues, who found
that 39 of GCTs entering phase III studies between 2016 to 2021 were delayed due to CMC,
safety, and efficacy issues; comparability issues stood at the top of the list of factors responsible
for the delays (Yang et al., 2022).
5.4 Conclusions
The results presented here provide insight into certain areas of challenge that can arise
when accelerated timelines and complicated production methodologies are further complicated
by mergers and other forms of operational integration. These challenges are not trivial. They
contribute to the problems faced by GCT companies when they try to meet FDA’s CMC
expectations and which compromise timely regulatory approvals. Regulatory agencies must
continue to recognize the challenges faced by companies making advanced therapies as the
companies struggle with current regulations and standards mostly tailored to the needs of more
conventional and well-characterized drugs and biologic products. Results suggest that more
guidance from regulators about expectations and standards in certain areas, such as
comparability and validations, are needed as these evolve, because this would help to reduce
miscommunications between acquiring and acquired teams. Further, more communication, not
only through guidance documents but also training programs and conference participation, could
help to circumvent the reticence of some companies surveyed here to interact one-on-one with
what they might regard as “regulatory police.” However, the problems of integration cannot be

116
solved simply by asking FDA to provide more CMC regulatory recommendations if large
changes in personnel, processes, and cultures are key problems that affect the development of
greater CMC efficiencies. These types of issues would appear to be useful targets on which
companies could focus to improve the success of their CMC integrations.
The cost of developing new advanced therapies is so high that small companies cannot
typically develop its products fully without the help of a larger partner. As this study suggests,
much of the decision-making is assumed by the acquiring company, but this may disenfranchise
key talent in the smaller company. A hybrid approach that empowers the collaborating partner
by offering more decision-making opportunities might help to assure the retention of the talent
and know-how that initially made the acquired company an attractive partner. The larger
company may be concerned that regulators would not accept innovative models for GCTs that
are sometimes seen as advantageous by smaller companies that are willing to take more
regulatory risk with alternative testing approaches. Nevertheless, this set of concerns is only a
subset of decisions that are made daily about product development. It seems clear from the
results that some of the challenges faced during integration can be related to missteps in
communication and leadership. These might be mitigated by working toward a more
collaborative approach that might educate both parties in the partnership about how to address
regulatory and logistical hurdles.
Findings also revealed large and persistent challenges related to personnel retention and
knowledge preservation. To manage these problematic areas, this study suggests that some
companies may play too little attention to the importance of integrating cultures, a foundational
factor correlated with the retention of talent who can assure the transfer of drug development
know-how of novel technologies. The earliest stage of due diligence can be a time when

117
companies can consider the impact of merging cultures and teams, so that attention can be paid
to preventing the large losses of personnel that often occur after a merger is announced. Further,
the findings that these problems persist throughout the implementation cycle suggests the need
for a more holistic and life-cycle approach to personnel management that can soften the loss of
key personnel at later stages of integration. Many companies continue to use models for of due
diligence and integration that they learned from previous experience with well-characterized
drugs or biologics. It would be interesting to investigate in future research whether the
interactions between these large and small companies are able to drive more innovative methods
with respect to personnel retention and decision-sharing or whether conservative methods
continue to dominate the approaches as CMC operations integrate.

118
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Appendix A. Survey Questions

Start of Block: Demographics, Exploration, Installation, Implementation, & Full
Implementation

Q1 Thank you for taking the time to participate in my research!

The purpose of this study is to identify views and challenges related to the implementation of
regulatory CMC strategies when companies acquire, merge or co-develop novel
biopharmaceutical technologies. If you have been involved with more than one such
restructuring program, please answer the following questions with respect to the program that
has centered most directly on your CMC operations. Please feel free to skip questions if they are
not appropriate for you. Your responses to this survey will remain confidential.

Q2 When thinking about the case on which you will base your CMC feedback, which of the
following best describes that company?
o Small Molecules / Synthetic Peptides
o Biologics (e.g. mAbs and Vaccines)
o Advanced Therapies (e.g. Gene and Cell Therapies)
o No CMC experience
o Other (Please Specify) ________________________________________________

Skip To: End of Survey If When thinking about the case on which you will base your CMC
feedback, which of the following bes... = No CMC experience

138
Q3 When thinking about the case on which you will base your CMC feedback, which of the
following best describes the type of operational integrations in which you have been involved?
o Collaboration / Partnership / Joint Venture
o Acquisition as Acquirer
o Acquisition as Acquired
o None of the Above

Skip To: End of Survey If When thinking about the case on which you will base your CMC
feedback, which of the following bes... = None of the Above

Q4 How many years of drug development experience do you have?
o < 2 Years
o 2 to 5 Years
o 6 to 10 Years
o > 10 Years

Q5 How many people does your company employ?
o < 200
o 201 to 500
o 501 to 5000
o > 5000

139
Q6 Which department best describes your functional area?
o Regulatory Affairs CMC
o Quality Assurance / Compliance
o Quality Control / Manufacturing
o Materials Management / Supply Chain
o Analytical Development / Process Development
o Other (Please Specify) ________________________________________________

Q7 Which best describes your current position?
o Vice President / Executive
o Director / Sr. Director
o Manager / Sr. Manager
o Scientist / Researcher
o Analyst / Associate
o Other (Please Specify) ________________________________________________

Q8 Did your collaboration/acquisition/merger keep the CMC operations of the two groups
completely independent?
o Yes
o No

Skip To: Q11 If Did your collaboration/acquisition/merger keep the CMC operations of the two
groups completely in... = No

140
Skip To: Q9 If Did your collaboration/acquisition/merger keep the CMC operations of the two
groups completely in... = Yes

Q9 What in your opinion are the pros and cons of not merging CMC operations and working as
isolated organizations?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

Q10 In retrospect how do you feel your CMC operational organizations should have integrated?
o Maintained as an independent organization
o Merged organizations
o Other (Please specify) ________________________________________________

Skip To: Q39 If In retrospect how do you feel your CMC operational organizations should have
integrated? = Maintained as an independent organization
Skip To: Q39 If In retrospect how do you feel your CMC operational organizations should have
integrated? = Merged organizations
Skip To: Q39 If In retrospect how do you feel your CMC operational organizations should have
integrated? = Other (Please specify)

141
Q11 Overall, how would you rate the degree of challenge associated with each of the following
activities throughout the process of integrating two (or more) CMC groups?

Very
Challenging
Somewhat
Challenging
Not Challenging Not Sure
Training staff
o o o o
Updating SOPs
o o o o
Generating
reproducible
data
o o o o
Aligning
expectations
with FDA
requirements
o o o o
Aligning
operational
expectations
o o o o
Aligning
organizational
culture
o o o o

142
Q12 As your organization began integrating operations, how concerned were you that challenges
in the following areas might delay FDA approvals?

Very
Concerned
Somewhat
Concerned
Not
Concerned
Not Sure
Not
Applicable
Aligning
documentation
o o o o o
Integrating
company
culture
o o o o o
Retaining
employees
o o o o o
Integrating
quality
systems
o o o o o
Meshing
regulatory
CMC
strategies
o o o o o
Transferring
technologies
o o o o o
Validating
manufacturing
processes
o o o o o
Validating
analytical test
procedures
o o o o o
Setting
product
specifications
o o o o o
Passing site
Inspections
o o o o o

143
Q13 How challenging were the following CMC activities as your partnership/merger proceeded?

Very
Challenging
Somewhat
Challenging
Not Challenging Not Sure
Satisfying
regulatory
expectations
o o o o
Maintaining
product quality
o o o o
Assuring batch
lot
reproducibility
o o o o
Documenting
quality systems
o o o o
Retaining
employees
o o o o
Assuring
knowledge
transfer between
parties
o o o o
Assuring
manufacturing
success rates
o o o o
Working under
budget
constraints
o o o o

Q14 Were you involved in due diligence activities for the merger/acquisition?
o Yes
o No

Skip To: Q16 If Were you involved in due diligence activities for the merger/acquisition? = No

144
Q15 When due diligence was conducted as part of the integration, how much importance do you
think was placed on assessing the following aspects of CMC operations?

Very
Important
Somewhat
Important
Not
Important
Not Sure
Not
Applicable
Plans for
CMC
validations
o o o o o
Gap analysis
for CMC
strategies
o o o o o
Sufficiency of
manufacturing
site
infrastructure
o o o o o
Sufficiency of
documentation
for
development
history of
acquired
product
o o o o o
Sufficiency of
SOPs
o o o o o
Need to train
staff
o o o o o
Staffing
adequacy
o o o o o
Differences in
company
culture
o o o o o

145
Q16 How well matched are your companies in the following areas when it comes to decision
making?
Parent
Company
Stronger
Similar Collaborating
Company
Stronger

10 9 8 7 6 5 4 3 2 1 0

Encouraging innovation

Assuring adequate resources

Planning CMC milestones

Meeting with FDA to align expectations

Q17 When senior executives planned restructuring that merged CMC groups, which was most
important when considering the following? Please rank from (1 - Most Important) to (4 - Least
Important)
______ Retaining key talent
______ Reducing staffing redundancy
______ Redefining organizational roles and responsibilities
______ Integrating organizational culture

146
Q18 When your department prepared to merge operational CMC activities, how concerned
were you with the following aspects?
Very Concerned
Somewhat
Concerned
Not Concerned Not Sure
Retaining
employees
o o o o
Aligning SOPs
o o o o
Ensuring
successful
knowledge
transfer
o o o o
Assigning roles,
responsibilities
and
accountability
o o o o
Meeting
regulatory
expectations
o o o o
Meeting
timelines
o o o o

147
Q19 Once the CMC and Quality departments had been reconfigured, how easy was it to
align the following aspects of CMC strategy with the new partner?
Easy Difficult Most Difficult Not Sure
Following
regulatory
guidances
o o o o
Setting phase
appropriate
validation
requirements
o o o o
Agreeing on CMC
strategies for
submissions
o o o o
Planning to
demonstrate
product
comparability
o o o o
Choosing/working
with suppliers
o o o o

148
Q20 When the organizational teams began to work together, please rate whether you agree with
the following statements.

Agree
Neither Agree nor
Disagree
Disagree Cannot Answer
The organizations
had dissonant
approaches when
incorporating ICH
and FDA
guidances
o o o o
Both organizations
understood their
roles
o o o o
Both organizations
had sufficient
input to CMC gap
analyses
o o o o
Both organizations
had sufficient
input to phase
appropriate
validation
initiatives
o o o o
Both organizations
shared sufficiently
in decisions about
day-to-day
operations
o o o o
Both organizations
determined when
implementation
would begin
o o o o
Members from
both partners led
planning
initiatives
o o o o

149
Q21 As the manufacturing operations began to partner prior to implementing tech transfers,
please indicate your level of satisfaction to ensure that operational changes were adequate to
meet FDA expectations.
Very Satisfied Satisfied Not Satisfied Cannot Answer
Updates were
made to the
manufacturing
infrastructure
o o o o
Quality systems
procedures were
revised
o o o o
Side by side
training was
completed
o o o o
Sufficient
staffing was
made available
o o o o

Q22 If you have other concerns related to the early stages of CMC operational integrations,
please specify.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

150
Q23 Please indicate whether you agree with the following statements regarding the alignment of
the partnering groups.

Better than
Expected
As Expected
Worse than
Expected
Not Applicable
Communicating
across sites
o o o o
Funding
o o o o
Sharing
knowledge
across sites
o o o o
Aligning
documentation
o o o o
Agreeing on
regulatory CMC
filing strategies
o o o o
Training
o o o o
Maintaining
manufacturing
success rates
o o o o
Meeting
consistent
product quality
test results
o o o o

151
Q24 In your view, how successful were operational integrations in the following areas as you
carried out the first studies as a new partnership/team?
Very Successful
Somewhat
Successful
Not Successful Not Sure
CMC Technical
Operations
o o o o
Regulatory CMC
strategies
o o o o
Quality Systems
o o o o
Documentation/
SOPs
o o o o
Training
o o o o

Q25 When making initial changes to begin CMC operational integrations, what in retrospect do
you think could have been done differently to ensure a successful program?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

Page Break

152
Q26 How did the operational integration affect CMC staff during the earliest tech transfers?
Agree
Neither Agree
nor Disagree
Disagree Not Sure
Staff morale
decreased
o o o o
Key personnel
left
o o o o
Trust in
leadership
decreased
o o o o
Staffing was
insufficient
o o o o
Projects were
delayed by
staffing
shortfalls
o o o o

Q27 As new teams were developed, how effective was the new team in implementing the initial
plans effectively?
Very Effective
Somewhat
Effective
Not Effective Not Sure
Transfer of
Product
Knowledge
o o o o
Technology
Transfers
o o o o
Operational
Integrations
o o o o

153
Q28 When implementing the initial activities, did you have delays in achieve the targeted
milestones? If yes, how long was the delay?
No Delay 1-3 Months 3-12 Months >1 year
Cannot
Answer
Transfer of
Product
Knowledge
o o o o o
Technology
Transfers
o o o o o
Operational
Integrations
o o o o o

Q29 Did the following problems that might be associated with restructuring cause issues
that delayed your regulatory submissions?
No Delays Some Delays Refuse to File Cannot Answer
Disagreements
within leadership
o o o o
Culture clashes
o o o o
Insufficient
project
management
o o o o
Other (Please
Specify)
o o o o

154
Q30 Please indicate your level of agreement with the following statements related to regulatory
oversight during your operational integrations.
Agree
Neither Agree
nor Disagree
Disagree Not Sure
Insufficient FDA
guidance was
available on
assuring product
comparability
after a merger or
acquisition
o o o o
FDA should
require
manufacturing
inspections for
commercialized
products after a
merger or
acquisition
o o o o

Q31 Please provide comments on what else FDA might do better to provide support for CMC
operations as two departments are meshed.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

155
Q32 When working in a collaboration, partnership or joint venture, do you think the supporting
organization working with the sponsor should have more decision-making opportunities for
developing Regulatory CMC strategies?
o Yes
o No
o Not Sure

Q33 Were regulatory submissions for drug development programs successful in satisfying FDA
requirements after operational integrations had been completed?

Successful
without Delays
Successful with
Delays
Not Successful Cannot Answer
Clearance of
new INDs
o o o o
Clearance of
IND
amendments
o o o o
Marketing
application
approvals
o o o o
Marketing
application
supplements
o o o o
Post approval
commitments
o o o o
Other (Please
Specify)
o o o o

Q34 In your new way of conducting CMC operations, do you have any other challenges not
discussed above for which you might propose a better solution?
________________________________________________________________
________________________________________________________________

156
________________________________________________________________
________________________________________________________________
________________________________________________________________

Q35 In 2020, FDA issued guidance “Human Gene Therapy for Rare Diseases” to accelerate
CMC activities in order to address shortened clinical timelines for BLA submissions.

Please rate your level of implementation of the following when considering regulatory CMC
strategies.

Fully
Implemented
Somewhat
Implemented
Did Not
Implement
Cannot Answer
We leveraged
contents from
marketed products
by “Simplified
IND or cross-
referencing shared
CTD sections”
o o o o
We completed
early Process
Performance
Qualification PPQ
at Phase I
o o o o
We conducted late
stage
manufacturing
process
validations at
Phase I
o o o o
We conducted
testing validations
(including
potency) at Phase
I
o o o o

157
Q36 How did working with another company impact decision making for accelerating regulatory
CMC strategies?
o Aligned with FDA guidance to accelerate CMC activities
o Some adoption of FDA guidance to accelerate CMC activities
o Did not consider FDA guidance
o Not Sure

Q37 Did you have challenges in the following areas even after fully implementing a new CMC
operational organization?

Very
Challenging
Somewhat
Challenging
Not Challenging Not Sure
Demonstrating
product
consistency to
satisfy FDA
expectations
o o o o
Defining
regulatory CMC
strategies to
meet FDA
expectations
o o o o
Meeting sponsor
and partner
expectations
o o o o
Retaining
employees
o o o o

Q38 What advice might you give to organizations entering a new partnership/merger/acquisition
to assure successful integration?
________________________________________________________________
________________________________________________________________

158
________________________________________________________________
________________________________________________________________
________________________________________________________________

Q39 Based on your experience, what are the biggest CMC hurdles to overcome for timely
submissions to regulatory agencies?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

End of Block: Demographics, Exploration, Installation, Implementation, & Full
Implementation

Start of Block: Block 1

159
Appendix B. Survey Data
Q2 - When thinking about the case on which you will base your CMC feedback, which of
the following best describes that company?

# Answer % Count
1 Advanced Therapies (e.g. Gene and Cell Therapies) 43% 24
5 Biologics (e.g. mAbs and Vaccines) 45% 25
2 No CMC experience 4% 2
3 Other (Please Specify) 4% 2
4 Small Molecules / Synthetic Peptides 5% 3
Total 100% 56

Q2_3_TEXT - Other (Please Specify)
Other (Please Specify) - Text
both mAbs and ATMPs
ADCs (noncytotoxic payload)

160
Q3 - When thinking about the case on which you will base your CMC feedback, which of
the following best describes the type of operational integrations in which you have been
involved?

# Answer % Count
1 Collaboration / Partnership / Joint Venture 43.40% 23
3 Acquisition as Acquirer 22.64% 12
4 Acquisition as Acquired 24.53% 13
5 None of the Above 9.43% 5
Total 100% 53

161
Q4 - How many years of drug development experience do you have?

# Answer % Count
1 2 to 5 Years 2.22% 1
2 6 to 10 Years 17.78% 8
3 > 10 Years 77.78% 35
4 < 2 Years 2.22% 1
Total 100% 45

162
Q5 - How many people does your company employ?

# Answer % Count
1 < 200 30.43% 14
2 201 to 500 8.70% 4
3 501 to 5000 26.09% 12
4 > 5000 34.78% 16
Total 100% 46

163
Q6 - Which department best describes your functional area?

# Answer % Count
1 Regulatory Affairs CMC 10.87% 5
2 Quality Control / Manufacturing 19.57% 9
3 Analytical Development / Process Development 47.83% 22
8 Other (Please Specify) 15.22% 7
9 Materials Management / Supply Chain 2.17% 1
10 Quality Assurance / Compliance 4.35% 2
Total 100% 46

Q6_8_TEXT - Other (Please Specify)
Other (Please Specify) - Text
process development
I have been part of collaborations while contributing as the analytical SME (past, mAbs and
ADCs), the QC lead (Past, cell therapy), and as the QA lead (currently, mAbs)
CMC/Technical Operations (encompasses AFD/PD which collaborates with all the above
options)
Program management
Biologics drug product development, including formulation, device, and analytical
development.
Science and technology
Scientist, Tech Transfer

164
Q7 - Which best describes your current position?

# Answer % Count
1 Vice President / Executive 6.52% 3
2 Director / Sr. Director 52.17% 24
3 Manager / Sr. Manager 19.57% 9
4 Scientist / Researcher 13.04% 6
5 Analyst / Associate 2.17% 1
6 Other (Please Specify) 6.52% 3
Total 100% 46

Q7_6_TEXT - Other (Please Specify)
Other (Please Specify) - Text
Associate Director (in between manager/director I suppose)
Validation engineer
President and Founder

165
Q8 - Did your collaboration/acquisition/merger keep the CMC operations of the two
groups completely independent?

# Answer % Count
1 Yes 47% 20
2 No 53% 23
Total 100% 43

166
Q9 - What in your opinion are the pros and cons of not merging CMC operations and
working as isolated organizations?

What in your opinion are the pros and cons of not merging CMC operations and working as
isolated organizations?
Even though the CMC teams were independent (2 separate companies), many of the projects
I've worked on had shared accountability for the certain CMC operations. For example, in one
collaboration, the PD/AD/MSAT responsibilities are shared 50/50 with our partnering
company so they attended every meeting, reviewed every protocol and report document, and
shared equal decision-making power. For QA and compliance oversight, including batch
release and stability, my company was solely responsible for those aspects. The pros of shared
accountabilities and decision making are that both teams are on the same page, have access to
the same information at the same time, and can build team rapport through frequent
interactions. This dynamic works quite well if the underlying company cultures are similar.
The cons of this type of structure, where two independent organizations collaborate, is that it
usually takes some time to align the way the two organizations work and communicate with
each other. Each company has its own other projects and priorities, and it can be challenging
to align project deliverables, timelines, and priorities. If the company cultures are highly
dissimilar, additional effort is needed to achieve alignment, and this can cause a certain
amount of frustration. Collaborating as two separate entities also can be challenging if the two
companies have different levels of experience when it comes to phase-appropriateness, quality
culture, compliance, and regulatory expectations.
Pro - already familiar with our own company approach and templates, operations were already
streamlined to a certain extent, only 1 set of reviewers to appease
Challenges for prioritization and resourcing, integration challenges, ultimately challenges for
staff retention vs startups (overpaying for acquisition made everyone wealthy allowing greater
risk taking) Need long term strategy for retention plus a strategy for sustainable not boom and
bust growth, together with strategic plan vs chaotic integration plan with changing executives
and strategy
I am not sure how to answer this question. I believe in regard to the Kite/ NCI relationship
there were a lot of processes between the 2 organizations that did not align so I am unsure in
this particular case if both could work as isolated organizations. It was a collaborated effort
between the 2 parties.
Companies that I have worked for have independent operations for about 2-3 years then merge
to the bigger company systems. Some systems are better than others but at the end of the day,
the acquired company will follow the operations of the acquiring company.
Gilead acquired Kite. Gilead has LOADS of CMC experience but they had zero experience in
the advanced/cell therapy arena. Kite really had the expertise in this area and we were allowed
to maintain leadership in CMC with some but minimal intervention. Kite is always able to
seek advice and guidance from Gilead CMC but Gilead looks to Kite as the leaders since we
have more experience.
The speed at the rate of organization was one of the more frustrating aspect. The cons of being
an isolated organization is the lack of visibility. This created a culture of fear among some
groups and a need to please the parent company by pushing projects that will ultimately not
succeed.

167
Different organizations may have different backgrounds/expertise that would not blend well
post-merger.
Pros: remaining nimble, employees remain content, low disruption of activities Cons:
redundancy in costs, missing opportunities to leverage expertise and knowledge, employees
from acquired company may feel uncertainty in their future
The two merging organizations may have different product portfolios and in such cases it
becomes even more critical to retain product-specific CMC expertise.
Cons: - alignment of objectives not as clear - access to historical information by the acquirer is
rendered difficult - harder to evolve the culture of the acquired toward that of the acquirer
Pros: - retention of key individuals w historical knowledge of the project ( business continuity)
Conclusion: the uniformization and merger of the CMC operation is inevitable in the medium
to longer term. Maintaining a separate CMC org makes sense in the case of i) the acquired is a
mature organization w track record of compliant and operational excellence ii) the area of
operation is sufficiently distinct (i.e biologics vs cell therapy)
PROs May leverage most mature CMC Ops organization to develop strategy for "newcomers"
or less experienced organization CONS Diverging regulatory approaches and decisions on
how to file new submissions or variations Risk to supply if regulatory landscape for change
management os not clearly understood for all jurisdictions where the product is marketed.
The organization we collaborated with had several mAbs, but no cell therapy experience. We
did not merge CMC operations. We transitioned it to the partner company, as they bought
majority share. Pros: leveraging different resources and know how (eg. PAI, reg-CMC) Cons:
communication, decision making (governance), information sharing, accountability.
Pros: (1) It takes a fairly long time to merge CMC operations and that delays the development
of the new cell based therapy (2) It is also a fairly expensive process and in this case both
parties were university/hospital based research institutes (3) From a GMP standpoint we were
able to treat the collaborator in Germany as a supplier so we were able to audit them as a
supplier. Cons: (1) in our case the one collaborator was in Germany and we were in Canada,
so we had to deal with the differences in the GMP regulations between the two jurisdictions on
a case by case basis. If we had merged the two systems at the start all of that would have
already been done.
The ability to focus directly on the deliverable at hand such as tech transfer/scale up without
additional pre-clinical/clinical data keeps information to the respective CMC party licensing
the product/technology was beneficial. It kept nice to have information at the higher strategic
level. Strategy meetings to confirm directional decisions are still held and communicated as
appropriate.
Pros: Clear functionality and responsibility.

168
Q10 - In retrospect how do you feel your CMC operational organizations should have
integrated?

# Answer % Count
4 Maintained as an independent organization 63.64% 14
5 Merged organizations 31.82% 7
7 Other (Please specify) 4.55% 1
Total 100% 22

Q10_7_TEXT - Other (Please specify)
Other (Please specify) - Text
Offer CMC packages such as IND filing

169
Q11 - Overall, how would you rate the degree of challenge associated with each of the
following activities throughout the process of integrating two (or more) CMC groups?

# Field Minimum Maximum Mean
Std
Deviation
Variance Count
1 Training staff 1.00 4.00 2.04 0.62 0.39 23
2 Updating SOPs 1.00 4.00 2.45 0.78 0.61 22
3
Generating reproducible
data
1.00 4.00 2.26 0.74 0.54 23
4
Aligning expectations
with FDA requirements
1.00 4.00 2.39 0.87 0.76 23
5
Aligning operational
expectations
1.00 3.00 1.70 0.69 0.47 23
6
Aligning organizational
culture
1.00 3.00 1.52 0.58 0.34 23

170
Q12 - As your organization began integrating operations, how concerned were you that
challenges in the following areas might delay FDA approvals?

# Question
Very
Concerned

Somewhat
Concerned

Not
Concerned

Not
Sure
Total
1
Aligning
documentation
22.73% 5 59.09% 13 13.64% 3 4.55% 1 22
2
Integrating
company culture
28.57% 6 42.86% 9 28.57% 6 0.00% 0 21
3
Retaining
employees
27.27% 6 63.64% 14 9.09% 2 0.00% 0 22
4
Integrating
quality systems
30.00% 6 45.00% 9 20.00% 4 5.00% 1 20
5
Meshing
regulatory CMC
strategies
18.18% 4 54.55% 12 18.18% 4 9.09% 2 22
6
Transferring
technologies
25.00% 5 50.00% 10 25.00% 5 0.00% 0 20
7
Validating
manufacturing
processes
15.00% 3 70.00% 14 10.00% 2 5.00% 1 20
8
Validating
analytical test
procedures
13.64% 3 63.64% 14 22.73% 5 0.00% 0 22
9
Setting product
specifications
18.18% 4 50.00% 11 27.27% 6 4.55% 1 22
10
Passing site
Inspections
14.29% 3 57.14% 12 28.57% 6 0.00% 0 21

171
Q13 - How challenging were the following CMC activities as your partnership/merger
proceeded?

# Question
Very
Challenging

Somewhat
Challenging

Not
Challenging

Not
Sure
Total
1
Satisfying
regulatory
expectations
13.64% 3 63.64% 14 13.64% 3 9.09% 2 22
2
Maintaining
product
quality
9.09% 2 40.91% 9 36.36% 8 13.64% 3 22
3
Assuring
batch lot
reproducibility
9.09% 2 45.45% 10 31.82% 7 13.64% 3 22
4
Documenting
quality
systems
9.09% 2 68.18% 15 9.09% 2 13.64% 3 22
5
Retaining
employees
45.45% 10 50.00% 11 4.55% 1 0.00% 0 22
6
Assuring
knowledge
transfer
between
parties
45.45% 10 40.91% 9 9.09% 2 4.55% 1 22
7
Assuring
manufacturing
success rates
13.64% 3 54.55% 12 18.18% 4 13.64% 3 22
8
Working
under budget
constraints
13.64% 3 31.82% 7 50.00% 11 4.55% 1 22

172
Q14 - Were you involved in due diligence activities for the merger/acquisition?

# Answer % Count
1 Yes 31.82% 7
2 No 68.18% 15
Total 100% 22

173
Q15 - When due diligence was conducted as part of the integration, how much importance
do you think was placed on assessing the following aspects of CMC operations?

# Question
Very
Important

Somewhat
Important

Not
Important

Not
Sure
Total
1
Plans for CMC
validations
16.67% 1 66.67% 4 16.67% 1 0.00% 0 6
2
Gap analysis for
CMC strategies
50.00% 3 16.67% 1 33.33% 2 0.00% 0 6
3
Sufficiency of
manufacturing site
infrastructure
50.00% 3 33.33% 2 16.67% 1 0.00% 0 6
4
Sufficiency of
documentation for
development history
of acquired product
14.29% 1 57.14% 4 14.29% 1 14.29% 1 7
5 Sufficiency of SOPs 14.29% 1 57.14% 4 28.57% 2 0.00% 0 7
6 Need to train staff 42.86% 3 42.86% 3 14.29% 1 0.00% 0 7
7 Staffing adequacy 42.86% 3 28.57% 2 28.57% 2 0.00% 0 7
8
Differences in
company culture
42.86% 3 0.00% 0 42.86% 3 14.29% 1 7

174
Q16 - How well matched are your companies in the following areas when it comes to
decision making?

# Field Minimum Maximum Mean
Std
Deviation
Variance Count
1 Encouraging innovation 0.00 9.00 5.00 3.05 9.30 20
2
Assuring adequate
resources
1.00 10.00 5.32 2.60 6.74 19
3
Planning CMC
milestones
2.00 10.00 6.69 2.57 6.59 16
4
Meeting with FDA to
align expectations
2.00 9.00 6.21 2.14 4.60 14

175
Q17 - When senior executives planned restructuring that merged CMC groups, which was
most important when considering the following? Please rank from (1 - Most Important) to
(4 - Least Important)

# Question 1 2

3 4 Total
1 Retaining key talent 60.00% 12 20.00%

4 15.00% 3 5.00% 1 20
2
Reducing staffing
redundancy
10.00% 2 15.00%

3 35.00% 7 40.00% 8 20
3
Redefining
organizational roles and
responsibilities
25.00% 5 55.00%

11 20.00% 4 0.00% 0 20
4
Integrating
organizational culture
5.00% 1 10.00%

2 30.00% 6 55.00% 11 20

176
Q18 - When your department prepared to merge operational CMC activities, how
concerned were you with the following aspects?

# Question
Very
Concerned

Somewhat
Concerned

Not
Concerned

Not
Sure
Total
1
Retaining
employees
31.82% 7 59.09% 13 9.09% 2 0.00% 0 22
2 Aligning SOPs 22.73% 5 36.36% 8 40.91% 9 0.00% 0 22
3
Ensuring
successful
knowledge
transfer
40.91% 9 45.45% 10 13.64% 3 0.00% 0 22
4
Assigning roles,
responsibilities
and
accountability
36.36% 8 31.82% 7 31.82% 7 0.00% 0 22
5
Meeting
regulatory
expectations
13.64% 3 63.64% 14 22.73% 5 0.00% 0 22
6
Meeting
timelines
50.00% 11 45.45% 10 4.55% 1 0.00% 0 22

177
Q19 - Once the CMC and Quality departments had been reconfigured, how easy was it to
align the following aspects of CMC strategy with the new partner?

# Question Easy Difficult
Most
Difficult

Not
Sure
Total
1
Following regulatory
guidances
59.09% 13 36.36% 8 0.00% 0 4.55% 1 22
2
Setting phase
appropriate validation
requirements
36.36% 8 40.91% 9 13.64% 3 9.09% 2 22
3
Agreeing on CMC
strategies for
submissions
27.27% 6 50.00% 11 13.64% 3 9.09% 2 22
4
Planning to demonstrate
product comparability
18.18% 4 54.55% 12 13.64% 3 13.64% 3 22
5
Choosing/working with
suppliers
40.91% 9 36.36% 8 9.09% 2 13.64% 3 22

178
Q20 - When the organizational teams began to work together, please rate whether you
agree with the following statements.

# Question Agree
Neither
Agree nor
Disagree
Disagree
Cannot
Answer
Total
1
The organizations had
dissonant approaches
when incorporating
ICH and FDA
guidances
27.27% 6 31.82% 7 31.82% 7 9.09% 2 22
2
Both organizations
understood their roles
27.27% 6 31.82% 7 31.82% 7 9.09% 2 22
3
Both organizations
had sufficient input to
CMC gap analyses
36.36% 8 18.18% 4 31.82% 7 13.64% 3 22
4
Both organizations
had sufficient input to
phase appropriate
validation initiatives
45.45% 10 22.73% 5 22.73% 5 9.09% 2 22
5
Both organizations
shared sufficiently in
decisions about day-
to-day operations
22.73% 5 22.73% 5 45.45% 10 9.09% 2 22
6
Both organizations
determined when
implementation would
begin
54.55% 12 9.09% 2 22.73% 5 13.64% 3 22
7
Members from both
partners led planning
initiatives
59.09% 13 13.64% 3 27.27% 6 0.00% 0 22

179
Q21 - As the manufacturing operations began to partner prior to implementing tech
transfers, please indicate your level of satisfaction to ensure that operational changes were
adequate to meet FDA expectations.

# Question
Very
Satisfied
Satisfied
Not
Satisfied

Cannot
Answer
Total
1
Updates were made
to the manufacturing
infrastructure
4.76% 1 57.14% 12 9.52% 2 28.57% 6 21
2
Quality systems
procedures were
revised
4.76% 1 61.90% 13 4.76% 1 28.57% 6 21
3
Side by side training
was completed
0.00% 0 47.62% 10 23.81% 5 28.57% 6 21
4
Sufficient staffing
was made available
0.00% 0 28.57% 6 57.14% 12 14.29% 3 21

180
Q22 - If you have other concerns related to the early stages of CMC operational
integrations, please specify.

If you have other concerns related to the early stages of CMC operational integrations, please
specify.
FYI - i approached this questionaire from not just US/FDA compliance but looking at
expectations across other regulatory agencies (JP, EU).
The availability of resources at the parent company to take on the work resulting from the
acquisition was very inadequate.
Lack of integration planning or expectations
There was disagreement or dissatisfaction with the newly combined companies, some of the
talent retained didn't actually want to stay and some of the people dismissed ended up being
more knowledgeable than those let go. There was quite a bit of knowledge loss during the
transition period because some key talent was dismissed and those in what were purported to
be "key" roles were retained, yet those individuals didn't have good understanding of the
technical details of their role.
Aligning point of contacts toward suppliers and CDMO was not satisfactory, also person in
plant responsibilities were not clear

181
Q23 - Please indicate whether you agree with the following statements regarding the
alignment of the partnering groups.

# Question
Better
than
Expected

As
Expected

Worse
than
Expected

Not
Applicable
Total
1
Communicating
across sites
4.55% 1 54.55% 12 36.36% 8 4.55% 1 22
2 Funding 13.64% 3 59.09% 13 13.64% 3 13.64% 3 22
3
Sharing
knowledge across
sites
4.55% 1 36.36% 8 54.55% 12 4.55% 1 22
4
Aligning
documentation
4.55% 1 54.55% 12 31.82% 7 9.09% 2 22
5
Agreeing on
regulatory CMC
filing strategies
4.55% 1 68.18% 15 18.18% 4 9.09% 2 22
6 Training 0.00% 0 68.18% 15 13.64% 3 18.18% 4 22
7
Maintaining
manufacturing
success rates
13.64% 3 54.55% 12 18.18% 4 13.64% 3 22
8
Meeting
consistent
product quality
test results
9.09% 2 68.18% 15 13.64% 3 9.09% 2 22

182
Q24 - In your view, how successful were operational integrations in the following areas as
you carried out the first studies as a new partnership/team?

# Question
Very
Successful

Somewhat
Successful

Not
Successful

Not
Sure
Total
1
CMC Technical
Operations
22.73% 5 50.00% 11 9.09% 2 18.18% 4 22
2
Regulatory CMC
strategies
22.73% 5 50.00% 11 13.64% 3 13.64% 3 22
3 Quality Systems 18.18% 4 50.00% 11 13.64% 3 18.18% 4 22
4
Documentation/
SOPs
18.18% 4 50.00% 11 9.09% 2 22.73% 5 22
5 Training 18.18% 4 40.91% 9 9.09% 2 31.82% 7 22

183
Q25 - When making initial changes to begin CMC operational integrations, what in
retrospect do you think could have been done differently to ensure a successful program?

When making initial changes to begin CMC operational integrations, what in retrospect do you
think could have been done differently to ensure a successful program?
R&R definitions, timeline/milestone targets alignment
Dedicate resources from the parent company to integrate the CMC operational integrations
instead of just adding the workload on top of the existing resource constraints.
Still in the early stages
A high-level overview/roadmap of the current and future states (IT, quality systems, suppliers,
manufacturing/testing sites, etc) with regular status updates would be ideal to align the two
organizations on a path to an integrated company. Piecemeal communication, or lack thereof
makes merging feel disjointed, lowers morale, and hastens key departures.
Plan what integration looks like, roles and responsibilities
The company made some poor decisions related to dismissing staff. Many of the Sr leaders at
the site were dismissed as part of the acquisition and they actually retained most of the
strategic understanding of the decisions that were made. Many of the people retained knew
what decisions were made but they didn't have a clear understanding of "why" the decision
was made.
Plan to retain key talent early in the process. Communicate often and clearly.
It has been going well.
Overlap in R&R, although inefficient, could have been more valuable in knowledge sharing
and team work during the initial time period.

184
Q26 - How did the operational integration affect CMC staff during the earliest tech
transfers?

# Question Agree
Neither Agree
nor Disagree
Disagree
Not
Sure
Total
1
Staff morale
decreased
40.91% 9 31.82% 7 13.64% 3 13.64% 3 22
2 Key personnel left 50.00% 11 27.27% 6 13.64% 3 9.09% 2 22
3
Trust in leadership
decreased
36.36% 8 31.82% 7 27.27% 6 4.55% 1 22
4
Staffing was
insufficient
59.09% 13 18.18% 4 13.64% 3 9.09% 2 22
5
Projects were
delayed by staffing
shortfalls
40.91% 9 27.27% 6 27.27% 6 4.55% 1 22

185
Q27 - As new teams were developed, how effective was the new team in implementing the
initial plans effectively?

# Question
Very
Effective

Somewhat
Effective

Not
Effective

Not
Sure
Total
1
Transfer of
Product
Knowledge
18.18% 4 50.00% 11 22.73% 5 9.09% 2 22
2
Technology
Transfers
18.18% 4 54.55% 12 4.55% 1 22.73% 5 22
3
Operational
Integrations
18.18% 4 54.55% 12 18.18% 4 9.09% 2 22

186
Q28 - When implementing the initial activities, did you have delays in achieve the targeted
milestones? If yes, how long was the delay?

# Question
No
Delay

1-3
Months

3-12
Months

Cannot
Answer

>1
year
Total
1
Transfer of
Product
Knowledge
18.18% 4 27.27% 6 22.73% 5 27.27% 6 4.55% 1 22
2
Technology
Transfers
13.64% 3 40.91% 9 13.64% 3 31.82% 7 0.00% 0 22
3
Operational
Integrations
18.18% 4 31.82% 7 9.09% 2 40.91% 9 0.00% 0 22

187
Q29 - Did the following problems that might be associated with restructuring cause issues
that delayed your regulatory submissions?

# Question
No
Delays

Some
Delays

Refuse
to File

Cannot
Answer
Total
1
Disagreements
within leadership
27.27% 6 40.91% 9 0.00% 0 31.82% 7 22
2 Culture clashes 50.00% 11 18.18% 4 0.00% 0 31.82% 7 22
3
Insufficient project
management
27.27% 6 45.45% 10 0.00% 0 27.27% 6 22
4
Other (Please
Specify)
9.09% 1 36.36% 4 0.00% 0 54.55% 6 11

188
Q30 - Please indicate your level of agreement with the following statements related to
regulatory oversight during your operational integrations.

# Question Agree
Neither
Agree nor
Disagree
Disagree
Not
Sure
Total
1
Insufficient FDA
guidance was available
on assuring product
comparability after a
merger or acquisition
18.18% 4 40.91% 9 27.27% 6 13.64% 3 22
2
FDA should require
manufacturing
inspections for
commercialized
products after a merger
or acquisition
36.36% 8 45.45% 10 4.55% 1 13.64% 3 22

189
Q31 - Please provide comments on what else FDA might do better to provide support for
CMC operations as two departments are meshed.

Please provide comments on what else FDA might do better to provide support for CMC
operations as two departments are meshed.
A review of the quality systems that have changed as a result of the merger. If previous
inspections focused on Company X, which was then merged with Company Y, a review of any
changes to quality systems with respect to the programs affected by the merger should be
executed to ensure product safety.
Consistent response regardless change of company size and culture after merger
I don't necessarily believe that the FDA needs to perform an inspection directly after the
integration, but perhaps at the next biannual inspection they should do a more thorough dive
into the operations and quality systems of the new (combined) organization.
No comment
Regular meetings to support CMC operational integration
Allow more/repeat meetings, e.g, if EOP1 meeting already happen prior to merger, should
allow a follow-up EOP1 meeting post- merger. Approaches changes across organizations and
leadership so difficult to execute something you were not part of.

190
Q32 - When working in a collaboration, partnership or joint venture, do you think the
supporting organization working with the sponsor should have more decision-making
opportunities for developing Regulatory CMC strategies?

# Answer % Count
1 Yes 63.64% 14
2 No 13.64% 3
3 Not Sure 22.73% 5
Total 100% 22

191
Q33 - Were regulatory submissions for drug development programs successful in satisfying
FDA requirements after operational integrations had been completed?

# Question
Successful
without
Delays

Successful
with
Delays

Not
Successful

Cannot
Answer
Total
1
Clearance of
new INDs
9.09% 2 50.00% 11 0.00% 0 40.91% 9 22
2
Clearance of
IND
amendments
22.73% 5 45.45% 10 0.00% 0 31.82% 7 22
3
Marketing
application
approvals
9.09% 2 27.27% 6 0.00% 0 63.64% 14 22
4
Marketing
application
supplements
13.64% 3 13.64% 3 0.00% 0 72.73% 16 22
5
Post approval
commitments
13.64% 3 13.64% 3 0.00% 0 72.73% 16 22
6
Other (Please
Specify)
0.00% 0 12.50% 1 0.00% 0 87.50% 7 8

192
Q34 - In your new way of conducting CMC operations, do you have any other challenges
not discussed above for which you might propose a better solution?

In your new way of conducting CMC operations, do you have any other challenges not
discussed above for which you might propose a better solution?
No
Major disconnect between sites regarding functions. Each site has a dedicated functional area
or areas, but the decision making cores are dispersed throughout multiple sites

193
Q35 - In 2020, FDA issued guidance “Human Gene Therapy for Rare Diseases” to
accelerate CMC activities in order to address shortened clinical timelines for BLA
submissions. Please rate your level of implementation of the following when considering
regulatory CMC strategies.

# Question
Fully
Implemented

Somewhat
Implemented

Did Not
Implement

Cannot
Answer
Total
1
We leveraged
contents from
marketed
products by
“Simplified
IND or cross-
referencing
shared CTD
sections”
4.76% 1 28.57% 6 9.52% 2 57.14% 12 21
2
We completed
early Process
Performance
Qualification
PPQ at Phase
I
9.52% 2 19.05% 4 38.10% 8 33.33% 7 21
3
We conducted
late stage
manufacturing
process
validations at
Phase I
14.29% 3 0.00% 0 38.10% 8 47.62% 10 21
4
We conducted
testing
validations
(including
potency) at
Phase I
4.76% 1 23.81% 5 28.57% 6 42.86% 9 21

194
Q36 - How did working with another company impact decision making for accelerating
regulatory CMC strategies?

# Answer % Count
1 Aligned with FDA guidance to accelerate CMC activities 26.32% 5
2 Some adoption of FDA guidance to accelerate CMC activities 31.58% 6
3 Did not consider FDA guidance 10.53% 2
4 Not Sure 31.58% 6
Total 100% 19

195
Q37 - Did you have challenges in the following areas even after fully implementing a new
CMC operational organization?

# Question
Very
Challenging

Somewhat
Challenging

Not
Challenging

Not
Sure
Total
1
Demonstrating
product
consistency to
satisfy FDA
expectations
10.00% 2 45.00% 9 15.00% 3 30.00% 6 20
2
Defining
regulatory
CMC
strategies to
meet FDA
expectations
5.00% 1 45.00% 9 25.00% 5 25.00% 5 20
3
Meeting
sponsor and
partner
expectations
5.00% 1 50.00% 10 15.00% 3 30.00% 6 20
4
Retaining
employees
35.00% 7 40.00% 8 0.00% 0 25.00% 5 20

196
Q38 - What advice might you give to organizations entering a new
partnership/merger/acquisition to assure successful integration?

What advice might you give to organizations entering a new partnership/merger/acquisition to
assure successful integration?
Assign dedicated resources for the new program to allow for a sudden increase in workload.
Prioritize/outline the future organizational structure with clear roles and responsibilities before
integration so employees and projects don't get lost in the mix
Prioritize values that an organization need to retain that should be consistent from top
managements through front line members for PMI.
Retina more staff to find out what information they have. Perhaps a slower integration (I
know it isn't likely given that the bean counters who wanted the merger in the first place did so
by being able to "reduce redundancy" in the staff as a part of the merger). There has been a lot
of knowledge loss during mergers that I've been involved with. Most frequently it is because
key staff are let go early in the process.
Place more emphasis on the importance of retaining employees
Make sure you have a means and willingness to share product and technology know-how.

197
Q39 - Based on your experience, what are the biggest CMC hurdles to overcome for timely
submissions to regulatory agencies?

Based on your experience, what are the biggest CMC hurdles to overcome for timely
submissions to regulatory agencies?
I've worked mainly at companies that have adequate funding, so funding is excluded from my
list but I'm sure it is a major factor. If funding is adequate, the biggest CMC hurdles have
been improper project planning and management, and poor team assembly skills or lack of
suitable human resources.
supplying sufficient stability data
Meeting regulatory requirements.
establishing specifications
Breakthrough therapy designation has led to jumping from a few Phase 1 batches to an
expectation of Phase 3 readiness in too short an amount of time. Updating a Phase 1
manufacturing processes to a commercial process requires extensive process and product
comparability and characterization that take more time than the clinical timelines, leaving the
CMC timeline as the bottleneck.
Focus and strong leadership with vision and executable path to commercialization
Organizations that act as a CMO need to have better policies and procedures to manage
customer requirements that are not in alignment with internal processes. For example, if a
customer wants to use a particular grade of material that is not approved by internal supplier
quality, there should be a process for how to handle customer requested materials that do not
align with internal requirements. I would also recommend submitting IND independently of
working in a partnership if there are too many differences in timelines between the 2 parties or
the processes are completely different between the 2 parties. For example NCI was on a
completely different schedule than Kite, we were ready to manufacture at much higher volume
but there was hardly any demand or clarity on when we would get the material we needed
from our partner to continue production. If a partnership or CMO situation occurs, provide
enough support for the project. For example, if you have a complicated process do not make
things more difficult by limiting technology such as ERP / MRP functions. We had a very
complicated chain of Identity process which could have been smoother if we had all the ERP
functions in oracle that other sites had access to.
Pandemic was a big hurdle in the middle of us trying to get process validation runs completed
in another country and to get the drug shipped and approved in another country
Manpower…. I have experienced really aggressive timelines for submissions and management
is so keen on the deadline not considering factors that can affect possible delays. They just
want you to work multiple roles to meet the deadline. I have seen this with expansion
projects/construction.
Project management, conflicting/redundant internal governing bodies
Organized and accurate data archiving system. The most challenging thing for us is to
determine exactly what data has gone into what filing, where is that data archived for data
verification purposes. As time goes on, more data is generated that often supplants older data
and we need to decide if/when that data should be shared, if/when we will update filings. Also,

198
all companies have personnel turnover, which results in loss of historical knowledge about
why specific data was used rather than other. I wish we had a reference program (like
Endnote) for data, which identified the exact reports data came from and the ability to explain
why “this” data from “that” report, etc. Knowledge and data management is challenging for all
companies…
I believe experience and communication are one of the biggest factors in the group. The lack
of communication between groups have led to the company missing some serious milestones.
This was driven by certain groups hiding their progress with the rest of the team. They misled
the company that the target deadlines were on track.
It depends on phase of development. For early phase development, it would be CMC data
availability related to safety. For BLA submission, it would be commercial readiness.
Collecting data in time to allow enough time to write the CTD sections of the submission.
Lack of harmonization
Having a team that is aligned operational --> regulatory. Either the operations staff doesn't
get input from their regulatory counterparts or the regulatory organization assumes that the
operations side "knows" what regulatory knows and will make appropriate decision. There
needs to be VERY GOOD communication between the two sides to hash out the path forward,
especially when things go wrong on the operations side.
Strong data package
1. all the data available - sound data 2. An experienced regulatory group which lead the
integration of all the building block in a coherent and cohesive manner 3. a sound and robust
storyboard - with a narrative that is more than here is just the data 4. trained and experienced
functional authors 5. solid suite of reviewed/audited source documents
One of the biggest challenges that I have experienced is the conflicting strategies to implement
"Phase appropraite" CMC activities while attempting to shorten the time to marketing
approval.
Alignment across sites and division of responsibilities
Lack of convergence on general requirements to approve new licenses or variations.
1. Thus far analytical development, contracted timelines, and new modalities (eg. critical
components) so not sure what the Agency is looking for.
There are many, on top of list are 1) defined comparability strategy, 2) setting meaningful
product specifications, 3) integrating control strategies across organizations and CDMOs, 4)
experienced SMEs in writing regulatory documents is scarce
With cell based therapies I think it would be things like: - cell line validation - batch to batch
variation - dealing with the short shelf life of the cell therapy and things like sterility testing -
requirements for adventitious agent testing often differs from country to country - validation of
shipping conditions and preparation at the site - screening requirements for donors often
differs from country to country
The level of risk each company (sponsor, CMO, and any partnership involvement) must be
aligned. I.e. milestones for payment and work done, must not be so strict to inhibit progress
towards a timely submission. This often requires making decisions based on incomplete data

199
sets which must be exercised often to build comfort at making those decisions and set the
culture at all levels of management.
GMP production timeline.

Abstract (if available)

Abstract Novel Gene and Cell Therapy (GCT) products offer important opportunities to treat rare and life-threatening diseases and therefore become candidates for dramatically expedited development and regulatory approval. However, the advantages of these expedited pathways can be threatened when operational aspects of product management are disrupted by corporate reorganizations after mergers and acquisitions. The combined effects of shortening and disrupting the developmental path puts unprecedented pressure on the testing and manufacture of these complex novel therapies. It can cause the activities associated with Chemistry, Manufacturing, and Controls (CMC) to become the rate-limiting factor for drug approvals. This exploratory study examined factors affecting CMC activities to reduce the hurdles for timely CMC development. The study surveyed the views of CMC professionals with experience in drug development, including mid to senior-level professionals working in both biotech and pharmaceutical companies. An implementation framework was used to structure and frame the research. Results suggested that aligning regulatory CMC strategies between the partners and regulators pose many challenges. Amongst the most common were dissonant approaches for incorporating regulatory guidances, conflicts with developing early-to-late-stage CMC strategies to meet FDA expectations, and difficulties in preserving product knowledge as teams change as a result of transitions. Results suggest that more direct communication and guidance from FDA on the expectations and standards for development of these products would reduce uncertainty; however, companies should also address vulnerable areas related to the retention of personnel and the meshing of dissonant cultures to assure the success of CMC integrations.

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Asset Metadata

Creator Luong, Hai (author)

Core Title Regulatory CMC strategies for gene and cell therapies during mergers and acquisitions: a survey of industry views

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Degree Conferral Date 2022-08

Publication Date 08/09/2022

Defense Date 06/16/2022

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag and controls,chemistry,drug development,gene and cell therapy,manufacturing,mergers and acquisitions,OAI-PMH Harvest,regulatory CMC strategies

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Bain, Susan (committee member), Cosenza, Mary Ellen (committee member), Kuo, Benson (committee member)

Creator Email hailuong@usc.edu,Haitl13@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC111376671

Unique identifier UC111376671

Legacy Identifier etd-LuongHai-11130

Document Type Dissertation

Format application/pdf (imt)

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Type texts

Source 20220816-usctheses-batch-973 (batch), University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

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