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Implementation of good manufacturing practice regulations for positron emission tomography radiopharmaceuticals: challenges and opportunities perceived by imaging thought leaders

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Implementation of good manufacturing practice regulations for positron emission tomography radiopharmaceuticals: challenges and opportunities perceived by imaging thought leaders

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IMPLEMENTATION OF GOOD MANUFACTURING PRACTICE REGULATIONS FOR
POSITRON EMISSION TOMOGRAPHY RADIOPHARMACEUTICALS:
CHALLENGES AND OPPORTUNITIES PERCEIVED BY IMAGING THOUGHT
LEADERS

by

Grant Dagliyan

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

May 2018

Copyright 2017 Grant Dagliyan

2
DEDICA TION……
I would like to dedicate this dissertation to my beautiful wife and best friend, Lilit, for her
constant love, support, AND PATIENCE! I would also like to dedicate this to my
parents, Aida and Gevork (1945-2005)—nothing made them prouder than to see their
children achieve. Finally, to my amazing son, Arthur, who I hope will one day reflect on
this accomplishment as a minor stepping stone to embark on his own academic and career
endeavor. While this dissertation will be a major capping stone for me academically, my
wife and son will always be my greatest source of pride and joy.

3
ACKNOWLEDGEMENTS
I would like to thank my thesis supervisor, Dr. Frances Richmond, for the many years of
encouragement, collaboration, and mentorship in both my academic and career
endeavors. This dissertation would not be possible without her strength, knowledge, and
dedication to her craft and beloved students. I would also like to thank Dr. Peter Conti
for recruiting and mentoring me in the field of translational imaging and having the trust
to let me manage and shape the USC Molecular Imaging Center through unconventional
pairings with regulatory science. I would also like to thank the rest of my committee
members, Andrew MacKay, PhD, and Michael Jamieson, DRSc, for their invaluable
support and feedback. Furthermore, I would like to thank all the staff at the USC
Regulatory Science program, especially Randa Issa, PhD, who has always been a phone
call away with any administrative hurdles. Another important source of support has been
Michelle Seitz who has edited this thesis masterfully. Finally, I would like to thank the
rest of my Doctoral Cohort, the first cohort of the DRSc program. I will always
remember with fondness the highs and lows we went through as a group and hope we can
all stay connected and continue to collaborate.

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TABLE OF CONTENTS
DEDICATION…… ............................................................................................................ 2
ACKNOWLEDGEMENTS ................................................................................................ 3
TABLE OF CONTENTS .................................................................................................... 4
LIST OF TABLES .............................................................................................................. 7
LIST OF FIGURES ............................................................................................................ 8
ABSTRACT… .................................................................................................................. 11
CHAPTER 1: OVERVIEW .............................................................................................. 12
1.1 Introduction ................................................................................................... 12
1.2 Statement of the Problem .............................................................................. 14
1.3 Purpose of the Study ..................................................................................... 14
1.4 Importance of the Study ................................................................................ 15
1.5 Limitation & Delimitations ........................................................................... 16
1.6 Organization of Thesis .................................................................................. 17
1.7 Definitions ..................................................................................................... 17
Molecular Imaging ........................................................................... 17
Nuclear Imaging: .............................................................................. 17
Positron Emission Tomography (PET) ............................................ 18
Single Photon Emission-Computer Tomography (SPECT) ............. 18
Radiopharmaceutical ........................................................................ 18
FDG……………………………………………………… .............. 19
CHAPTER 2: LITERATURE REVIEW .......................................................................... 20
2.1 Introduction ................................................................................................... 20
2.2 PET Radiopharmaceuticals: Historical Overview ......................................... 23
2.3 Importance of PET Radiopharmaceuticals .................................................... 28
2.4 Applications of PET Radiopharmaceuticals .................................................. 29
2.4.1 PET in Oncology .............................................................................. 29
2.4.1.1 Molecular Imaging of Cancer by PET has Several
Specific Applications: ......................................................... 30
2.4.1.2 PET Imaging of Neurological Conditions ........................... 31
2.4.1.3 PET Imaging as a Tool for Drug Development .................. 31
2.4.2 PET Safety Issues ............................................................................. 33
2.4.3 NRC Oversight of Radiation Exposure Risk .................................... 34
2.4.3.1 Radiation Exposure to Patients ........................................... 34

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2.4.3.2 Radiation Exposure to Personnel ........................................ 37
2.5 FDA Oversight of PET Radiopharmaceutical Production ............................ 38
2.5.1 PET cGMPs ...................................................................................... 38
2.5.2 FDA Part 212 vs. USP Chapter <823> ............................................ 39
2.6 PET Radiopharmaceutical Investigational Studies ....................................... 44
2.6.1 Radioactive Drug Research Committee (RDRC) Route .................. 45
2.6.2 Investigational New Drug (IND) Route ........................................... 47
2.7 PET Drug Manufacturing Challenges ........................................................... 49
2.7.1 Compliance Challenges at Columbia University ............................. 50
2.7.2 IBA Molecular ................................................................................. 52
2.8 Exploring Challenges Posed by Radiopharmaceutical Regulation ............... 53
2.9 Framing Research on cGMPs ........................................................................ 55
2.10 Core Implementation Components & Implementation Drivers .................... 59
2.11 Implementation Framework Applied to PET cGMPs ................................... 62
CHAPTER 3: METHODOLOGY .................................................................................... 64
3.1 Overview ....................................................................................................... 64
3.2 Survey Development ..................................................................................... 64
3.3 Focus Group .................................................................................................. 65
3.4 Survey Distribution and Analysis.................................................................. 66
CHAPTER 4: RESULTS .................................................................................................. 67
4.1 Analysis of Survey Results ........................................................................... 67
4.2 Profiles of Respondents ................................................................................. 67
CHAPTER 5: DISCUSSION .......................................................................................... 100
5.1 Summary ..................................................................................................... 100
5.2 Methodological Considerations ................................................................... 100
5.2.1 Delimitations .................................................................................. 100
5.2.2 Limitations ..................................................................................... 104
5.2.2.1 Development and Dissemination of the Survey
Instrument ......................................................................... 104
5.2.2.2 Respondent Sampling and Survey Methodology .............. 105
5.2.2.3 Implementation Framework .............................................. 107
5.3 Maturity of GMP Implementation ............................................................... 108
5.4 Challenges and Barriers to Implementation ................................................ 111
5.4.1 Equipment/Facility Upgrades and Maintenance ............................ 112
5.4.2 Staffing and Training ..................................................................... 114

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5.5 Usefulness of GMP regulations ................................................................... 118
5.6 Predicted impact of the GMP regulations ................................................... 120
REFERENCES: ............................................................................................................... 126
APPENDIX A: USP 823 VS CGMP 212…………………………………………………137
APPENDIX B: Survey Instrument, Pre-Focus Group…...………………………………...144
APPENDIX C: Survey Instrument, Post-Focus Group……………………….……….…...152

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LIST OF TABLES
Table 1: Advantages & Disadvantages of Various Molecular Imaging
Techniques (modified from (James & Gambhir, 2012) ............................... 21
Table 2: FDA Approved PET Radiopharmaceuticals (as of 2014) ........................... 23
Table 3: Historical Developments in PET Imaging ................................................... 27
Table 4: Standard PET/SPECT Isotopes .................................................................... 29
Table 5: Examples of Radiation Dose Exposure (modified from (SNMMI,
2012) ............................................................................................................ 36
Table 6: Radiation Dose Limits under RDRC (Food and Drug Administration,
2010) ............................................................................................................ 46
Table 7: Comparison of RDRC, eIND, and IND Approaches for PET probes
(Mosessian et al., 2014) ............................................................................... 49
Table 8: Focus Group Participants ............................................................................. 65
Table 9: In-House Documentation ............................................................................. 92
Table 10: Respondents’ Comments about Challenges to GMP Implementation......... 94
Table 11: Necessity of PET cGMPs ............................................................................ 97
Table 12: Unforeseen Challenges in PET cGMP Implementation .............................. 98
Table 13: Advice to Stakeholders or Other Groups Involved in PET cGMP
Implementation ............................................................................................ 99
Table 14: Typical Costs of Establishing a Radiopharmaceutical Production
Center (Devine & Mawlawi, 2010) ........................................................... 113
Table 15: FDA Approved PET Radiopharmaceuticals (post 2014) .......................... 124

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LIST OF FIGURES
Figure 1: Translational Integration of Molecular (PET) Imaging (Phelps, 2000a) ..... 22
Figure 2: Mechanism of FDG (Miele et al., 2008) ...................................................... 25
Figure 3: Role of PET in Drug Development (Hoffman & Gambhir, 2007) .............. 32
Figure 4: Major Sources of Ionizing Radiation Exposure of the Population of
the United States in 2006 (Schauer, 2009) .................................................. 35
Figure 5: Decision Tree on the Applicability of RDRC versus IND .......................... 47
Figure 6: Conceptual Framework for Implementation of Practices and Programs
(modified from (Fixsen et al., 2005)) .......................................................... 56
Figure 7: Stages of Implementation (modified from (Bertram et al., 2013) ............... 58
Figure 8: Core Implementation Components (modified from (Fixsen et al.,
2005)) ........................................................................................................... 60
Figure 9: Implementation Drivers (modified from (Bertram et al., 2013) .................. 62
Figure 10: Employment Setting .................................................................................... 68
Figure 11: Employment Position ................................................................................... 69
Figure 12: Experience in the PET Environment ........................................................... 70
Figure 13: Roles Related to the PET Environment ....................................................... 71
Figure 14: Time Spent on PET cGMP Activities .......................................................... 72
Figure 15: Batches Released per Day............................................................................ 73
Figure 16: State of Implementation of cGMP (21 CFR Part 212) ................................ 74

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Figure 17: Stage of Progress of cGMP Activities ......................................................... 75
Figure 18: State of Hiring to Implement PET cGMP Activities ................................... 76
Figure 19: cGMP Requirements Implemented Sufficiently to Pass FDA Audit .......... 77
Figure 20: Costs Associated with Facility Compliance ................................................ 78
Figure 21: Degree of Challenge Posed by Different Elements Required for
Facility Compliance ..................................................................................... 79
Figure 22: Satisfaction with FDA Feedback and Support ............................................. 81
Figure 23: Perceived Usefulness or Particular Support Programs ................................ 83
Figure 24: Likelihood of Using Standardized Templates ............................................. 84
Figure 25: Will New PET cGMP Hamper the Development of Novel PET
Radiopharmaceuticals? ................................................................................ 85
Figure 26: State of Training for PET cGMP Activities................................................. 86
Figure 27: Interactions with Industry Leaders with Respect to PET cGMP
Activities ...................................................................................................... 87
Figure 28: Roles Played by Consultants........................................................................ 88
Figure 29: Current Status of Facility Upgrades or Renovations for PET cGMP
Compliance .................................................................................................. 89
Figure 30: Current Status of Equipment Acquisition for PET cGMP Compliance ...... 90
Figure 31: Expertise to Develop Standardized cGMP Documentation ......................... 91
Figure 32: Importance of Organization Resources........................................................ 93

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Figure 33: Probability of Adopting Standardized Templates for a Fee ........................ 95
Figure 34: ANDA Approved Break-Even PET Drug Doses ......................................... 96
Figure 35: Challenges of Market Sustainability (Zigler, 2016) .................................. 123

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ABSTRACT…
The application of positron emission tomography (PET) radiopharmaceuticals has been
an important area of expertise for academic medical centers. However, the ability of
these centers to contribute to the evolution of this important technology will hinge on
their ability to satisfy new regulatory requirements, perhaps the most challenging of
which are the new FDA regulations that govern current Good Manufacturing Practices
(cGMPs) for radiopharmaceuticals. This study explored the challenges and opportunities
presented for academic centers by requirements to implement cGMPs in their facilities.
A novel survey instrument was developed, critiqued by a focus group of highly reputable
imaging leaders and then disseminated to imaging experts. Results provided insight into
the views of those individuals with regard to the potential of these changes to facilitate or
hamper the development of innovative PET drugs. The results showed that most PET
cGMP facilities viewed their sites as mature in implementation of PET cGMPs.
However, a more in depth review of FDA audits and overall number of FDA inspections
indicates an opposing view of maturation. Our findings indicated that cost of
implementing PET cGMPs were significant; acquisition and validation of equipment and
staff hiring and training contributed substantially to these costs. Most respondents had
positive or neutral views with regard to FDA feedback and support. Further, most
respondents did not feel the implementation of PET cGMPs would hamper their
development of novel PET radiopharmaceuticals. However, they also had concerns that
the higher costs of GMP compliance might lead to the closure of many academic
manufacturing facilities operating under PET cGMPs.

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CHAPTER 1: OVERVIEW
1.1 Introduction
Rapidly occurring discoveries in computing technology, molecular biology and
imaging are driving the development of a scientific field called “molecular imaging.”
Studies using molecular imaging rely on the selective interaction of a molecular probe
with a biological target, visualized through nuclear, magnetic resonance, optical,
ultrasound, or other methods. The goals of molecular imaging scientists are multifaceted.
They include the immediate outcome of developing new imaging probes for various
biomedical applications. In the longer term, they aim to facilitate the clinical
development of novel imaging agents and methods for therapeutic diagnosis, monitoring
and assessment of gene delivery, expression, and cellular processing, in intact
microenvironments (Pysz, Gambhir, & Willmann, 2010).
Despite the growing importance of PET imaging, the development of
radiopharmaceutical drugs has been plagued by serious constraints from a regulatory
perspective. Validation and translation of imaging probes is an expensive, time
consuming, and difficult process that typically demands collaboration between academia
and commercial entities to satisfy regulatory requirements. Furthermore, these
requirements have been challenging for the FDA to put into place because of the special
characteristics of PET drugs (Keppler, Thornberg, & Conti, 1998). Regulatory agencies
typically prefer to define a unitary regulatory framework for all pharmaceuticals. PET
drugs challenge this preference because they are made as small batch lots of injectable
product with short half-lives unstable for the long analytical testing regimes that are part

13
of the regulatory requirements. Because it is difficult to bring new PET pharmaceuticals
to market through a traditional marketing approval route, most radiopharmaceutical drugs
are still considered to be investigational. This adds additional complexity to their use
because the administration of these drugs requires added layers of oversight (Hung,
2013).
The new current good manufacturing practices (cGMP) for PET drug products
now set federally-enforceable minimum requirements for the methods “to be used in, and
the facilities and controls used for the production, quality control, holding, or distribution
of a safe and effective PET drug product intended for human use” (Food and Drug
Administration, 2017a). Under this law, if a manufacturer failed to meet quality and
purity requirements or comply with rules for compounding, processing, packing, or
holding, it might be barred from applying for future manufacturing approvals for two to
four years (Food and Drug Administration, 1997).
Over the last 5 years, much activity has been directed toward revising the
regulatory landscape around radiopharmaceutical products. The FDA has expanded and
clarified the regulatory framework of PET radiopharmaceuticals by 1) updating the
RDRC guidance documents, 2) implementing new cGMP requirements for the
production of PET drugs, and 3) promulgating guidance documents to describe
acceptable approaches to establish compliance with cGMP regulations(Food and Drug
Administration, 2009, 2010). With the implementation of new PET rules and guidelines,
the regulatory environment for PET drugs will face a new phase of increased oversight in
the next few decades. The impact of these changes will be difficult to estimate. Some

14
feel that they will benefit the quality and safety of these drugs but also hamper their
availability and developmental time (Harapanhalli, 2010).
1.2 Statement of the Problem
The development of novel PET radiopharmaceuticals is crucial for advancing the
diagnosis, prognosis, and therapy of major diseases and disorders. However, some in the
imaging community have expressed concerns about the difficulties to meet the clinical
needs and commercial demands for new radiotracers (Hung, 2013). Major barriers to the
development of novel radiopharmaceuticals are time, complexity, and cost of the
regulatory process (Keppler et al., 1998). These regulatory compliance issues include
challenges in demonstrating adequate manufacturing and distribution methods that satisfy
cGMP requirements, as well as the validation of safety and efficacy within the relatively
rigid constraints of current new drug application processes. Such regulatory hurdles may
pose economic barriers related to costs of meeting regulatory requirements. The
elements of the regulatory process specific to PET cGMP implementation that are most
problematic are not well understood by the research community. Insight into this
problem is limited by the paucity of systematic studies of the experience, concerns, and
insights imaging leaders in academia, industry, and federal regulating bodies (Keppler et
al., 1998).
1.3 Purpose of the Study
The purpose of this study was to gain more insight into the experience, concerns,
and insights of imaging thought leaders with regard to the development of new PET
radiopharmaceuticals and the manufacture of established PET radiopharmaceuticals for
clinical uses. The study first reviewed the relevant literature and then used survey

15
methods to probe the experience, concerns, and insights of imaging leaders in academia,
industry, and federal regulating bodies.
By using the implementation framework of Fixsen and colleagues, a new survey
instrument was developed with the goal of exploring a number of issues associated with
the key implementation drivers of competency, leadership, and organization at different
stages of new PET cGMP implementation for commercial and academic PET
manufacturers (Fixsen, Naoom, Blase, Friedman, & Wallace, 2005). An additional focus
of the study was to identify the implementation stage or stages at which one or more
implementation drivers may fail or stall cGMP implementation. The study also explored
the significance of different benchmarks of competency, leadership, and organization
drivers at the different stages of implementation. Furthermore, it attempted to identify
any new or unforeseen implementation drivers not examined in previous Implementation
Framework studies, which might be unique to this study.
1.4 Importance of the Study
This study provided a systematic overview of current experience and opinions of
imaging community leaders related to the regulatory framework of PET
radiopharmaceuticals. For those in industry, this information may help to guide go-no go
decisions in the development of drugs, and thus allow the better allocation of millions of
dollars which are currently lost in failed clinical trials and unnecessary regulatory
submissions. For regulators, such information is useful to address the needs of the
imaging community, through the development of thoughtful and balanced guidance
documents and relevant standard operating procedures. Educators in regulatory science
will benefit from a study that provides a comprehensive evaluation and analysis of the

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regulatory framework of PET radiopharmaceuticals from which students of this science
can learn. This understanding might lead to a modified regulatory paradigm of PET
radiopharmaceuticals through additional insights that can be considered by all
stakeholders.
1.5 Limitation & Delimitations
This exploratory study had limitations that must be taken into account. First, the
study population was limited to qualified individuals who could be identified by
databases or literature searches and who were willing to respond to surveys and
participate in the focus groups. The numbers of experts with extensive experience in the
development of radiopharmaceuticals were relatively small, and these individuals are
often very busy and often do not have the time to complete a survey. Thus, it may be that
the respondents do not represent fully the views of the universe of respondents involved
in development of radiopharmaceuticals, and this could challenge the validity of any
broad generalizations. It was also difficult to find clear, significant statistical
relationships within the data because opinions were often difficult to quantify.
Investigator bias was another limitation that cannot go without being acknowledged; I am
currently employed in a radiopharmaceutical laboratory and come to the work with
potential bias that must be recognized and controlled where possible by the experimental
design. The use of surveys rather than interviews restricts the nature of the feedback that
I could receive, and this undoubtedly reduced to a depth of the results and conclusions.
This study was delimited to an evaluation of PET pharmaceuticals and their U.S.
regulations and restricted its considerations to events that have occurred since PET drugs
were introduced in the early 1970s. It did not focus more widely on other imaging

17
methods such as Single Photon Emission-Computer Tomography (SPECT) tracers.
Further, it was delimited to a snapshot in time within the next two-year span.
1.6 Organization of Thesis
Chapter 1 provides a brief summary of the background of PET drugs and the
purpose of the study related to current regulatory challenges in the development of new
PET compounds. It considers the significance of the study, and it defines key terms
important to the study. Chapter 2 reviews the relevant literature, and more specifically,
analyzes the current thinking of the imaging community through an analysis of
publications and presentations. Chapter 2 also highlights the historical development and
current importance of PET tracers, the regulatory framework of PET drug development,
and the issues and challenges as reflected in published literature and opinion pieces.
Chapter 3 outlines the methodologies that were used to develop and analyze results from
the survey instrument. Chapters 4 and 5 summarize the results of the study and provide a
basis to discuss further the questions posed by the study.
1.7 Definitions
Molecular Imaging
Molecular imaging is the visualization, characterization, and measurement of
biological processes at the molecular and cellular levels in humans and other living
systems.
Nuclear Imaging:
Nuclear imaging is a method of producing images by detecting radiation from
different parts of the body after a radioactive tracer material is administered. Nuclear

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medicine imaging, including PET and SPECT (single photon emission tomography),
reveals physiological processes occurring in living systems.
Positron Emission Tomography (PET)
Positron emission tomography (PET) is a medical imaging technique that uses
radiopharmaceuticals that emit positrons (positively charged electrons). A
radiopharmaceutical such as Fluorodeoxyglucose (FDG) is injected into the patient. PET
is used predominately in determining the presence and severity of cancers, neurological
conditions, and cardiovascular disease. It is also used to identify and stage cancers in the
initial diagnosis and to check for recurrences.
Single Photon Emission-Computer Tomography (SPECT)
A SPECT scan uses a gamma camera to detect radioisotopes that emit
high-energy radiation. The gamma camera works with a computer to create
three-dimensional images of the distribution of the tracer in the body. SPECT is most
often used in cardiology to provide information about blood flow through the heart
muscle that can be used to diagnose heart disease. It is also used for brain and bone scans
and to detect infection and certain types of tumors.
Radiopharmaceutical
A radiopharmaceutical can be a simple radioisotope or, more commonly, a
radioisotope attached to some type of biological compound such as a drug, glucose, or an
antibody. The radiopharmaceutical can be injected, ingested, or inhaled by a patient.
Radiopharmaceuticals are designed to go to specific organs or tissues, such as cancerous
tumors, or to bind with specific molecules such as neurotransmitters in the brain. In
molecular imaging and nuclear medicine exams, special cameras are used to trace the

19
radiation given off by the radioisotope within the body. This can provide doctors with
valuable information about various biological processes.
FDG
Fluorodeoxyglucose (FDG) is a compound in which a radioactive fluorine atom is
attached to a molecule analog of glucose. Once in the body, the FDG molecule is
absorbed by various tissues, just as normal glucose would be, and the radiation from the
fluorine is used to map the distribution of glucose within the patient.

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CHAPTER 2: LITERATURE REVIEW
2.1 Introduction
PET radiopharmaceuticals have been one of the major achievements in the
evolution of imaging sciences. The Society of Nuclear Medicine and Molecular Imaging
(SNMMI) provides the following description of PET imaging technology:
Positron emission tomography (PET) is a medical imaging technique that
uses radiopharmaceuticals that emit positrons (positively charged
electrons). A radiopharmaceutical is injected into the patient. The fluorine
emits positrons which react with the first electron they come in contact
with, annihilating both and producing energy. This energy takes the form
of two photons (particles of light) with a very specific energy level that
shoots off in opposite directions. When these photon pairs are detected by
the PET scanner, the location of the original fluorine atom can be
extrapolated. Although positron/electron annihilation is one of the most
powerful reactions known to science, the amount of mass involved is so
small that the actual energy produced is not harmful to the patient, and
the fluorine decays rapidly into harmless oxygen. PET involves the
detection of positrons emitted during the decay of a radionuclide that has
been injected into a patient (SNNMI, 2013)

Nuclear medicine imaging, including positron emission tomography (PET) and
single photon emission tomography (SPECT), can reveal physiological processes as they
occur in living systems with high sensitivity and resolution. Thus, much effort has been
directed at developing novel PET imaging agents for a variety of applications (Miele et
al., 2008). Table 1 summarizes its advantages and disadvantages with respect to the major
molecular imaging techniques.

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Table 1: Advantages & Disadvantages of Various Molecular Imaging
Techniques (modified from (James & Gambhir, 2012)
Imaging
Technique
EM
Radiation
Spectrum
Advantages Disadvantages
Positron emission
tomography (PET)
High energy
gamma rays
High sensitivity;
quantitative;
translational research
Cyclotron needed;
radiation of subject
Single photon
emission computed
tomography
(SPECT)
Lower energy
gamma rays
Many molecular
probes available
Relatively low spatial
resolution; radiation
Computed
tomography (CT)
X-rays Bone and tumor
imaging
Limited 'molecular'
applications; radiation
Magnetic resonance
imaging (MRI)
Radio waves Highest spatial
resolution
Relatively low
sensitivity
Optical
bioluminescence
imaging
Visible light Highest sensitivity;
quick, easy, low
cost, and relatively
high throughput
Low spatial
resolution, limited
translational
applications
Optical fluorescence
imaging
Visible light
or near-
infrared
High sensitivity Low spatial
resolution, limited
translational
applications
Ultrasound High-
frequency
sound
Real time; low cost Limited spatial
resolution

The success of PET imaging depends on the synergistic collaboration of physics,
chemistry, engineering, molecular biology, and clinical medicine. These synergistic
dependencies have made the development of PET technology particularly complex.
Thus, it has taken over half a century to move from “bench to bedside.” Not only must
attention be paid to novel PET radiopharmaceuticals, but to the concomitant need for

22
evolution in PET imaging scanners, cyclotrons, validated imaging labs, and appropriate
software solutions, as shown illustratively in Figure 1 (Phelps, 2000a).
Figure 1: Translational Integration of Molecular (PET) Imaging (modified from
(Phelps, 2000a)

PET imaging equipment has advanced rapidly, but its rapid evolution has not
been matched by growth in the numbers of commercially available PET drugs. The most
successful and frequently used radiopharmaceutical, 2-[18F]fluoro-2-deoxy-D-glucose
(FDG), is one of only a handful of commercially approved PET radiopharmaceuticals in
the U.S. In 2013, two new PET imaging agents, F18-Florbetapir and C11-Choline, were
approved by the FDA. F18- Florbetapir is a PET radiopharmaceutical which binds to
beta-amyloid making it a valuable tracer for evaluation of dementia (Romano & Buratti,
2013). C11-Choline is a PET radiopharmaceutical which is transported into tumor cells
through a carrier-mediated transport mechanism. It then undergoes intracellular

23
phosphorylation by choline kinase and remains trapped in the cell. Tumor cells exhibit a
higher rate of C-11-Choline uptake, which makes C11-Choline ideal for cancer imaging,
and more specifically for prostate cancer imaging (Challapalli et al., 2014). The table
below provides an overview of the currently approved PET drugs and their approved
indications.
Table 2: FDA Approved PET Radiopharmaceuticals (as of 2014)
PET Radiopharmaceutical Approved Indications
Carbon-11 choline PET imaging of patients with suspected prostate cancer recurrence based
upon elevated blood prostate specific antigen (PSA) levels
Fluorine-18 florbetapir Diagnostic agent for PET imaging of the brain to estimate beta-amyloid
neuritic plaque density
Fluorine-18 sodium fluoride PET bone imaging agent to delineate areas of altered osteogenesis
Fluorine-18 fludeoxyglucose PET imaging agent to assess myocardial hibernation, abnormal glucose
metabolism in oncology
Nitrogen-13 ammonia PET agent used for evaluation of myocardial
blood flow (perfusion)
Rubidium-82 chloride PET myocardial perfusion agent

2.2 PET Radiopharmaceuticals: Historical Overview
In order to evaluate the regulatory barriers involved in the development of new
PET radiopharmaceuticals, it is first important to understand the historical evolution of
PET regulations. The history of PET radiopharmaceuticals appeared to start David Kuhl,
whose seminal work on tomography with single photon emission was essential to
elucidate the basic principles of PET imaging. By the 1960s, Kuhl had developed the
first radionuclide recording system (Mark II). However, Kuhl was dissatisfied with the
two-dimensional tool and after his return from military service he constructed a new 3D

24
radionuclide photo recording system. This new 3D model depended upon a procedure in
which the scanner revolved around the patient’s body as it produced the image. Kuhl was
also a pioneer in implementing an analog method of back projection. This advanced
method is still being used today to enhance PET imaging quality and depth (Williams,
2008).
The availability of radionuclides that emit N-13, O-15, F-18, and C-11 is a
fundamental precondition for the type of imaging capabilities being developed by Kuhl.
The short half-life of these radionuclides, once considered a disadvantage, has over the
last 40 years presented less of an obstacle with the introduction of faster radiochemistry
protocols and the availability of onsite accelerators called cyclotrons. On-site cyclotrons
are machines that produce nucleotides for immediate use in health-care settings
(Gambhir, 2002). The first medical cyclotron, designed by Ter-Pogossian, was installed
in 1961 at Washington University in St. Louis by Allis-Chalmers. Washington University
was the site of another significant milestone when Phelps and Ter-Pogossian introduced
the first PET scanner utilizing a fixed set of ring detectors that enabled 3-D imaging.
Installing detectors in a ring-like pattern enabled the collection of 3-dimensional data, by
imaging an organ or body of interest across various image planes (Phelps, 2000a;
Williams, 2008).
Development of cyclotrons, PET scanners, and radiochemistry protocols were
important building blocks for the PET community. However, the discovery that may have
had the largest impact on the field was the introduction of the radiopharmaceutical, FDG,
a marker of glucose metabolism. FDG was successfully synthesized in 1976 by Wolf and
his colleagues at Brookhaven National Laboratories and, to this date, remains the main

25
tracer for PET clinical imaging. FDG administration in humans was easy to justify
because of its very favorable risk-benefit profile. From a risk point of view, exposure of
patients to radiation was minimized because only a small dose of radiation had to be
given. From a benefit point of view, FDG had the remarkable ability to provide insight
into glucose metabolism and thus pinpoint areas of changed metabolic activity. (Conti et
al., 1996)
Figure 2: Mechanism of FDG (modified from (Miele et al., 2008)
Illustrates the functional mechanism of FDG, which mimics glucose trapping by a
radioactively labeled fluoride atom. This mechanism allows scientists to image the
trapped radioactive glucose analog as a PET tracer.

FDG PET is used clinically to stage cancer, detect metastases, and monitor and
evaluate responses to therapy. The ability of FDG PET to detect cancer is based upon
elevated glucose metabolism in the malignant versus normal tissue as a result of

26
increased expression of glucose activity across the cellular membranes of tumors. Since
FDG reflects glucose metabolism, it has also been a useful tracer to study inflammation,
neurological disorders, and other metabolically active biological phenomena (Gambhir,
2002).
PET is not limited to FDG. A large number of other PET radiotracers have been
investigated and are currently being evaluated for clinical use (James & Gambhir, 2012).
These radiotracers will provide invaluable information on many aspects of physiology
and pathology including, but not limited to, cellular proliferation, metabolism,
oxygenation, and perfusion.
Despite the fact that the essential elements of PET imaging, including PET
instrumentation, image processing methods and radiochemistry capabilities, were
developed from the 1960s to 1970s, the commercialization of PET scanners lagged for
another decade. It was not until 1975 that the first commercial PET scanner became
available, but even then, this equipment was used only in clinical trials and research.
Over the following two decades, PET imaging capabilities improved as a result of
technological advances that decreased the costs and improved the access to PET imaging
capabilities. This allowed the technology to move from research labs to hospitals and
clinics across the country. By the mid-1990s, PET imaging had become a ubiquitous and
important diagnostic tool for treating patients (Digby & Keppler, 2000).
In the last twenty years, the field of imaging with radiopharmaceuticals has
evolved further and has hybridized with other imaging methods such as computed
tomography (CT). A CT scan uses several x-rays to produce a tomographic image of
specific body areas so that researchers and clinicians can visualize anatomical and

27
functional data in one fused image. For example, an oncologist can use hybridized
technologies, such as PET/CT, to assess the size of a tumor from an anatomical CT
image, and concurrently evaluate whether the tumor cells are metabolically active or
inactive after therapy by inspecting a fused PET image that uses glucose metabolism as a
marker. PET/CT and other hybrid imaging systems such as PET/MRI will be important
tools in the growing field of personalized medicine, in order to enhance the specificity of
treatments to track and improve patient outcomes (Nunn, 2007). A detailed review of the
history of PET /CT methods is beyond the scope of the thesis but additional reviews of
this topic can be found elsewhere (Phelps, 2000a).
Table 3: Historical Developments in PET Imaging
Year Development
1954 David Kuhl invented a photo recording system for radionuclide scanning.
1961 Allis-Chalmers installed the first U.S. "medical center" cyclotron at Washington University
Medical School. The cyclotron was designed by M.M. Ter-Pogossian.
1962 David Kuhl introduced emission reconstruction tomography. This method later became known
as SPECT and PET. It was extended in radiology to transmission X-ray scanning, known as
CT.
1972 David Kuhl performed the first quantitative measurement of cerebral blood volume in living
patients.
1983 Henry Wagner carried out the first successful PET imaging of a neuroreceptor using himself as
the experimental subject.
1998 FDG PET studies were used to assess the response of an initial dose of chemotherapy to predict
the response to subsequent high-dose chemotherapy.
2000 Time Magazine recognizes Siemens PET/CT Biograph scanner as the invention of the year.
2008 The first hybrid PET/MRI system for humans, manufactured by Siemens, was installed.

28
2.3 Importance of PET Radiopharmaceuticals
Technological advances in molecular imaging have changed the landscape in the
field of molecular medicine. The ability to see inside a human body without invasive
procedures has, and continues to improve therapy by increasing safety, allowing earlier
stage diagnosis, and reducing costs of procedures that otherwise would require surgical
intervention (Zimmermann, 2013). PET allows functional information about the in vivo
status of certain biochemical processes to be evaluated. Metabolic activity in the tissue
and organs can be assessed, for example, by injecting biologically active compounds or
drugs labeled with positron emitting isotopes. These radiotracers are processed internally
in the same way as the body's nonradioactive counterparts to provide information on the
level of activity in a targeted biochemical pathway. PET also enables researchers and
physicians to visualize and navigate the human body in vivo without the use of surgical
procedures to determine the state of functionality of a particular organ (Vallabhajosula,
Solnes, & Vallabhajosula, 2011).
PET technology can be highly effective and convenient, but its use depends on the
availability of suitably labeled tracers. Table 4 highlights common PET isotopes, whose
half-lives vary from minutes to hours. The short duration of action imposes constraints on
the production of radiopharmaceuticals, which must be carried out close to the clinical
facility. The short half-life of the nucleotide also limits the size of each produced batch
to a quantity that can be dispensed within hours. Quality control is a challenge because
most validation tests used to assure product quality and identify microbial contamination
cannot be completed before the radioisotope has decayed and been rendered useless
(Zigler, 2009). These challenges can limit the full exploitation of this technique and pose

29
problems for clinicians, scientists, and regulators who are concerned with assuring the
safety of products that are so limited in their effective life by the rapidly decaying
nucleotide (Norenberg, Petry, & Schwarz, 2010).
Table 4: Standard PET/SPECT Isotopes
Isotope Half-life Modality Production
11
C 20.3 minutes PET cyclotron
13
N 9.97 minutes PET cyclotron
15
O 2.03 minutes PET cyclotron
18
F 109.8 minutes PET cyclotron
64
Cu 12.7 hours PET cyclotron
124
I 4.18 days PET cyclotron

2.4 Applications of PET Radiopharmaceuticals
2.4.1 PET in Oncology
PET imaging has many applications. Currently, its most prevalent use is for the
precise localization of malignant tumors as part of cancer treatment. Such methods help
to identify whether the malignancy has metastasized to other regions of the body.
Sequential PET images over time help the clinician to assess if the tumor has responded
to therapy and if it remains in remission. PET imaging has been approved by the FDA
for the diagnosis and staging of a multitude of cancers, including those of the brain,
breast, colorectal system, head, neck, and lung (Conti & Keppler, 2000). PET has also
been approved for use in the therapeutic evaluation of lymphoma, melanoma,

30
musculoskeletal tumors, ovarian cancer, pancreatic cancer, and thyroid cancer. (Digby &
Keppler, 2000)
2.4.1.1 Molecular Imaging of Cancer by PET has Several Specific Applications:
• Screening: PET imaging of tumor metabolic activity can help identify a tumor as
malignant or benign, and thus provides an alternative to diagnosis by surgical
biopsy.
• Staging: PET is sensitive in detecting the spread of cancer. Verification of
metastases allows for better management of the patient’s disease by the physician.
• Assessment of treatment: PET can help in the evaluation of tumor metastases and
metabolic activity, leading the oncologist to determine an appropriate treatment
strategy, in situations where several different chemotherapy methods are
available. The effectiveness of each of the strategies depends on the adequate
characterization of the tumor and its response to the chemotherapy agent. This
capability is a one step toward personalized treatment based on metabolic activity.
• Evaluation of recurrence: PET imaging helps the physician to assess if a cancer
has recurred after treatment. In most cases, an alternative form of therapy can be
introduced as soon as failure of the first therapeutic approach is detected.
• Assessment of tumor characteristics: Tumor metabolic activity has traditionally
been assessed by the rate of glucose uptake. Additional examples of tumor
characteristics that can be evaluated with the application specific PET
radiopharmaceuticals include angiogenesis, proliferation, and apoptosis (Hoffman
& Gambhir, 2007).

31
2.4.1.2 PET Imaging of Neurological Conditions
PET radiopharmaceuticals are also commonly used in neurological studies, where
they aid the diagnosis and staging of Alzheimer’s and Parkinson’s disease. Traditional
clinical approaches to the diagnosis of such conditions must typically wait until the
patient has dementia, about five to ten years after the onset of the disease. PET imaging
with Fluorine-18 florbetapir allows beta-amyloid neuritic plaque density to be imaged at
an earlier stage (Landau et al., 2013). Patients with dementia also tend to exhibit low
cerebral glucose metabolism, which can be evaluated with FDG PET (Gulyas & Halldin,
2012).
2.4.1.3 PET Imaging as a Tool for Drug Development
A major hurdle to overcome in a drug discovery program is the identification of a
lead compound with the most appropriate biological activity. Less than one percent of
tested compounds show sufficient potency to be considered to be commercially viable.
Assessment of potency and distribution in experimental PET imaging studies can help
validate the relative efficacy of compounds early in the drug development process. BY
screening radiolabeled lead compounds, it is possible to identify and fast track
compounds with a higher probability of clinical efficacy into Phase I translational studies.
This will help save millions of dollars in unnecessary basic research and clinical trials for
potentially uncompetitive compounds (Willmann, van Bruggen, Dinkelborg, & Gambhir,
2008).
Imaging biomarkers can be used as surrogate endpoints, prognostic biomarkers, or
predictive biomarkers. As a surrogate endpoint, usually in late drug development,
evaluations using an imaging biomarker can potentially replace clinical endpoints, such

32
as tumor shrinkage. Prognostic imaging biomarkers, such as FMISO (previously
discussed for its use in assessing tumor hypoxia), can be used before treatment to predict
likely positive or negative outcomes in cancer treatment (Hendrickson et al., 2011).
Because patients with hypoxic tumors invariably respond poorly to treatment responses,
the ability to detect hypoxia helps physicians in making a decision on possible treatment
options. Finally, imaging biomarkers such as FDG can be used to evaluate the efficiency
of a specific drug treatment, for example, on tumor growth (Dunphy & Lewis, 2009).
Figure 3: Role of PET in Drug Development (modified from (Hoffman &
Gambhir, 2007)

33
2.4.2 PET Safety Issues
When any diagnostic product is evaluated for use in patients, regulators and
clinicians must consider its safety. Radiopharmaceuticals have had a relatively benign
safety profile. Nevertheless, in any risk analysis of radiopharmaceuticals, two safety
issues stand out: radiation-related adverse effects and reactions related to drug impurities.
These safety concerns have had a particularly high level of attention for more than 50
years (Devine & Mawlawi, 2010). The unique safety concerns associated with
radiopharmaceuticals and, more particularly, with PET products were recognized
formally by federal regulators in 1946. Initially, the FDA considered radiation safety to
be a specialization best handled outside of the Agency and deferred its regulation to the
U.S. Atomic Energy Commission (AEC), which later became the Nuclear Regulatory
Commission (NRC). However, in 1975, the expanded use of radiopharmaceuticals in
human patients prompted the AEC and the FDA to agree that radiopharmaceuticals were
a special type of drug that should be subject to the same approval and oversight
mechanisms as other pharmaceuticals. Thus, radiopharmaceuticals became subject to the
dual oversight of the two agencies. The NRC was given the responsibility of regulating
radiation exposure, whereas the FDA was charged with evaluating the safety and efficacy
of drug products. The risks of radiation exposure are discussed only briefly below
because they are outside of the scope of this study. The risks associated with safety and
efficacy under FDA purview have to a large extent focused on the potential risks
associated with the potency and purity of the drug itself and most recently on the use of
GMP methods to assure a quality product (Hricak et al., 2011).

34
2.4.3 NRC Oversight of Radiation Exposure Risk
Risk is typically characterized as a function of the severity of injury that might
result from exposure to a hazard and the frequency with which the hazard can result in
injury. When trying to minimize risks from radiation exposure, the key areas of focus
include challenges associated with the obligatory exposure of patients, accidental or
occupational exposure of personnel and threats of terrorist dispersal. Hazardous
accidental exposure to radioactive material poses a concern whenever unsealed
radioactive sources are in use. Accidents related to accidental exposure or overdoses are
rare in the United States (Devine & Mawlawi, 2010).
2.4.3.1 Radiation Exposure to Patients
Radiation dosage levels experienced by patients from standard FDG PET scans
have been studied thoroughly. Typically, exposure of various organs is measured by
estimating the absorbed dose to organs and tissues, reported in units of milligray (mGy),
and millisievert (mSv), the effective dose corresponding to the radiation specific damage
in humans. The maximum absorbed dose for any organ is below 141 mGy and the
maximum effective dose is below 10 mSv, in a standard FDG PET scan. The effective
dose from a CT scan in conjunction with a PET scan is equal to 14mSv. The combined
effective dose from a PET/CT scan is equal to roughly 24 mSv, which is a substantially
higher radiation dose exposure whose effects must be considered more carefully. The
radiation associated with these tests must be interpreted in the context of the overall
exposure to radiation of the same patients from other sources. These tests constitute the
major source of radiation exposure for most, second only to exposure to radon and other
environmental sources (Schauer, 2009).

35
Figure 4: Major Sources of Ionizing Radiation Exposure of the Population of
the United States in 2006 (Schauer, 2009)

36
Table 5: Examples of Radiation Dose Exposure (modified from (SNMMI,
2012)
Typical Activities Radiation Dose
Watching television 0.01 mSv/year
Air travel (round trip from Washington, D.C., to
Los Angeles, Calif.)
0.05 mSv
Average annual exposure living in the United
States
3 mSv/year
Average annual exposure from breathing radon
gas
2 mSv/year
Tobacco products (amount for a smoker’s lungs
from 20 cigarettes a day)
53 mSv/year
Medical Imaging Radiation Dose
Medical chest X-ray (one film) 0.1 mSv
Nuclear medicine thyroid scan 0.14 mSv
Full set of dental X-rays 0.4 mSv/year
Mammogram (four views) 0.7 mSv
Nuclear medicine lung scan 2 mSv
Nuclear medicine bone scan 4.2 mSv
Nuclear cardiac diagnostic test (technetium or
Tc-99m)
10 mSv
Abdominal CT scan 10 mSv
Various PET studies (
18
F FDG) 14 mSv
Cancer treatment (received by tumor) 50,000 mSv

Because exposure of a patient to radiation is inherently risky, the balance between
risk and reward must be weighed on a case by case basis before the scan is administered.
The relatively high radiation exposure from a PET/CT or even a stand-alone PET drug
administration has been cause for regulatory concern. Most FDG PET scans are
administered to cancer patients, where the risk of damage from the radiation dose is low
compared to the benefits of the scan for monitoring and treatment. Nevertheless, the

37
recent trend to combine PET scanning with CT to provide both functional and anatomical
information can greatly increase radiation exposure from the combination of the external
CT source (x-ray beam) and the injected PET radiopharmaceutical (Hricak et al., 2011).
By combining PET and CT, penetration of the photon annihilation (and radiation)
from a dose of F-18FDG, the most common PET drug, can be 10-20 times higher than
that typical in traditional diagnostic procedures. Such exposure is still considered to be in
a range where the benefit outweighs the risk. However, the balance between risk and
benefit may shift substantially when the imaging methods are used in pediatric, pregnant,
or lactating patients. Before a PET/CT scan is scheduled, the FDA recommends that
female patients should be carefully screened for the possibility of pregnancy, and if found
pregnant, the study should be canceled immediately. The radiation dose exposure to the
fetus from a PET/CT scan may potentially be damaging, although very few studies
provide radiation dosimetry data in pregnant patients (Devine & Mawlawi, 2010).
2.4.3.2 Radiation Exposure to Personnel
It is also important to limit radiation exposure of personnel involved in the
production and administration of the radiopharmaceutical. The annual occupational limit
for adult staff exposed to radiation has been set by the Environmental Protection Agency
(EPA) at a total effective dose of 50 mSv. In comparison, the effective limit for
individuals who work outside of the radiopharmaceutical sphere is set at 3 mSv per year
(Devine & Mawlawi, 2010). Personnel exposed to occupational radiation are required to
wear personal dosimeters to monitor their annual effective dose. Shielding remains the
best method to reduce radiation exposure from a PET drug. Lead containers are used to
transfer the radioactive dose. Distance and time are very important concepts in avoiding

38
unnecessary radiation exposure from PET drugs. Most exposure time occurs at the time
of patient injection, so syringe shields are used to protect the hands and fingers of the
health care professional giving the drug, who are trained to leave the patient immediately
after injection to avoid unnecessary exposure. Researchers and research organizations
charged with the manufacture of radiopharmaceuticals are required to take radiation
safety training courses and must monitor the status of exposed personnel to minimize
such issues. Establishment of a radiation safety office and oversight by a licensed
radiation safety officer are also very important in preventing radiation hazards (Hricak et
al., 2011).
2.5 FDA Oversight of PET Radiopharmaceutical Production
2.5.1 PET cGMPs
The regulatory control of PET radiopharmaceutical manufacturing has not
traditionally been a subject of focus for the FDA. Until recently, USP standards served
as the basis for PET drug production under the supervision of state regulatory bodies.
The source for these rules, USP, has provided quality standards for drugs that are
marketed in the United States since the 1800s and has had specific standards for PET
drugs since 1988 (Hung, 2001). In most regards, PET drugs were approached as
compounded products, whose rules for production could be satisfied by following the
USP General Chapter <823>, “Radiopharmaceuticals for Positron Emission
Tomography- Compounding” (Hung, 2013). This Chapter became the singular gold
standard for reference on PET drug manufacturing until the late 70s (Schwarz, Dick,
VanBrocklin, & Hoffman, 2014). The reliance on this standard was clearly in evidence
when a published Senate report endorsed the continued use of USP standards as a

39
framework for the regulation of PET drugs as late as 1997 (Jeffords, 1997). That
proposal stated that “Makers and users of PET radiotracers will continue to be subject to
the requirements of the various state boards of medicine and pharmacy which they are
currently required to meet.”
2.5.2 FDA Part 212 vs. USP Chapter <823>
The minimum requirements under 21CFR 212 versus USP Chapter 823 differ in
several respects. The more detailed 21CFR 212 includes stricter requirements to ensure
better radiopharmaceutical practices and oversight. These additional requirements
increase the quantity of paperwork, the amount of microbiological testing and instrument
qualification, and the frequency of analytic testing to ensure that release specifications
are met (Schwarz et al., 2014). The Appendices section, Appendix A, highlights the
major changes between the two requirements.
Historically, PET radiopharmaceuticals have been produced in limited quantities
by academic institutions. In the last decade, however, these products are increasingly
made in centralized, for-profit PET radio-pharmacies that are able to make larger
quantities of PET drug products and to distribute them more widely to imaging centers
(Norenberg et al., 2010). To assure effective distribution, many radio-pharmacies are
linked into a rapid-response chain or network so that the product can be transported very
quickly to its site of use. Unique challenges are posed because the central hub of the
rapid response network must standardize the operating procedures of multiple production
sites that form spokes around it (Barrio, Marcus, Hung, & Keppler, 2004).
Despite the need to satisfy USP standards, not all constituencies have been
comfortable with the relatively relaxed oversight of PET drugs that was felt to occur

40
without more specific federal regulations. A push for PET cGMPs came mostly from the
recently emerging commercial PET manufacturers, who found it difficult to interpret the
USP guidelines and therefore to be confident in their compliance with USP standards
(Zigler, 2009). Their views seemed at odds with those of the academic medical centers
where the bulk of production still took place. Those centers appeared to prefer the more
relaxed regulatory oversight and relatively rare inspections often initiated by individual
state regulators only when problems were reported. Their views seemed to stem from
concerns regarding their capabilities to support the kind of rigorous quality system
typically imposed by the FDA given their modest academic resources. A major change
in regulations could shift the balance between the for-profit radio-pharmacies and the
academic institutions as the academic sites are “priced out of the market”.
Initially, the FDA had expressed the intent to govern PET radiopharmaceuticals
with GMP standards identical to those of conventional pharmaceutical products.
However, it would be challenging for manufacturers to comply with those regulations
when they manufacture PET radiopharmaceuticals because PET radioisotopes degrade
rapidly(Jeffords, 1997). The need to comply would place enormous pressure on
production to be carried out as rapidly as possible. Even then, the ability to conduct final
product testing prior to release would be limited because of the inherent instability of the
drug. Thus, concessions were needed to identify a compromise (Schwarz et al., 2014).
The need to come to a middle ground was reinforced after Congress amended
Section 121 of the U.S. Food & Drug Modernization Act (FDAMA) of 1997 to alter the
regulatory framework of PET drugs, and charged FDA with the task of developing a new
approval pathway and separate cGMP regulations for PET pharmaceutical products

41
(Food and Drug Administration, 1997). Prior to this new legislation, Section 121 of
FDAMA did not require an NDA or ANDA pathway for PET drug manufacturing until
PET cGMP requirements were published; they only stated that the PET drugs would be
required to be compounded under USP standards. Thus the FDA came under pressure to
frame new regulatory requirements (Keppler et al., 1998).
On December 9, 2009, the FDA issued its final cGMP regulations for the
production of PET drugs, specified in 21 CFR 212 (Norenberg, Schwarz, & VanBrocklin,
2011). The regulation, which became effective December 12, 2011, contains a number of
specific requirements for PET drugs. Under these requirements, the PET manufacturing
facility must register with the FDA and must also submit a marketing submission, usually
in the form of a New Drug Application (NDA), by December 11, 2011. Three
compounds, F-18 FDG, F-18 Fluoride (NaF), and N-13 Ammonia, were able to follow
the shorter Abbreviated New Drug Application (ANDA) process because they could be
made as generic drugs against an available reference listed drug (RLD) to which they
could refer (Schwarz et al., 2014). Whether developed as a new or generic drug, however,
the manufacturer must satisfy the quality requirements spelled out in the cGMP
regulations.

42
Current good manufacturing practices for PET drug products establish
the minimum requirements for the methods to be used in, and the facilities
and controls used for, the production, quality control, holding, or
distribution of a safe and effective PET drug product intended for human
use…. PET CGMPs establish basic requirements to assure that final drug
products are pure, safe, efficacious, packaged and labeled appropriately.
To accomplish these multiple objectives, the requirements attempt to
balance the typical manufacturing practices expected of all
pharmaceuticals with the special needs of products that have a short half-
life and an expensive and inherently risky manufacturing process. Going
forward, the cGMPs spelled out in Part 212 will be the official regulatory
law for standard clinical PET drugs (Food and Drug Administration,
2009)

The delay in establishing PET cGMPs from 1997 to 2009 reflected a struggle
between two opposing forces of risk and benefit. The risk of overburdening the PET
small manufacturers, such as those in academic centers where resources are modest, with
overly stringent FDA regulatory requirements introduced the risk of losing research
related to new PET drugs (Harapanhalli, 2010). However, the benefit of having more
rigorous GMP regulations was the better assurance of product quality and safety. The
U.S. Senate illustrated its appreciation of the need for balance quite clearly, in the quote
below from Senate Report No. 43, 105
th
Congress, 1
st
Session, 1997:
PET radiopharmaceuticals have been used in patients in the United States
over 30 years. Recent research and advances in imaging technology have
enhanced the clinical importance of PET…. At present, there are 70 PET
centers in the United States, almost all of which are part of academical
medical centers. PET Technology and its applications were developed in
large part with almost 2 billion in federal research funds. Yet, while PET
is widely used in Europe, its benefits have not been widely available to
American patients, mainly because of lack of reimbursement and
inappropriate and costly regulations promulgated by FDA (Jeffords,
1997)

43
The deadline for adoption of PET cGMPs for PET drugs was set at June 2012. It
was supposed to be set two years after the publication of 21 CFR Part 212, but a 6-month
extension was provided by the FDA (Hung, 2013). Currently, all PET drug producers are
required to register by submitting drug establishment and drug listing information to the
FDA through electronic submissions (Food and Drug Administration, 2009).
The PET cGMP regulations in 21 CFR Part 212 had significant differences from
cGMP regulations for other finished pharmaceuticals, 21 CFR parts 210 and 211. The
PET cGMPs imposed less stringent requirements on clean rooms, on post production
QA/QC testing and on reporting in general (Food and Drug Administration, 2017b).
Additionally, 21 CFR part 212 includes more clearly defined organizational
requirements, simplified aseptic processing requirements, and the requirement for QC
verification for sub-batches of drug product. Part 212 is also unique in allowing for a
staff member to self-verify the oversight of production, QC approval and release final
product for human use (Schwarz et al., 2014).
One of the open questions as regulations become strict is what problem will be
mitigated by the additional cost and effort associated with satisfying the additional
regulatory requirements of 21 CFR Part 212. Despite multiple examples of poor
manufacturing compliance, PET drugs have maintained a good safety record. Silberstein
and his colleagues surveyed the adverse event records from 22 PET manufacturing
centers and found no adverse events reports for the 81,801 PET drug doses that they
provided (Silberstein & Pharmacopeia Committee of the Society of Nuclear Medicine,
1998). Further, an FDA notice titled Positron Emission Tomography Drug Products;
Safety and Effectiveness of Certain PET Drugs for Specific Indications (Food and Drug

44
Administration, 2000) on the production and administration of FDG F18 and ammonia
N13 concluded that the specified PET drugs are safe and effective when they are
manufactured under specified conditions. These observations have led the leaders of
many academic centers to oppose the new and more stringent PET cGMP requirements,
arguing that little is gained and much is lost by requiring such strict compliance (Hung,
2013). They point out that financial burden to implement the cGMP regulation is too
onerous, and may require some academic centers to cease their operations. Because
academic centers are the main locations at which new products and treatments are
currently developed, the GMP requirements may hinder the innovation central to the
development of new PET imaging agents (Zimmermann, 2013).
2.6 PET Radiopharmaceutical Investigational Studies
The use of PET radiopharmaceuticals in clinical trials is common and has been
subject to special consideration and regulatory restrictions. All clinical protocols
administering investigational radiological products must be performed under an
investigational new drug (IND) application or under the direct oversight of a Radioactive
Drug Research Committee (RDRC) (Food and Drug Administration, 2012). The two
committees deal with different kinds of research. The RDRC investigational route was
introduced by the FDA to provide a quicker and less onerous regulatory pathway to
perform basic research studies (Suleiman, 2006). An RDRC is an FDA-approved
committee overseeing the review of studies to ensure they are intended for only basic
science research and are safe and acceptable (Food and Drug Administration, 2010).

45
2.6.1 Radioactive Drug Research Committee (RDRC) Route
The RDRC program began when the FDA published a Federal Register notice on
July 25, 1975 classifying all radioactive drugs as either new drugs requiring an IND for
investigational use (21 CFR 312) or as generally recognized as safe and effective when
administered under the conditions specified in the RDRC regulations (21 CFR 361.1)
(Food and Drug Administration, 1975). The RDRC program permits basic research using
radioactive drugs in humans without an IND when the drug is administered to obtain
insight into “metabolism of a radioactive drug or regarding human physiology,
pathophysiology, or biochemistry” as long as the intervention is not intended for
therapeutic or diagnostic goals, and is not designed to test the safety or efficacy of the
drug. Typically, the doses of the drug are lower than those used for imaging
interventions. Nonetheless, the research study is approved by an FDA-approved RDRC
based on requirements for experimental design and protections to human subjects similar
to those of other types of clinical trials. Like other studies in humans, these studies
require the oversight of an investigational review board (IRB) and include mandatory
reporting of adverse events to the RDRC. Exploratory studies under RDRC guidance are
restricted by the number of patients, radiation dose, and designed similar to exploratory,
Phase 0 clinical studies under FDA oversight, described below (Food and Drug
Administration, 2010).

46
Table 6: Radiation Dose Limits under RDRC (Food and Drug Administration,
2010)
Type of Exposure mSv
Whole body, active blood-forming organs, lens of the eye, and gonads:
Single dose 30
Annual and total dose commitment 50
Other organs:
Single dose 50
Annual and total dose commitment 150

The RDRC program was a program uniquely developed to address some of the
challenges of using unapproved drugs for basic research. According to the FDA,
Human research using a radioactive drug or biological product may be
conducted under an RDRC only (e.g., without an IND) when that research
is basic science research and not research that is intended for immediate
therapeutic, diagnostic, or similar purposes, or to determine the safety
and effectiveness of the radioactive drug or biological product for such
purposes (Food and Drug Administration, 2010).
Thus, studies under an RDRC can be faster, cheaper, and more efficient.
When the RDRC rules went into effect in July 1975, the reported use of PET
labeled drugs was low. With the passage of time, the reported use of PET labeled drugs
and corresponding research using these radioactive drugs under RDRC oversight has
grown significantly. However, reporting requirements for drugs produced by this route
are not always accurately disclosed by RDRC committees, so that it has been difficult to

47
quantitate the number of studies and radioactive drugs being used under the authority of
the various RDRCs (Suleiman, Fejka, Houn, & Walsh, 2006).
2.6.2 Investigational New Drug (IND) Route
The IND route is used for trials that involve the assessment of drugs that might
eventually be marketed commercially. An Investigational New Drug submission is a
required process “for authorization from the FDA (1) to administer an investigational
drug or biological product to humans, (2) to obtain exemption from the premarketing
approval requirements that are otherwise applicable, and (3) to lawfully ship the
investigational drug or product for the purpose of conducting clinical investigations”
(Food and Drug Administration, 2012).

Figure 5: Decision Tree on the Applicability of RDRC versus IND

Figure 5 illustrates the decision-making pathway for studies under IND or RDRC.
Within the IND regulations are not only traditional applications for later stage clinical

48
trials but also a simplified option for exploratory investigations called Exploratory
Investigational New Drug (eIND) Applications. They require fewer
pharmacology/toxicology studies for approval and are limited to less than 30 subjects
(Mosessian et al., 2014). Studies using a more traditional IND route take longer to
initiate, require more data and supporting documentation, and generally go through a
longer review period by the FDA than RDRC or eIND initiated studies. However, IND
status is essential if the drug is to be used for clinical research studies. Table 7
summarizes the different investigational regulatory pathways for PET drugs.

49
Table 7: Comparison of RDRC, eIND, and IND Approaches for PET probes
(Mosessian et al., 2014)
Pathway RDRC eIND IND
Purpose - Only for basic research,
where the pharmacologic dose
of the drug to be administered
is known not to cause any
detectable pharmacologic
effect in humans
- Not intended for
diagnostic/therapeutic use
- Only for basic research
- Can be used to screen 2–5
probes simultaneously
- For micro-dose studies
- When completed, must
withdraw and transition to
an IND
- Not intended for
diagnostic or therapeutic
use
- For clinical investigation
of radiolabeled probes
- For therapeutic,
diagnostic and
preventative use
- For determining safety
and efficacy
Requirements - Clinical protocol
- Manufacturing under USP
823 or CFR 212 guidelines
- Dosimetry studies in
rodents
- Limited safety/tox studies in
rodents (determined by
institutional RDRC)
- No safety pharmacology
studies
- Clinical protocol
- Manufacturing under
USP 823 or CFR 212
guidelines
- Dosimetry studies in
rodents
- Toxicology studies in 1
species
- Safety pharmacology in 2
species
- No genotoxicity studies
- Clinical protocol
- Manufacturing under
USP 823 or CFR 212
guidelines
- Dosimetry studies in
rodents
- Toxicology studies in 2
species
- Genotoxicity studies

Approval

Subject #
Approval by RDRC and IRB
Up to 30
Approval by FDA and IRB
Up to 30
Approval by FDA and IRB
No limit

2.7 PET Drug Manufacturing Challenges
The need to satisfy cGMPs is not restricted to marketed products; investigational
products also must use products produced under at least a modified form of cGMPs or
abide by USP 823 regulations. This issue is important because many of the PET
radiopharmaceutical drugs are still in investigational stages either under the oversight of
an RDRC or through an IND application (Food and Drug Administration, 2012). From

50
the history of regulatory oversight that has taken place over the short time since the
regulations for radiopharmaceutical, GMPs have been in effect, implementation of the
new PET cGMP requirements has not been an easy task. Recent inspections by FDA are
bringing light a troubling number of compliance issues that were recently catalogued in a
podium presentation by FDA’s Brenda Uratani at the 2012 Annual Meeting of the
Society of Nuclear Medicine (Uratani, 2012). They included 1) inadequate training and
QA oversight of manufacturing personnel; 2) lack of sterility assurance; 3) lack of
assurance that test results are reliable and accurate; 4) deficiencies in production and
product release; and 5) inadequate documentation (Uratani, 2012).
Uratani (2012) also provided an update on the structure of future FDA
inspections, which are categorized as either pre-approval inspections or routine
surveillance inspections. Pre-approval inspections occur after submission of new NDA
and ANDA applications, generally 6-12 months after submission. Routine inspections
can occur as for-cause inspections as situations require, or as randomly timed inspections
that cycle about every 2 years, as resources and priorities of the agency allows (Hung,
2013; Uratani, 2012). A deeper understanding of the kinds of problems that exist can be
seen by evaluating two examples of regulatory non-compliance of an academic institution
(Columbia University) and for a commercial radiopharmacy (IBA Molecular)
respectively.
2.7.1 Compliance Challenges at Columbia University
The Kreitchman PET Center at Columbia University has been historically
regarded by experts as the nation’s leader in the use of PET for psychiatric research.
However, an article in the July 2010 issue of the New York Times brought to public

51
attention concerns about radiopharmaceuticals that previously had been largely outside of
the public eye. The article accused the Kreitchman PET Center of research misconduct,
by alleging that the Center routinely violated FDA regulations over a four-year period, by
injecting psychiatric patients with radiotracer drugs that contained dangerous levels of
impurities. Drugs with impurities can have unpredictable consequences on patients
receiving the injections. The article suggested that the patients involved in research at the
Center might be mainly patients who suffered from schizophrenia and other brain
disorders.
According to the New York Times, an FDA investigation carried out in January of
2010 found six categories of violations, including high levels of impurities and failures to
validate the identity, strength, and purity of each active ingredient (Carey, 2010). They
identified that, since 2007, at least 10 batches of drugs had been injected into human
subjects with impurities that exceeded the allowable limits; in four injections, the
impurity levels were more than double these limits. Of particular concern was the fact
that employees altered paper records to hide the presence of a drug impurity that was
clearly evident from computer records. Former employees complained that such
practices were not only commonplace, but systematic, and were allowed by the
laboratory director. Following the FDA investigations and warning letters, Columbia
University suspended research at the nationally recognized brain-imaging center. In
2011, the FDA “concluded that Columbia's Radioactive Drug Research Committee
(RDRC) did not ensure the necessary conditions for radioactive drugs to be considered
safe and effective, nor did the RDRC ensure the quality of radioactive drugs” (Forrest,
2011).

52
2.7.2 IBA Molecular
An FDA Warning Letter was issued to IBA Molecular, Inc. on October 24, 2008,
summarizing the results of a four-day inspection of IBA’s manufacturing facility in
Virginia (Sooter, 2008). The inspection first identified that the facility had failed to
register itself as a drug manufacturing establishment. More importantly, the drugs that it
produced were considered by the FDA to be adulterated as a result of deviations from the
USP monograph that was used to guide manufacturing. Numerous areas of
manufacturing operations were found to be out of compliance. An inadequate quality
control program was reflected in the absence of sufficient analytical procedures and
appropriate tests for drug impurities. The facility failed to use appropriate aseptic
techniques in a controlled environment and failed to perform appropriate maintenance on
its manufacturing equipment. These deviations cast doubt on the sterility and safety of
products, but the laboratory failed to investigate deviations and out-of-specification test
results.
On June 4, 2008, IBA issued a response letter to FDA-483. The FDA found the
remediation plan proposed in the letter to be insufficient in addressing the key problems
that were found during the inspection. The FDA asked IBA to correct the violations
listed in the Warning Letter promptly and reserved the right to take legal action against
IBA. The FDA also reserved the right to withhold approval requests for export
certificates or NDAs and to inspect the facility again. On March 16, 2011, the FDA
completed an evaluation of IBA’s collective actions in response to the warning letter and
concluded that “based on the evaluation and inspection, [IBA has] addressed the

53
violation(s) contained in the original Warning Letter” (Food and Drug Administration,
2011).
2.8 Exploring Challenges Posed by Radiopharmaceutical Regulation
It seems clear from the enforcement actions, literature and anecdotal evidence to
date that implementation of cGMPs in radiopharmaceutical production has proven
challenging (Hung, 2013). The key stakeholders, especially those in academia, find the
new regulations to require a significant investment of new resources (Zimmermann,
2013). Cash strapped centers have difficulty to bring their staff, infrastructure, and
monitoring systems into PET cGMP compliance. However, the literature is not well-
developed in this area, and most of what we know about industry experience in this
newly emerging area comes from conference presentations. For example, several
important insights into the challenges of PET cGMP implementation were presented on
June 9
th
, 2014, at the Society of Nuclear Medicine and Molecular Imaging (SNMMI)
annual meeting. The speakers provided a summary of challenges presented to a Coalition
of PET Drug users(Kubler, 2016), the organization formed in November 2010, that
represents both academia and industry and aims to assist the PET community in terms of
PET cGMP implementation.
At the SNMMI meeting, Steve Ehrhardt of Certus International discussed the
challenges of “hard and soft cGMP requirements” from the perspective of inspected sites.
Hard requirements were defined as objective and clearly stated, whereas soft cGMP
requirements were subjective and interpretive. Examples of hard cGMP requirements for
personnel would be the requirement to have an adequate number of personnel to perform
PET drug manufacturing; in contrast, he considered the need for adequate training to be a

54
soft requirement. In reference to Quality Assurance, the presence of written SOPs would
be a hard requirement and QA oversight would be a soft requirement. He asserted that
the reliance on soft and hard cGMP interpretations can lead to unpredictable findings
from different investigators. Thus manufacturers are concerned that inspectional
observations can be inconsistent from one inspection to another (Ehrhardt, 2014).
Sally Schwarz from Washington University described the results of a survey from
31 respondents on FDA submission and subsequent challenges at the same meeting
(Schwarz, 2014). The main challenges in terms of PET Drug Applications included a lack
of experience amongst FDA review staff and unclear requirements regarding the nature
of supporting documentation and vendor information related to equipment and supplies.
Respondents of that same survey also noted several challenges with regard to FDA
inspections, including lack of experience by the inspectors leading to inconsistent
inspections or inspections based on the 21CRF 211 rather than 212 requirements as
already noted by the speaker above and a perceived undue focus on aseptic techniques
and microbiologic requirements (Schwarz, 2014).
VanBrocklin (2014) from UC San Francisco discussed other regulatory
challenges posed by small academic entities. These included insufficient opportunities
for dialogue with the FDA, inadequate institutional resources to submit documents by the
relatively costly and knowledge-intensive electronic process, and inconsistencies in
standards based on the size of the manufacturing operation in terms of numbers of doses
produced and staffing levels (H. F. VanBrocklin, 2014). The Coalition, led by
VanBrocklin and Schwarz (2016), submitted comments to the FDA on March 24
suggesting that improvements were also needed to the ANDA submission process. These

55
improvements included more dialogue between FDA and the PET drug manufacturers,
improvements in awareness and educational opportunities, and exemption from some
parts of the required application processes (Schwarz, 2014; H. F. VanBrocklin, 2014).
It seems clear from the literature review above that the regulations in place
currently pose challenges for drug developers attempting to implement the regulations.
The anecdotal evidence to date suggests tensions related to the costs and difficulties of
implementing cGMPs for radiopharmaceuticals. However, it is not clear whether these
concerns are widely distributed amongst the PET manufacturing community.
2.9 Framing Research on cGMPs
To study systematically the challenges of implementing a manufacturing
operation as complex as that needed for radiopharmaceutical manufacture, it would seem
important to begin with a framework that can structure the survey research in a way that
might improve its comprehensiveness and balance. Thus for this study, a comprehensive
and well-respected implementation framework was selected to assist the survey
development process so that adequate attention was given to defined parts of the
implementation process.
Implementation is defined by Fixsen and colleagues as “a specific set of activities
designed to put into practice an activity or program of known dimensions.” (Fixsen et al.,
2005). Fixsen and colleagues define three stages to implementation:
Paper implementation: new policies and procedures are developed with the hope
of leading to change but, the implementation process is aborted. Typically, the
paper records provide a plan for implementation, but full implementation is not
achieved.

56
Process implementation: not only is paper implementation in evidence but new
operating procedures are attempted, as reflected by training sessions, changes in
protocol or work instructions, and the presence of appropriate supervisory efforts;
however, all of these do not appear to secure actual changes or benefits.
Performance implementation: new operating procedures are implemented in such
a way that they actually change outputs and create benefits for consumers or
users.
Fixsen et al (2005) developed a framework for conceptualizing implementation as
a system with five components that are present in any implementation scenario whether
well or badly organized (see Figure 6 below).
Figure 6: Conceptual Framework for Implementation of Practices and
Programs (modified from (Fixsen et al., 2005))

They include a source, destination, communication link, and feedback mechanism
that operate within a sphere of influence.

57
1. Source: refers to the best portion(s) of a practice or program that is already
developed and evaluated. This portion is the basis or model for the innovation
being implemented. In the case of radiopharmaceutical cGMP implementation,
this source would be the new regulatory requirements and associated guidances.
2. Destination: refers to the entity that will use the innovation and thus adopts,
houses, supports, and funds its installation. This destination would be the
pharmaceutical manufacturing operation in the academic center.
3. Communication link: refers to the individual or group working on implementing
the innovation/practice. This link would include the staff of the facility who are
charged with implementing the changes required by the regulations.
4. Feedback mechanism: refers to the flow of information regarding the
effectiveness of the implemented innovation/program on the performance of the
individuals and/or groups upon which it acts. Included in this element might be
internally generated information about the effectiveness of the implementation,
such as internal audits of the facility by individuals charged with quality
oversight, or feedback resulting from third-party or regulatory audits.
5. Influence: refers to outside factors—political, economic, religious, etc.—that may
have an effect on the above-mentioned individuals/groups.
The results of implementation in a broad sense can include a change in the
structure, professional behavior and/or outcomes within an organization. Ultimately, the
goal of the implementation is to change the relationship with consumers and

58
stakeholders. In this research, we considered that the stakeholders included not only the
organization and the health-care community that it serves with its products but also the
regulators who want to assure that rules are being followed. In order to achieve these
changes, Fixsen and colleagues (2005) suggest that implementation must be carried out in
stages (Figure 7). Fixsen used an evaluation of various studies utilizing the
implementation framework to develop an expanded framework in 2013, based on the
implementation drivers that they considered to be important at different stages of
implementation (Bertram, Blase, & Fixsen, 2013) (Figure 7).
Figure 7: Stages of Implementation (modified from (Bertram et al., 2013)

The first step, the ‘Exploration and Adoption’ step, is the phase in which a person
or group considers various facets of the innovation or change and suggests ways of
implementing it. The second ‘Program Installation’ step is the phase in which the

59
operations are performed that will allow the change to be implemented. Examples of
such changes include changes in staffing, funding, reporting, and so on. The third step is
“Initial Implementation”. Change cannot occur all at once or evenly so that this step can
be rather ‘awkward’. According to Fixsen et al (2005),
During the initial stage of implementation, the compelling forces of fear of
change, inertia, and investment in the status quo combined with the
inherently difficult and complex work of implementing something new.
And, all of this occurs at a time when the program is struggling to begin
and when confidence in the decision to adopt the program in being tested.

The program reaches the fourth step, “Full Operation” if it survives the “Initial
Implementation”. At this stage, the newly implemented program becomes fully
operational and eventually becomes the “accepted program” (Bertram, King, Pederson, &
Nutt, 2014). Subsequent to implementation is the fifth ‘Innovation’ step when the fully
operational program is recognized to have created undesirable changes that are eventually
discarded, or desirable changes that become embedded in the status quo. The last and
final step, ‘Sustainability’, is perhaps the most difficult. The newly implemented
innovation must be maintained for years, despite an ever-changing environment.
Elements such as funding, staffing, and political environments may change, but a
functional and effective program must survive despite these changes.
2.10 Core Implementation Components & Implementation Drivers
Implementing a set of steps such as those described above requires a commitment
of resources and people that are considered by Fixsen and colleagues (2005) as core
components. They consider these to be “the most essential and indispensable
components of an implementation practice or program”. In the schema of Fixsen, core

60
components are described as principally concerned with the people implementing the
changes. They include staff/practitioner selection, training, ongoing consultation and
coaching, staff and program evaluation, facilitative administrative support, and systems
interventions. Core implementation components are diagrammed in Figure 8 below.
Figure 8: Core Implementation Components (modified from (Fixsen et al.,
2005)

Staff/practitioner selection is choosing the most qualified people for carrying out
the program or practice. The selection process may depend on outside factors that may
limit the pool of available applicants. These factors may include the state of the
economy, availability of other competing opportunities for qualified individuals, and the
ability for educational programs to prepare new entrants appropriately. Preservice and

61
inservice training then provide staff/practitioners with the knowledge, background, and
skills necessary for their positions. Since some skills are better learned at the job, rather
than in training, consultants/coaches are available to help during this process. These
training and coaching interventions are the primary ways of bringing about change in
behavior. Staff evaluation addresses the performance of staff and provides feedback to
managers on the effectiveness of the training and coaching. Program evaluation then
assesses the performance of the organization as a whole. Facilitative administrative
support provides guidance and leadership to staff and supports the overall process.
Systems interventions are approaches and tactics used to work with systems outside of the
organization to ensure funding and resources are available to support the work of the
practitioners. These components are synergistic and when combined maximize their
impact on the culture and behavior of an organization and its staff. These components
can also provide balance within the implementation process; a weakness in one area can
often be overcome if strengths are present in other areas.
There has been a significant modification of the core implementation components
into three groups of implementation drivers (leadership, competency, and organization)
since the original presentation of the work (Fixsen et al., 2005). By evaluating
implementation drivers, it is possible to assess the effective progression through the
different implementation stages. Feedback about the state of the implementation drivers
provides the basis to establish program changes necessary to improve implementation
outcomes.
Competency drivers in the modified Implementation Framework consist of
training, coaching, staff selection and performance assessment. Leadership drivers

62
consist of technical and adaptive leadership. Organization drivers are comprised of
systems level intervention, facilitative administration, and decision support through data
system. The figure below summarizes theses implementation drivers.
Figure 9: Implementation Drivers (modified from (Bertram et al., 2013)

2.11 Implementation Framework Applied to PET cGMPs
Current views of implementation are based on the scholarly foundations prepared
by Pressman & Widavsky’s (1973) study of policy implementation, Havelock &
Havelock’s (1973) classic curriculum for training change agents, and Rogers’ (Rogers,
1983, 1995) analyses of factors influencing decisions to choose a given innovation. These

63
foundations were tested and further informed by the experience base generated by
pioneering attempts to implement Fairweather Lodges (Fairweather, Sanders, Tornatzky,
& Goldstein, 1974) and National Follow-Through educations models (Stivers & Ramp,
1984; Walker, Hops, & Greenwood, 1984). Petersilia (1990) concluded that “The ideas
embodied in innovative social programs are self-executing.” Instead, what is needed is an
“implementation perspective on innovation - an approach that views postadoption events
as crucial and focuses on the actions of those who convert it into practice as the key to
success or failure (p,129)”.
In this study, I used the implementation framework of Fixsen and colleagues
(2005), to evaluate the stage of cGMP implementation, and the perceived state of
implementation drivers at different PET drug manufacturing sites. This particular
implementation model, designed from studies of educational and service organizations,
seemed particularly suited to study the implementation of PET cGMPs; like education or
public services, PET facilities rely heavily on the knowledge base of the personnel who
must carry out the implementation. The policy implementation framework can be used
not only to guide the assessments of implementation stages but also to explore the
challenges and changes that are seen to be particularly problematic in the implementation
process.

64
CHAPTER 3: METHODOLOGY
3.1 Overview
This investigational study utilized a survey approach in which an appropriate
instrument was developed using the implementation framework of Fixsen and colleagues
(2005) to assess the state of implementation of cGMPs in PET cGMP production
facilities. Content validity was critiqued by convening a focus group of experts on GMP
implementation and survey design. The survey was then used to analyze the views of
experts in the medical imaging community in order to gauge their views on the
challenges and usefulness of the new cGMP regulations.
3.2 Survey Development
The survey was developed using a web-based survey tool (Qualtrics,
www.qualtrics.com). It was divided into 3 parts. The first part requested demographic
information with regard to the job classification, primary research or clinical focus, and
nature of employment setting. The second part addressed the state of implementation of
the site at which the respondent worked, as well as the significance of implementation
drivers in the context of PET cGMP implementation. The third part explored the views
of the respondents with respect to regulatory barriers, challenges, and guidance in the
implementation of GMPs and in the development of new PET radiopharmaceuticals more
generally, using questions of mixed format including yes/no, Likert scales, rank-ordering,
and text entry formats.

65
3.3 Focus Group
The focus group consisted of a selected group of senior directors, managers, and
research faculty directly involved or exposed to the PET imaging community. It was
important to have a representative group from both academia and industry to provide a
balanced review and feedback of the survey tool. The draft survey was sent by email two
to four weeks prior to the date of the focus group meeting to give the participants ample
time to review the document. The list of focus group participants is highlighted in the list
below.
Table 8: Focus Group Participants
NAME TITLE
Frances J. Richmond, BNSc,
MSc, Ph.D. (Focus Group -
chair)
Professor, Chair, Department of Regulatory and
Quality Sciences
Michael Jamieson, DRSc
Assistant Professor, Clinical Pharmacy and
Pharmaceutical Econ. and Policy
Eunjoo Pacifici, PharmD,
Ph.D.
Assistant Professor of Regulatory and Quality
Science Director, Internationcal Center for
Regulatory Science
Peter S. Conti, MD, Ph.D.,
FACR, FACNP
Professor of Radiology, Pharmacy and Biomedical
Engineering
Sherly Mosessian Ph.D. Chief Administrative Officer, UCLA
Serge K. Lyashchenko Cyclotron Radiopharmacy Supervisor, MSKCC
Phillip DeNoble Radiopharmacist, MSKCC

The focus group was scheduled for 60-90 minutes in a convenient location at the
university’s Regulatory Science office complex, 1540 Alcazar Street, Los Angeles. A
moderator, scribe, and audio-visual technician were present to assist with the proceedings
of the focus group. Participants were asked for their permission to appear on video,
which served as a useful evaluation tool after the meeting. I served as moderator and

66
provided an overview of the research project and purpose of the survey. I then engaged
the participants in a critique of the survey. Feedback from the focus group participants
was used to edit and finalize the survey instrument.
3.4 Survey Distribution and Analysis
The finalized survey was distributed electronically through a web-based survey
platform, Qualtrics. The first panel of individuals included a selected group of PET
cGMP community experts who received email links to the survey. We anticipated at least
40 respondents to complete the survey, based on the experience of others with similar
surveys to professional medical audiences where response rates vary. This was the
response number that actually was obtained.
The second and third sets of survey respondents were solicited through electronic
distribution to the World Molecular Imaging Society (WMIS) and the Society of Nuclear
Medicine and Molecular Imaging (SNMMI). The anticipated number of distributions was
about 500 potential participants. The purpose, directions, and a prize notification (IPAD)
for participation were printed on the top of the survey.
Data from each survey was analyzed and evaluated statistically in those instances
where such statistics are appropriate. Generally, in an exploratory study such as this, only
basic statistics described by mean and modal values are appropriate for purposes of data
aggregation. A cross-tabulation tool available through Qualtrics was also available to
substratify the results of some questions by using demographic data obtained from the
initial questions. Results of the analysis were presented and summarized through
representative graphs, charts, and tables.

67
CHAPTER 4: RESULTS
4.1 Analysis of Survey Results
The survey was first disseminated to a selected group of PET cGMP community
experts that included 106 potential participants who received email links to the survey
between January 4
th
and Feb 10
th
, 2016. Forty-eight (48) of these surveys were started,
and forty (40; 67%) were completed in full. The second set of survey respondents was
contacted through the membership lists of two imaging societies by using anonymous
email links. The World Molecular Imaging Society (WMIS) sent out the email soliciting
participants on January 6, 2016. The Society of Nuclear Medicine and Molecular
Imaging (SNMMI) sent out a similar email request on January 14, 2016. An additional
143 respondents completed the survey through this distribution mechanism. The survey
was kept open until March 14, 2016, for all participating groups.
4.2 Profiles of Respondents
Most individuals who completed the PET survey were employed in the
university/hospital setting (71%, 114/161). The remaining 47 respondents self-identified
as working in commercial sectors (12%, 19/161), the federal government (7%, 11/161) or
“Other” settings (11%, 17/161) (Figure 10). The “Other” category included job titles such
as “Consultant”, “both University and Biotech”, “Retired” and additional categories not
listed as a survey option.

68
Figure 10: Employment Setting
Where are you employed?

Some job titles were provided to assist respondents in identifying their current
positions, but only about half selected one of these positions. As shown in Figure 11,
20% (32/159) were Chemists/Technicians, 12% (19/159) were Administrators, 10%
(16/159) were Radiopharmacists, 7% (11/159) were Regulatory/Quality Specialists and
4% (6/159) were Cyclotron Operator/Engineers. Notably, the other half were employed
in “Other” (47%; 75/159) categories. The most common self-identifications were a center
director, scientist, manager, and student but other choices are also identified as shown in
Appendix B.

69
Figure 11: Employment Position
I am currently employed as a…

Many respondents reported that they had over 10 years of experience in the PET
radiopharmaceutical production environment (47%, 65/138). The remaining respondents
were split nearly evenly into their experience levels, with about 17-18 % in each of the 0-
2 year, 3-5 year and 6-10 year categories (Figure 12).

70
Figure 12: Experience in the PET Environment
I have been involved in the environment of PET radiopharmaceutical
production for…

The main roles related to the implementation of PET cGMP activities were fairly
evenly distributed between the three identified job roles identified by the descriptors
“Administrative” (31%, 38/124), “Regulatory” (31%, 38/124), and “Technical” (29%,
36/124). A minority of respondents (9%, 12/124) identified their roles as “Other” (Figure
13).

71
Figure 13: Roles Related to the PET Environment
My main role related to the implementation of PET cGMP activities
is…

PET cGMP activities were described by choices including Cyclotron operations,
chemistry synthesis, QA/QC for product release, development of manufacturing/quality
documentation, management of regulatory submissions (e.g., ANDA, NDA, IND), and
“Other”. When asked how they distributed time between these operations, the majority of
the respondents identified that regulatory and documentation activities occupied more
than 20% of their time. On average, the activity that occupied most time in this
respondent group was the management of regulatory submissions. This activity appeared
to account for about 19% of the time, though the range of allotted times had considerable
variation (Figure 14). In contrast, of 70 responses, 58 spent less than 20% of their time on
Cyclotron operations.

72
Figure 14: Time Spent on PET cGMP Activities
I spend the following percentage of time in the following PET cGMP
activities.

# Question Less
Than
20%
21-
40%
41-
60%
61-
80%
81-
100%
Response Mean
1
Cyclotron operations 58 9 2 - 1 70 1.24
2
Chemistry synthesis 34 21 7 4 3 69 1.86
3
QA/QC for product release 36 23 7 3 2 71 1.76
4
Development of
manufacturing/quality
documentation
33 26 10 2 3 74 1.86
5
Management of regulatory
submission (ANDA, NDA,
IND, etc.
34 22 11 2 5 74 1.95
7
Other 6 3 1 1 2 13 2.23

73
The majority of respondents indicated that their operations released 1-2 (40%,
59/149) or 3-5 batches per day (34%, 50/149). About 9% (14/149) released 6-10 batches
and 17% (26/149) released over 10 batches per day (Figure 15).
Figure 15: Batches Released per Day
How big is your operation (based on batches released in a day)?

Respondents were queried about the state that best describes cGMP (21 CFR Part
212) implementation at their facility. Nearly half (45%, 34/75) stated that they have a
fully functional cGMP facility. Twenty-one percent (16/75) were in the process of
writing controlled documentation/procedures and training staff on cGMP. Seventeen
percent (13/75) were learning and exploring options and 7% of respondents had secured
resources. Only a small number had been audited by the FDA (7%; 5/75). Finally, 3%

74
(2/75) had started to hire necessary staff but had not put the documented systems into
place (Figure 16).
Figure 16: State of Implementation of cGMP (21 CFR Part 212)
Which statement best describes the state of cGMP (21CFR Part 212)
implementation at your facility?

The respondents were asked to characterize their stage of progress in the
following areas: 1) Assessing PET facility needs, 2) Evaluating cGMP requirements,
3) Examining potential barriers to implementing requirements or 4) Assessing
organizational resources, on a scale of 1-10. The responses averaged between 7.52 for
“Assessing organizational resources” (67 responses, SD 2.75) to 8.21 for “Assessing PET
facility needs” (71 responses, SD 2.65). The other two areas had intermediate values of
7.96 for “Evaluating cGMP requirements” (69 responses, SD 2.65) and 7.67 for

75
“Examining potential barriers to implementing requirements” (69 responses, SD 2.67)
(Figure 17).
Figure 17: Stage of Progress of cGMP Activities
We are interested in the degree to which you have implemented
quality systems in your operations. Which of the stages best
characterizes the progress of your activities in the areas below?

When asked about the current state of hiring in order to implement PET cGMP,
44% (32/72) described their current staffing as adequate and equipped with sufficient
GMP expertise. Thirteen percent (9/72) responded that they had expanded their operation
by hiring new staff with GMP expertise and 10% (7/72) stated that the current staffing is
adequate but lacks GMP expertise. Thirty-three percent (24/72) stated that they must still
hire more staff (Figure 18).

76
Figure 18: State of Hiring to Implement PET cGMP Activities
Which of the following choices identify the current state of hiring to
implement PET cGMP activities at your facility?

Participants had a similar distribution of views when asked whether certain
aspects of cGMP requirements were implemented at a level sufficient to pass an FDA
audit. These included: Modifying (Standard Operating Procedures) SOPs (64%, 44/69),
Conducting IQ/OQ/PQ of equipment & facilities (58%, 40/69), Preparing and submitting
FDA regulatory applications (ANDA/NDA) (54%, 37/69), Advanced training for staff
(62%, 43/69), QA/QC validation activities implemented on a prescribed schedule (65%,
45/69), and Annual or quarterly audits (57%, 39/69). A minority of respondents (16%,
11/69) acknowledged that none of the identified areas were implemented at a level
sufficient to pass an audit (Figure 19).

77
Figure 19: cGMP Requirements Implemented Sufficiently to Pass FDA Audit
In your opinion, which of the following aspects of cGMP
requirements do you believe to be implemented at your PET cGMP
facility at a level sufficient to pass an FDA audit? Check all that
apply.

When asked to estimate the costs associated with bringing their facility into
compliance with PET cGMP requirements, the responses varied according to the areas
suggested to require an upgrade. Facility improvements were viewed to be most costly.
Of choices between $0-50K, $51-100K, $101-200K, $201-500K and over $1M, the most
common selection was over $1 million (20/51). In contrast, the most common selection
for equipment acquisition/upgrades was between $201 and $500 thousand (19/51
responses). Consultant payments were most commonly estimated to cost between $51K
and $100K (17/44). Process (18/48) and Equipment (18/47) validations had lower
estimates most typically of $0 to $50K. The cost of hiring and training of additional staff

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had a relatively wide range of estimates, mostly between $51-100K (13/50), $101K-200K
(14/50), and $201-500K (13/50) (Figure 20).
Figure 20: Costs Associated with Facility Compliance
Please estimate, to the best of your ability, the costs that have been
associated with bringing your facility into compliance with PET
cGMP requirements.

# Question
0-
50K
51-
100K
101-
200K
201-
500K
Over 1
million
Responses Mean
1 Facilities improvements 7 4 8 12 20 51 2.37
2
Equipment
acquisition/upgrade
6 6 7 19 13 51 2.51
3
Hiring and training of
additional staff
6 13 14 13 4 50 3.40
4 Investment in consultants 14 17 9 3 1 44 3.68
5 Process Validations 18 12 11 4 3 48 3.50
6 Equipment Validations 18 10 12 5 2 47 3.53
Respondents were asked to rate the level of challenge presented by four potential
obstacles to PET cGMP implementation. Most respondents identified that all of the

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four listed elements were Somewhat Difficult to Very Difficult [Finding financial
resources (17/62); Lack of internal organizational resources, (15/63); Finding and hiring
staff, (19/63); Writing/submitting regulatory documents (13/61)]. The modal value for
most answers centered was “Somewhat Difficult”, but the range was wide. Notably,
more than 20% of respondents identified that acquisition of financial resources and/or
lack of internal resources were “Very Difficult” (Figure 21).
Figure 21: Degree of Challenge Posed by Different Elements Required for
Facility Compliance
How challenging have you found the following potential obstacles for
your PET cGMP implementation?

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# Question Very
Difficult
Difficult Somewhat
Difficult
Neutral Somewhat
Easy
Easy N Mean
Value
1
Lack of
internal
organizational
resources
14 11 14 15 4 5 63 3.32
2
Writing and
submitting
PET Drug
Applications
5 13 14 13 12 4 61 2.92
3
Financial
resources
13 15 17 12 2 3 62 3.00
4
Finding/hiring
knowledgeable
staff
6 17 19 13 6 2 63 2.60

The respondents were asked to describe their companies’ level of satisfaction with
regard to the FDA feedback and support in certain specified areas of activity. Modal and
median values in all areas centered around “Neutral” to “Satisfied” [Review of PET drug
submissions (Neutral (17/53), Satisfied (25/53); Support/Clarity of communication
[Neutral (17/53), Satisfied 24/53)]; Adequacy and consistency of standards [Neutral
(22/53), Satisfied (20/53)]; Opportunities for dialogue [Neutral (20/54), Satisfied
(19/54)]; Experience of FDA staff [Neutral (18/52), Satisfied (19/52)] (Figure 22). Only
10-15% of respondents registered dissatisfaction with FDA support in these different
categories.

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Figure 22: Satisfaction with FDA Feedback and Support
Please describe how satisfied your organization is with the role of the
FDA feedback and support in the following areas of interest.

# Question Very
Dissatisfied
Dissatisfied Neutral Satisfied Very
Satisfied
N Mean
1 Support/clarity
of
communications
2 3 17 24 7 53 3.58
2 Review of PET
drug
submissions
2 3 17 25 6 53 3.57
3
Experience of
FDA staff
3 3 18 19 9 52 3.54
4
Opportunities for
dialogue
2 4 20 19 9 54 3.54
5 Adequacy and
consistency of
standards
2 6 22 20 3 53 3.30

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Respondents were asked about the usefulness of certain assistance that might
facilitate the implementation of GMPs, including funding opportunities for PET GMP
activities, standardized PET cGMP facility SOPs, standardized PET drug applications
and annual training for FDA/PET drug manufacturers, using a five-point scale from Very
Useful to Very Unimportant. The majority of respondents regarded all of these options as
important. The most attractive option seemed to be that of providing funding
opportunities for PET cGMP activities, with more than 80% suggesting that such help
would be Very Useful (30/64) to Useful (24/64). Annual training for FDA/PET drug
manufacturers was viewed by about 75% of respondents as Very Useful (25/64) or
Useful (23/64). Standardized PET drug applications were seen by 71% as Very Useful
(27/64) or Useful (19/64) and standardized PET cGMP facility SOPs were seen by about
two-thirds of respondents as Very Useful (28/65) or Useful (14/65) (Figure 23).

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Figure 23: Perceived Usefulness or Particular Support Programs
How useful would it be to your organization if the following were
available from the PET community or FDA?

# Question Very
Useful
Useful Neutral Unimportant Very
Unimportant
N Mean
1 Standardized
PET Drug
Applications
27 19 12 5 1 64 1.97
2 Standardized
PET cGMP
Facility SOPs
28 14 15 6 2 65 2.08
3 Funding
Opportunities
for PET
cGMP
activities
30 24 8 1 1 64 1.73
[4 Annual
Training for
FDA/PET
Drug
Manufacturers
25 23 9 5 2 64 2.00

A large majority of respondents appeared to welcome the potential availability of
free standardized templates and other materials related to cGMP and regulatory activities,

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such as Standardized PET Drug Applications [Very Likely, 38% (25/65) and Likely, 38%
925/65)], Standardized Training Material [Very Likely, 42% (27/64) and Likely, 30%,
(19/64)] and Standardized Facility SOPs [Very Likely, 38% (25/66) and Likely, 26%,
(17/66)]. However, Standardized facility SOPs were viewed by a higher number of
respondents as items that they would be either Unlikely or Very Unlikely to implement
(10/66 and 1/66 respectively) (Figure 24).
Figure 24: Likelihood of Using Standardized Templates
Would your organization be likely to adopt standardized templates in
the following areas if they were available for free?

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# Question Very
Likely
Likely Undecided Unlikely Very
Unlikely
N Mean
1
Standardized
PET Drug
Applications
25 25 9 4 2 65 1.97
2
Standardized
Facility SOPs
25 17 13 10 1 66 2.17
3
Standardized
Training
Material
27 19 10 6 2 64 2.02

When asked if the new PET cGMP requirements will hamper the development of
novel PET radiopharmaceuticals, responses were mixed. A slightly higher proportion
responded No than Yes (43%, 30/69 versus 33%, 23/69). Thirteen percent (9/69) had no
opinion. A small number chose the response “Other” (10%, 7/69) (Figure 25).
Figure 25: Will New PET cGMP Hamper the Development of Novel PET
Radiopharmaceuticals?

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Training appeared to be a less vexing issue than some of the other areas
constraining GMP implementation. Nearly half of respondents identified that their
organizations are currently training staff (47%) and the other half that staff is adequately
trained (46%). Only 7% identified that they had difficulty to train staff. When these
respondents were asked in an open text box to comment on those difficulties, 3 comments
were provided; “aseptic procedures – lack of access to expertise”, “It’s a challenge to
have candidates follow the “boring” procedures day in and day out and not tinker with
the process”, and finally “the need to do eCTD even with training classes is going very
poorly for regulatory staff”.
Figure 26: State of Training for PET cGMP Activities
Which of the following choices identify the current state of training to
implement PET cGMP activities?

87
Respondents had mixed views when five choices were offered regarding the
degree to which industry leaders or consultants were used during PET cGMP
implementation. Responses suggested that about 30% (20/67) worked for sites that
became fully operational without the help of consultants, whereas 27% (18/67) became
fully operational with the help of outside consultants. A further 16% (11/67) stated that
they have hired or engaged appropriate consultants. About one-quarter (24%, 16/67) of
the respondents identified that their organizations were still evaluating available options
with potential consultants. Only two respondents (3%) identified that their organization
was not operational and had no resources allocated to hire outside expertise.
Figure 27: Interactions with Industry Leaders with Respect to PET cGMP
Activities
Which of the following choices best identifies the interactions that
you will or have had with industry leaders or consultants with
respect to PET cGMPs?

88
When asked about the tasks given to consultants, most identified that they were
engaged to assist in writing regulatory documents (27%, 15/55). Less frequently, they
were hired to audit facilities/processes (18%, 10/55) or to help implement PET cGMPs
(15%; 8/55). Relatively few respondents identified that consultants were hired to assist
construction (7%, 4/55), train staff (7%, 4/55) or develop needs assessments (5%, 3/55).
Twenty percent (11/55) chose “Other”.
Figure 28: Roles Played by Consultants
If consultants were obtained, what were they hired to do? Choose all
that apply.

When asked about the current status of facility upgrades or renovations for PET
cGMP compliance, somewhat more than half of the respondents identified that their
facilities were fully commissioned and operational (55%, 39/71); 11% were in the
construction phase (8/71) and 20% (14/71) were evaluating needs and costs. Only a few
facilities were in the design phase (7%; 5/71), and 6% (4/71) were in facilities that
required no upgrades or renovations. Only one respondent stated that they did not know
(1%, 1/71).

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Figure 29: Current Status of Facility Upgrades or Renovations for PET cGMP
Compliance
Which of the following choices best describes the current status of
facility upgrades or renovations for PET cGMP compliance?

Respondents were also asked about the current status of equipment acquisition for
PET cGMP compliance at their facility. Most commonly respondents identified that new
equipment had been fully installed and validated (41%, 29/71), or that equipment was
judged to be adequate and fully functional (18%, 13/71). However, many were not at this
stage; some were still installing and validating needed equipment (23%, 16/71),
identifying resources for equipment acquisition (15%, 11/71) or ordering necessary
equipment that was not yet installed (1%, 1/71). A single respondent did not know.

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Figure 30: Current Status of Equipment Acquisition for PET cGMP Compliance
Which of the following choices best describes the current status of
equipment for PET cGMP compliance?

When describing the expertise of their group to develop their own standardized
cGMP documentation, 62% of respondents (40/65) believed that staff could write the
necessary documentation in-house for all of their cGMP Standard Operating Procedures.
Twenty-two percent (14/65) felt that they could write all of their drug applications (NDA,
ANDA, IND, RDRC). Seventeen percent (11/65) felt that their Staff and Equipment
Qualification training materials could be developed in-house. Amongst those who
required assistance with documentation, 27% (11/41) identified that they could write only
part of the cGMP SOPs in-house and 29% (12/41) could write only part of the training

91
materials in-house. Most commonly, help appeared to be needed with drug applications;
44% (18/41) stated that they could write only part of those applications in-house. A
minority of respondents felt that they could write very little documentation in-house.
Thirty-seven percent (11/31) of the respondents stated that they could write very little of
the SOP documentation in-house, 39% (12/31) could write very little of drug applications
in-house and 26 % (8/31) could write very little of the training materials in-house.
(Figure 31).
Figure 31: Expertise to Develop Standardized cGMP Documentation
Describe the expertise of your group to develop your own
standardized cGMP documentation for the following categories?

Respondents were asked where they sought assistance if they could not write all
the documentation in-house. In Table 9 below is a subset of the replies.

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Table 9: In-House Documentation
1. Other organizations with similar needs or consultants
2. Consultants
3. Hired consultant for first-time ANDA and for electronic submission
4. Consultant
5. A third party partner that operates the production facilities.
6. Regulatory consultants.
7. Vendor who has access to FDA electronic gateway and knows how to format the documents for
electronic submission
8. The BC Ministry of Health
9. Outside consultants, academic partners, customers

Respondents were asked to classify how certain organizational resources,
including Adequate Funding, Adequate Staffing, Appropriate Facilities and Equipment
and Training/Coaching, affected their ability to comply with the implementation of
GMPs using a scale from Very Important (Rank 1) to Least Important (Rank 4).
Respondents most commonly rated Adequate Funding as Very Important with 37 of 61
responses in Rank 1. Appropriate Facilities and Equipment were rated midway between
Very Important and Least Important [Rank 1 (11/61), Rank 2 (23/61), Rank 3 (22/61)
Rank 4 (5/61)]. Adequate Staffing had the third position in comparison to the others
[Rank 1 (12/61), Rank 2 (21/61), (Rank 3 (23/61), Rank 4 (5/61)]. Training and Coaching
typically ranked last [Rank 1(1/61), Rank 2 (7/61), Rank 3 (9/61), Rank 4 (44/61)]
(Figure 32).

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Figure 32: Importance of Organization Resources
Please rank the importance of the following organizational resources
to affect your ability to comply with implementation of GMPs.

The respondents were asked to comment on their challenges to GMP
implementation, some of which are shared below in Table 10.

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Table 10: Respondents’ Comments about Challenges to GMP Implementation
1. Another challenge is the eCTD formatting and submission. Currently, we purchase this through
consulting but having a resource available to PET cGMP organizations at a reasonable cost will
be an asset.
2. Support from the hospital has been critical to success
3. We didn’t hire consultants but we did receive valuable support and insight through discussions
with members of SNMMI and the PET Drug Coalition. It basically came down to spending too
many hours at work and too few at home. I suspect this was true at a number of PET centers
and not just ours
4. I moved from commercial to academic environment. The lack of support, knowledge,
compliance and acceptance of cGMP requirements is extreme. Academics seem to think they
are immune to regulations and personnel compliance is difficult at best.
5. A lot is required but not is actually needed.
6. No standardized SOPs are available across the industry.
7. Describe the expertise of your group to develop your own standardized cGMP documentation
for the following: categories below. Survey did not allow us to answer in each category - but
the answer is the same for all cases- we have in house capabilities.
8. Lack of understanding of cGMP requirements and importance by the management.
9. Financial sourcing is a major impediment.
10. cGMP is a moving target. Each time the rules change and more assays or processes are
required, more equipment and space are needed. This puts academic labs making their own
cGMP radiotracers for phase 0 trials out of business or forces them to contract with a company
to label and ship their own compound. That is also expensive and functionally, the radiotracers
made using the "old" cGMP guidelines are just as pure, well characterized and safe as ones
made with the new guidelines.

When asked if their organization would be likely to adopt certain types of standardized
templates for applications, SOPs or training materials if they were available for a fee of
less than $50,000, most respondents appeared to be in favor of adoption or undecided
although a full range of responses was seen (Figure 33).

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Figure 33: Probability of Adopting Standardized Templates for a Fee
Would your organization be likely to adopt standardized templates in
the following areas if they were available for a fee (below 50K)?

The respondents were asked their opinion on how many ANDA approved PET
drug doses would have to be produced daily to break even from a business perspective.
Figure 34 shows that opinions varied widely between 1-21 doses. The median production
rate was 12 and the average production rate was calculated to be 12.3 (259/21) doses per
day to break even.

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Figure 34: ANDA Approved Break-Even PET Drug Doses

Respondents typically appeared to believe that PET cGMPs are necessary and
important for quality patient care [Strongly Agreed: 44%, (28/64); Agreed: 41%,
(26/64)]. Only 14% (9/64) Disagreed and 2% (1/64) Strongly Disagreed. Further, most
felt that PET cGMPs will improve the safety and quality of PET radiopharmaceuticals
[Strongly Agreed: 33%, (21/63); Agreed: 44%, (28/63)]; in contrast less than a quarter
did not [Disagreed: 19%, (12/63); Strongly Disagreed: 3%, [2/63]). A minority had no
opinion (1) or could not answer (4) the question (not shown in Table 11). In concordance
with those views, most disagreed with the statement that PET cGMPs are unnecessary
and cost prohibitive [Disagreed: 45%, (27/60); Strongly Disagreed: 32%, (19/60);
Agreed: 20% (12/60) and Strongly Agreed: 3% (2/60)]. The level of agreement with the
statement, “The cost of implementing PET cGMPs will lead to the closure of many

97
commercial PET pharmacies”, was balanced more evenly [Disagreed: 45%, (26/58);
Agreed: 38%, (22/58); Strongly Disagreed: 12%, (7/58) and Agreed: 5%, (3/58)].
Similarly, the statement “PET cGMPs will lead to the closure of many academic-based
PET manufacturing facilities” elicited mixed responses that were skewed modestly
toward agreement over disagreement [Agree: 49%, (30/61); Disagree: 36%, (22/61)] with
only a few strongly held opinions [Strongly Agree: 10%, (6/61); Strongly Disagree: 5%,
(3/61)] (Table 11).
Table 11: Necessity of PET cGMPs
# Question Strongly
Agree
Agree Disagree Strongly
Disagree
N Mean
1
PET cGMPs are unnecessary
and cost prohibitive
2 12 27 19 60 3.05
2
PET cGMPs are necessary and
important for quality patient
care
28 26 9 1 64 1.73
4
The cost of implementing PET
cGMPs will lead to the closure
of many commercial PET
pharmacies
3 22 26 7 58 2.64
6
PET cGMPs will improve the
safety and quality of PET
radiopharmaceuticals
21 28 12 2 63 1.92
7
PET cGMPs will lead to the
closure of many academic
based PET manufacturing
facilities
6 30 22 3 61 2.36

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Respondents were asked to expand in a text box on their biggest unforeseen challenge in
PET cGMP implementation, and their responses are shown in Table 12.
Table 12: Unforeseen Challenges in PET cGMP Implementation
1. Lack of financial resources and expertise to implement the requirements.
2. Expertise and knowledge
3. Training
4. Adequate pay for staff/Staff compensation for time.
5. Navigating the gap between Phase I and NDA GMP expectations.
6. Knowledge and training.
7. The cost for PET cGMP operation.
8. Dispensing unit doses for local use. The radiopharmacy is not local, so we're
having trouble figuring out if we can dispense for our own use or not.
9. Regulatory documentation.
10. Regulation by inspection on the part of the FDA- Bar keeps getting raised until
it is difficult for all facilities to meet them.
11. The Regulations and the availability
12. The space requirements for certain cGMP requirements, such as storing certain
items or conducting certain tasks in a dedicated or separate area.
13. Delays in implementing the new system.
14. Increase of the operational costs and training of the personnel.
15. Reluctance of the own staff to adopt GMP spirit and philosophy. Lack of
support from the management.

When asked further, “What advice or comment would you provide for
stakeholders or other groups that are involved in PET cGMP implementation?”
respondents replied as shown in Table 13.

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Table 13: Advice to Stakeholders or Other Groups Involved in PET cGMP
Implementation
1. Ensuring that auditors understand PET cGMP and its differences compared to
regular cGMP. Local resources from societies or other interest groups will be
needed to sustain existing PET cGMP facilities and allow for new ones to come on
board. Funding opportunities through grant agencies or societies, even if in small
amounts, will be helpful in accomplishing this goal.
2. Conduct a detailed cost analysis to ensure 212 compliance is really required
3. Respect those who have been through the process in the past.
4. Invest in other related technologies as well, such as theranostics.
5. Hire trained people in this field.
6. Share the cost with partners.
7. Don't do it alone.
8. Get consultants beforehand. The regulations are too vague to drive detailed
requirements.
9. Work with Health Canada (equivalent of FDA), your Ministry of Health and the
suppliers in a coordinated manner
10. Follow what has worked before, and do not try to complicate things or do more
than what is required. The laws are actually pretty simple with respect to the
requirements: say what you are going to do and follow it.
11. Embrace the changes and ensure that poorly run facilities do not damage
reputation of good/excellent facilities--academic or industry
12. Look to simplification of the procedures, without reducing the overall quality of
the process. It's very important to get the feedback of the regulatory agencies and
the FDA feedback and support for the continuous implementation process of QA.
13. This is a team effort - engage all the staff. Try to educate management in the
importance and main spirit of cGMP to get more support and understanding. Invite
colleagues from other centers to share their experiences in the implementation of
cGMP.
14. Funding, work on Funding

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CHAPTER 5: DISCUSSION
5.1 Summary
Previous research summarized in Chapter 2 gave some insight into the advantages
and challenges of regulatory oversight in PET drug development. That literature
suggested that a number of regulatory barriers could impede the development of new
PET radiopharmaceuticals but no systematic study appeared to exist regarding the views
of the manufacturers of PET tracers, the principal stakeholders affected by these rules.
Thus, the goal of this study was to examine the implementation of recent PET cGMP
regulations through the eyes of that stakeholder. Such feedback is essential to identify the
challenges and opportunities seen by imaging thought leaders that could better inform
policy changes, support mechanisms for improvement or target education. The feedback
achieved here from more than 180 respondents goes a long way toward a better
understanding of industry views. However, the results must be interpreted carefully
within the context of the limitations and delimitations that might affect the interpretation
and conclusions.
5.2 Methodological Considerations
5.2.1 Delimitations
In this study, I delimited the respondent group to those in the specific field of PET
radiopharmaceutical manufacturing, and even more specifically, to those in American
organizations. This deliberate delimitation was imposed because U.S. rules governing
radiopharmaceutical management are national rather than international. Other countries
have their own rules that can differ from U.S. models for regulation in many respects.

101
For example, the developmental path and requirements for the registration of
radiopharmaceuticals differ in the EU. As stated by (Verbruggen et al., 2008),
Different situations may be faced with respect to the nature and intended
application of radiopharmaceuticals within a clinical trial or depending
on the fact whether the relevant product is or is not described in a
monograph of a pharmacopeia or approved following an MA (Marketing
Authorization). From a practical point of view the following situations
might occur:
-Licensed radiopharmaceutical products used within their authorized
indications,
- Licensed radiopharmaceutical products used outside their
authorized indications,
- Radiopharmaceuticals having established clinical use that is
prepared in accordance with approved regulations and meet
approved quality requirements (e.g. as described in a monograph of a
pharmacopeia),
- New radiopharmaceuticals or tracer agents outside the previous
categories.
Users must comply with different requirements as a function of such a
distinction and the application of good clinical and/or pharmaceutical
practice (GCP and GPP) standards, which may have been implemented at
different levels in some European countries.

Further, the nature and tone of regulatory interactions can vary; U.S. regulatory
relationships have often been characterized as contentious whereas European approaches
have generally been considered as collaborative, although these characterizations appear
to be changing (Löfstedt & Vogel, 2001).
The survey was further delimited to one aspect of the activities related to
radiopharmaceuticals, the implementation of GMPs. This area was identified to be of
key interest because the new requirements are both recent and impactful. The literature
in Chapter 2 amply illustrated anecdotal concerns that the new rigorous rules would

102
substantially affect the viability of some radiopharmaceutical operations. Even if that
were not to be true, it is considered to be good practice to conduct post hoc evaluations
related to the impact of the regulations on stakeholder activities after they have been put
in place for some time, as a matter of effective regulatory strategy (Allen, 2007). The fact
that the U.S. rules have been in place since 2012 and the finding here that most
companies are well-advanced in their implementations seem to be reasons why an
evaluation of the policies and requirements is timely.
The study was further delimited by constraining the respondent population to
individuals directly involved in PET drug manufacturing operations. This narrowing was
carried out in two ways, first by providing an initial set of questions about job profiles to
exclude inappropriate participants, and second by obtaining help with survey
dissemination from an appropriately focused professional organization rather than relying
on personal networks. Nonetheless, selection bias can be introduced easily into any
research study in which surveys are disseminated to selected respondents (Sadler, Lee,
Seung-Hwan Lim, & Fullerton, 2010). These challenges can be amplified when using the
internet to reach participants (Kaye & Johnson, 1999). To reduce sampling bias, we
attempted to poll a broad distribution of PET cGMP users in university/hospital settings,
commercial sectors, the federal government, consultants, university, and biotech
communities. While it is not possible to be sure that this group of respondents
represented fully the overall population of radiopharmaceutical manufacturers, the
findings that respondents represented organizations of widely varying sizes and levels of
production gave some confidence that results are generalizable. Further, the
representation of individuals quite evenly across a spectrum of functions representing

103
administrative, regulatory and technical activities would be evidence that the results do
not represent the singular point of view of a particular subgroup of personnel.
Finally, the study was delimited to a specific time span. The development and
implementation of new regulations and policies have a life cycle, so the information
generated during this time period will probably not be the same as it might be if the
survey was disseminated 5-10 years in the future when regulations have been
implemented and fine-tuned over time. Programs based on a new policy can differ in the
rates at which they can be implemented and deliver measurable outcomes (Blackburn &
Schaper, 2012). Researchers have cited the complexity of implementation to justify the
need for continued evaluation when a policy is implemented:
The problems of implementation are overwhelmingly complex and
scholars have frequently been deterred by methodological considerations
... a comprehensive analysis of implementation requires that attention be
given to multiple actions over an extended period of time (Van Meter &
Van Horn, 1975).
In this situation, I felt that the timing of the survey, three years after the
requirements for GMPs were in place, was important so that any major sources of impact
that might affect the viability of some operations could be captured. However, the field
and its associated regulations will potentially change over time, and this could affect both
the implementation of these regulations and the views of the industry. The present results
then could be used as a benchmark to map changes in views and practices.

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5.2.2 Limitations
5.2.2.1 Development and Dissemination of the Survey Instrument
Several potential limitations could also affect the nature of the data collected here.
The first relates to the design of the research instrument itself. The survey instrument
must do two important things. Not only must it accomplish the research objective but it
also must define the respondent population. Thus, a certain number of questions had to
be devoted to exploring the demographics that would establish the backgrounds of the
respondents. The use of several questions to establish the backgrounds of the participants
is important to assure that the respondent pool is limited to the types of individuals who
will have domain expertise in the area of PET radiopharmaceutical GMPs. It then is
possible to know the types of respondents who are participating in the survey but not to
be so confident that those respondents reflect the PET manufacturing community as a
whole as discussed above. This important challenge to external validity has been
discussed elsewhere (Cook & Campbell, 1979). The fact that individuals were spread
amongst a spectrum of functions across the organizations, and the fact that typically the
organizations are small, makes it likely that we have not missed a subgroup of individuals
who would have differing views.
Even though it is important to explore demography, demographic questions can
take away from the space that can be devoted to exploring the respondent views on
GMPs without making the survey overly long. Long surveys are not optimal because
respondents can tire of answering the survey questions and abort the survey before it is
finished. Further, the types of respondents sought here, managers and staff in busy PET
manufacturing operations, are likely to have particularly busy professional lives so that

105
we might predict problems with tolerating and completing a long survey. As stated by
Layne and Thompson (1981), “quality of data is also commonly believed to be affected
by questionnaire length. As the questionnaire length increases, respondents can become
tired, annoyed, bored and/or distracted by external factors.” For example, Heberlein and
Baumgartner (1978) suggested that each additional question will decrease response rate
by 0.5% and each additional page by 5%. Thus, I was careful to restrict the numbers of
questions in the current survey to 29. This put a high priority on asking effective and
insightful questions that often had complex multipart formats. The use of a focus group
to fine-tune these questions was important. Nevertheless, it is likely that some questions
that might have provided more insight were not asked, and this restriction may limit the
depth of the analysis.
It is also important to acknowledge my own personal bias because I work in an
academic center faced with the challenges of PET cGMP implementation. My own
experiences could have unintentionally affected the neutrality of the survey questions.
Researcher bias has been historically evident in social science research (Lord, Ross, &
Lepper, 1979). As the survey designer, I aspired to be impartial and refrain from using
leading questions. To this end, I found much value in having the survey exposed to
constructive peer review by a focus group with industry leaders/colleagues and the
regulatory science faculty.
5.2.2.2 Respondent Sampling and Survey Methodology
The survey was disseminated to a selected group of PET cGMP community
experts who received direct email links and to a second set of survey respondents who

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were contacted through the membership lists of two imaging societies (WMIS &
SNMMI) by using anonymous email links. As noted elsewhere, this electronically-based
approach can have the advantage of “eliminating face to face body language or tonal
voice cues. The survey was also anonymous to eliminate the worst effects” (Shuttleworth,
2008).
Since selection bias is one of the concerns when surveying respondents, care was
taken in choosing respondents whose roles and responsibilities were limited to those with
experience in the field of PET. However, the numbers of experts with extensive
experience in the development of radiopharmaceuticals are relatively small and these
individuals are often very busy and reluctant to complete surveys. Thus, I expected even
before the survey was disseminated that the response rate to the survey could be low. In
general, electronic surveys can have varying rates from 10-80%. Publications with
electronic survey response rates as low as 10-20% in difficult to reach respondent groups
have been considered to be acceptable (Schonlau, Ronald, & Marc, 2002). Thus, the
response rate of 67% for such a small community of stakeholders was remarkable. This
high response rate perhaps suggested that the topic was of substantial interest to the
radiopharmaceutical manufacturing community. At the same time, it is important to note
that the sample may still have some bias. The majority of individuals completing the
survey were from the university/hospital settingThese results should be interpreted
knowing that the dominant views will, therefore, be those of individuals with experience
in academic production facilities.

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5.2.2.3 Implementation Framework
A central goal of this dissertation was to assess the “major gaps (that) exist
between what is known as effective practices (i.e., theory and science) and what is
actually done (i.e., policy and practice)”. Several major reports have highlighted the gap
between the development of policies and their effective implementation as effective
treatments and services (cf. Fixsen et al., 2005). However, the field of implementation
science is relatively new in comparison to that of many social science fields (Fixsen et
al., 2005) so that the numbers of models for its study are relatively few.
In this study, I chose to use implementation framework of Fixsen and colleagues
(2005) to evaluate the state of implementation of cGMPs at the different academic
pharmaceutical sites. The framework of Fixsen provides a staging rubric and vocabulary
important in examining maturity and stage-related barriers. While previous studies using
this framework focused on service settings, the experience of using it for the type of
program evaluation conducted here seemed to be useful and appropriate. The match to
the problem under study was enhanced perhaps by the fact that this tool, often used in
educational settings with specialized individuals, was being applied to facilities that also
rely heavily on the specialized knowledge base of the personnel who carry out the
implementation. The fact that the framework divided the exploration into sensible sub
areas related to the maturity of implementation also helped us to characterize the relative
levels of maturity in this GMP implementation process, as discussed further below.

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5.3 Maturity of GMP Implementation
A central objective of this survey was to identify the stage of maturity of PET
facilities with regard to cGMP. Thus, questions were designed to identify features that
have been associated with various stages of implementation. However, perhaps the most
direct evidence of maturity was reflected in the answers of the respondents to a simple
question about their views regarding their state of implementation. Notably, about half of
the respondents felt that they had a fully functional PET cGMP facility. The other half
were less mature. For example, about one-quarter were at the stage of hiring people or
writing documentation, attributes typical of an organization at the program installation
phase, and about one-quarter were in the early “exploration phase” of securing resources
and exploring options. This finding may not be surprising, given the importance of
implementing GMPs as quickly as possible to avoid interruptions of a vital product to the
associated healthcare facilities (IAEA, n.d.).
Further questioning concerning the state of progress with regard to GMP
implementation confirmed that most organizations have completed assessments of their
needs and are in early to full implementation stages. However, some organizations are
clearly ahead of others, as reflected, for example, by findings that at least half have
sufficient numbers of appropriately trained staff, but at least one third feel that they must
hire more staff. In addition, the fact that hardly more than half felt that certain activities,
such as validation activities and training, were carried out at a level sufficient to pass an
FDA audit suggests work left to do at many facilities.
Despite the high level of maturity of many organizations, only 7 percent of the
facilities represented by these respondents had been audited by the FDA. This is not

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surprising considering the backlog of ANDA applications submitted by all sites as
required by the new PET cGMP requirements. Many sites in the U.S. submitted their
documentation by December 2015, the start of the program, but most of these sites have
had to wait for a long time for FDA site visits (Schwarz, 2014). Such delays in arranging
site audits could have had negative consequences for public health because they might
have impeded access to needed product. Thus, sites have been allowed to manufacture
ANDA PET drugs while waiting for an FDA site audit and subsequent ANDA approval.
The FDA provides clear language highlighted below in the Guidance titled FDA
Oversight of PET Drug Products: Questions and Answers published in December 2012
(Food and Drug Administration, 2012).
FDA does not intend to disrupt existing clinical use of PET drugs as long
as appropriate submissions are made and producers of PET drugs are
moving to comply with regulatory requirements. In December 2011, FDA
announced that until June 12, 2012, FDA does not intend to take
enforcement action against a PET facility currently producing PET drugs
for clinical use for a failure to submit an NDA by December 12, 2011,
provided that the facility complies with all other FDA requirements,
including current good manufacturing practices (CGMPs). FDA will not
exercise enforcement discretion after June 12, 2012. Therefore, if a
facility wishes to continue to produce PET drugs for clinical use after
June 12, 2012, they must have submitted an NDA or ANDA by that date,
or be producing the drugs under an investigational new drug application
(IND). PET facilities who are unable to submit an NDA or ANDA by June
12, 2012, or operate under an IND must find a new supplier who has
submitted an NDA or ANDA. All PET producers must be operating under
an approved NDA or ANDA, or effective IND, by December 12, 2015.

Because so few audits have been completed, it is not possible at this time to
validate whether the views of the respondents who report a fully functional GMP facility
are correct by examining the outcomes of FDA inspections. Thus, the high level of

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maturity suggested by survey respondents cannot be accepted as true until the majority of
sites have completed full FDA site audits and received final ANDA application responses
from FDA. An interesting follow-up study in future would be a comparison between the
assessments of GMP readiness by facility staff and by the FDA.
Fixsen identifies a final stage of maturity in which implementation is maintained
over time, defined as “sustainability” (2005). It is too early to identify if this stage will be
problematic because the implementation programs of the PET facilities are relatively
young. However, it should in future be possible to examine the degree to which sites can
maintain effective GMP implementation based on the ongoing findings of FDA. The
FDA is required to conduct follow up surveillance and compliance inspections of ANDA-
approved sites as identified in the PET CGMP Drug Process and Pre-approval
Inspections/Investigations document published on the FDA website (Food and Drug
Administration, 2015).
1) Routine Surveillance 212 CGMP Inspection of PET Producer Sites
Routine surveillance inspections evaluate whether a PET drug production
facility complies with the PET CGMP regulations. The routine
surveillance of PET facilities also facilitates timely decisions on the
application review process and in deciding government contracts.
2) Pre-approval Inspection (PAI) of Producer Sites
A pre-approval inspection (PAI) is performed to provide assurance that a
PET drug production facility that is named in a PET New Drug
Application (NDA) or Abbreviated New Drug Application (ANDA) is
capable of producing the PET drug in accordance with CGMPs, and that
the submitted application data are reliable, accurate, and complete.
3) Compliance Inspections

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Compliance Inspections are inspections done to evaluate or verify
corrective actions after a regulatory action has been taken. First, the
coverage given in compliance inspections must be related to the areas
found previously deficient and subject to corrective actions.

Only after the FDA has established a more extensive record of audits will it
become clear whether sites are maintaining compliance. It will also confirm whether
FDA will take a less stringent approach to the PET GMP Part 212 requirements
compared to Part 211 GMP requirements, as some anecdotal reports have suggested
(Schwarz et al., 2014). Those reports are consistent with survey results and comments
from our current study, but it is still early in the process to make strong conclusions.
Nevertheless, it will be important to see how the FDA achieves a balance between the
capabilities of smaller facilities and the stringest rules that it applies to pharmaceutical
companies. The Coalition for PET Drug Approval (Schwarz et al., 2014), highlighted the
need for a less stringent burden of regulatory affairs functions at academic centers
(Berridge, Cutler, Ehrhardt, & Nazerias, 2016). Furthermore, the presentations
highlighted at the 2016 SNMMI Annual Meeting titled “PET GMP Compliance and
Lessons Learned from FDA Inspections” identified major areas of concern, usually key
to passing an FDA inspection, such as internal resources and in-house capabilities to
comply with regulatory documentation and submissions, that might be difficult for small
sites with restricted capabilities and limited staff numbers.
5.4 Challenges and Barriers to Implementation
Not only was this dissertation directed at understanding the implementation
maturity of GMP facilities but also at enumerating the challenges that those facilities face

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when trying to implement PET GMP regulations. One important potential barrier that
was identified in Chapter 2 was the cost of implementing cGMPs. Responses indicated
that costs associated with compliance were significant. In our study, the factors seen to
be responsible for increasing the costs to implement GMP compliance were similar to
those typically suggested by previous publications (Allen, 2007; Meyers, 2012;
Pavlotsky, 2017). These included equipment/facility upgrades and maintenance,
regulatory documentation, validation requirements and personnel costs.
5.4.1 Equipment/Facility Upgrades and Maintenance

According to respondents in this study, facility improvements were the costliest
part of GMP implementation, and equipment acquisition was judged to be a significant
part of that cost. The estimates identified by respondents correlates well with cost
estimates suggested for PET Drug Manufacturing facilities in other publications (Conti,
Keppler, & Halls, 1994; Schyler, 1995), as well as our own recent expenditures for
facility upgrades (personal communication). These particular expenses might, however,
be considered as one-time investments. The costs associated with a PET
radiopharmaceutical manufacturing site are in many ways unique compared to those of
other types of drug manufacturing facilities in part because they revolve around the use of
a cyclotron, that in itself is a very expensive piece of equipment to buy and run. The
International Atomic Emergency Agency (IAEA, n.d.) published a detailed technical
report that describes the main cost drivers of setting up a cyclotron/radiopharmacy
facility and the annual upkeep (IAEA, 2009). Table 14 summarizes those findings but
does not include the costs of personnel. Typical personnel costs for

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cyclotron/radiopharmaceutical centers are an additional 300-500K depending on the
production volume of the operation (IAEA, 2009). While these numbers might not seem
very high in comparison to those that might be typical for production in a large
pharmaceutical company, they are of considerable concern to academic centers
attempting to operate on a non-profit basis (Food and Drug Administration, 2012).
Table 14: Typical Costs of Establishing a Radiopharmaceutical Production
Center (Devine & Mawlawi, 2010)
Capital Expenditure Original Cost ($) Annual cost ($)
Construction
Shielded vault/Cyclotron Room $ 1,700,000 $ 112,000.00
Radiopharmaceutical synthesis laboratory $ 700,000 $ 56,000.00
QC laboratory $ 1,400,000 $ 112,000.00

Radionuclide production and synthesis equipment
Cyclotron (10–19 MeV) $ 1,300,000 $ 160,500
Hot cells $ 400,000 $ 32,000
Mini-cells for synthesis modules $ 150,000 $ 20,000
Automated synthesis unit $ 150,000 $ 17,000
Radiation safety monitoring $ 250,000 $ 16,000

Radiopharmaceutical QC $ 240,000.00 $ 47,600.00
Total Cost $ 6,290,000.00 $ 573,100.00

Regardless of additional costs, the new requirements for cGMPs have obligated
PET radiopharmaceutical facilities to change. Survey results suggest that most sites now
have upgraded their facilities for PET cGMP compliance and have newly installed and
validated equipment. These findings are consistent with the expectations of a site that has
initiated the early stages of implementation and submitted ANDA applications.
However, presentations from the Coalition of PET Drug Approval at the SNMMI annual

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meeting suggested that the positive perceptions held by some organizations that their
facilities and equipment were fully validated often varies from that of the regulatory
inspector. A site visit at our facility (personal communication) was consistent with the
findings of others at the meeting that the inspector’s view of validation went beyond that
typically recommended by the typical vendor. For example, inspectors requested per use
validation using released data from manufactured batch records to demonstrate
Performance Qualification (PQ) conformance, in order back up the validity of the defined
release criteria. Furthermore, extensive software validation and audit trail compliance
were expectations for which many companies were unprepared (Berridge et al., 2016).

5.4.2 Staffing and Training
Interestingly, almost all respondents noted costs of hiring and training of
additional staff between 50,000-1 million dollars. Staffing and training expenses are
ongoing commitments year after year, and must in some way be recouped as part of the
pricing of products and services. Other publications evaluating financial burdens of
GMP implementation have highlighted similar findings (Allen, 2007; Meyers, 2012;
Pavlotsky, 2017). Although those previous studies focused on approximating the costs of
GMP compliance in biomanufacturing plants, the facility and personnel resources are
similar to overall resource requirements typical for radiopharmaceutical manufacturing
sites (Denault, Coquet, & Dodelet, 2008).
When new policies and procedures are introduced, facilities must write standard
operating procedures and train personnel to execute the required activities in a way that is
compliant with the quality policies of the facility and with governmental regulations.

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From the survey responses, it would seem that training is not viewed as the most
important concern for most PET facilities. Where such difficulties existed, they appeared
to be associated with specialized operations such as aseptic processing or eCTD
development. Interestingly, one individual noted that it was difficult to assure that
procedures were developed or executed without “tinkering”. This observation may be
significant. In other types of manufacturing environments, many of the deviations that
are found to be troublesome are those in which a worker does not adhere to good
manufacturing practices (QMN, 2017), often by “tinkering” with procedures.
In many organizations, the initial efforts to implement new regulations can rely on
the help of consultants (Turner, 1982). In this study, organizations seemed evenly split
with respect to their use of consultants. The fact that one-quarter were still evaluating the
potential use of consultants may underline the recurring message that seems to run
through the survey, that a significant minority of the organizations are not fully mature in
their cGMP implementation. When consultants were used they were often tasked with
particular activities, such as auditing or writing regulatory documents. This is not
dissimilar to what is reported for other types of biopharmaceutical manufacturing
facilities. For example, biomanufacturing plants frequently outsource certain GMP tasks
(Denault et al., 2008). In the PET facilities, consultants appear to play a large role in
assisting in the writing of regulatory documents. Of interest was the finding that the
participation of consultants was not restricted to GMP documentation, but also could be
recognized in the production of NDAs, ANDAs, INDs, and RDRCs as well as training
materials for staff and equipment qualification.

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Not surprisingly, adequate funding was found to rank highest when asked about
factors affecting a site’s ability to comply with the implementation of GMPs. If resources
are limited, organizations may resist hiring consultants for such activities as regulatory
documentation because they are concerned that such consultants may add cost.
Nonetheless, the use of consultants can be advantageous. Consultants are considered
experts in specific areas of expertise (Ashkenas, 2013) whose intermittent role can help
the facility to avoid financial commitments associated with the hiring of personnel in the
longer term. At the same time, it can potentially yield efficiencies and improvements in
quality. Positive outcomes from hiring consultants have, for example, been suggested by
research in the wine industry that has somewhat similar GMP requirements to the
radiopharmaceutical industry (Barthelemy, 2017). For example, Barthelemy (2017)
identified that the use of consultants resulted in higher quality performance ratings and
more consistent performance ratings for winemakers. Consultants typically deploy a
general set of best practices from their years of experience with previous clients.
Because best practices [guided by consultants] are more tested than the
practices of individual firms, they decrease the likelihood of very low
performance. On the other hand, uniqueness is a necessary condition for
outstanding performance. Because best practices are less unique than the
practices of individual firms, they also decrease the likelihood of very high
performance (Barthelemy, 2017).

At the same time, Bartholemy (2017) observed that organizations using
consultants typically did not have the highest quality ratings. Those few winemakers
with exceptional quality ratings often preferred to use in-house resources instead of hiring
outside consultants. Generally, these sites employed talented personnel whose targeted

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approaches appeared to surpass the quality that was typical when outside consultants
were used. I might predict that the same patterns may emerge in the PET cGMP
community, where sites with strong reputations have particularly capable in-house
personnel. These individuals may eventually serve are as outside consultants for other
sites with less familiarity with quality practices. However, it might also be the case that
sites will see no incentive to having unusually strong GMP practices or reputations. As
pointed out by Medina and Richmond (2015), quality practices are ruled by a one-sided
incentive structure, in which average quality is generally acceptable. As long as sites
pass their audits and submit adequate regulatory dossiers, they have the same operational
opportunities as sites that exceed minimum standards. Thus, the primary requirement is
to avoid demonstrably poor performance.
Another parallel that seems to emerge from the work of Bartholemy (2017) as
well as the research here is the positive relationship between a facility’s financial
resources and the hiring of consultants. This observation is ironic because the sites with
fewer resources may actually be the sites that have a greater need for consultant services.
Thus, it may be especially important for the FDA and PET imaging community to
provide the PET community with regulatory resources, such as standardized SOPs,
ANDA, IND templates that might typically be provided by consultants.
One of the primary sources of guidance for regulatory and quality activities is the
FDA. In our study, most respondents were either neutral or satisfied with the FDA
feedback and support but identified that standardized PET drug application templates and
standardized PET cGMP facility SOPs would be very useful or useful. They were also
very likely or likely to adopt standardized templates if they were available for free. When

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asked about the probability of adopting standardized templates if the supplier demanded a
fee of less than 50K, most appeared to be in favor of adoption or undecided. In other
areas in which organizations have developed harmonized templates such as the ICH
Common Technical Document Format for NDAs or standardized clinical data standards
developed by CDISC, improved quality and consistency of regulatory and quality
activities have been recognized (Perez, 2009; Zink & Mann, 2012). Respondents here
appeared to feel that grants and collaborative and training opportunities through FDA and
imaging societies could also help with the development and implementation of these
resources.
Given the high overall cost of operating PET radiopharmaceutical centers, one
might question why such centers continue to operate at all. Some answers to this
question seem to be advanced by the IAEA (2009). They center around the non-tangible
benefits for the institution as a whole, not only for their ability to improve health care and
to demonstrate scientific/ technological expertise but also to improve the self-sufficiency
of the institution and the pride that it and the nation can take in its ability to stay at the
cutting edge.
5.5 Usefulness of GMP regulations
When the new GMP regulations were introduced, their stated goal was to enhance
patient welfare by standardizing expectations for manufacturing practices in of the PET
radiopharmaceutical sector (Food and Drug Administration, 2012). It may be
understandable why FDA was concerned about the introduction of quality standards.
PET radiopharmaceutical facilities are a specialized type of drug compounding facility.
The PET regulations were developed at a time when compounding pharmacies were

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coming under scrutiny for practices that posed real risks to patients. Prior to 2013,
compounding pharmacies were regulated under the authority of State Boards of
Pharmacy (USP 797) and other State regulations that had relatively modest quality
standards and much less oversight of overtaxed state enforcement agencies (Foehr, 2014).
Most patients in the US today assume that all drugs, including compounded drugs
from a pharmacist, are safe. However, compounded drugs are not always produced
according to a validated process in properly calibrated and cleaned equipment by
production personnel with the requisite knowledge and training. Further, the ingredients
often are not obtained from FDA-approved sources and appropriate laboratory testing is
seldom performed to verify the potency, purity, and quality of the compounded drug.
(Digby & Keppler, 2000). These deviations from acceptable practice became particularly
problematic as some compounding pharmacies began to operate as de facto
manufacturing facilities; they were generating large-scale batches of compounded drugs
in the absence of individual patient prescriptions. Further, some were making products
that were even more dangerous, by compounding drugs that were unapproved for use in
the U.S. (Gudeman, Jozwiakowski, Chollet, & Randell, 2013). Lax rules led to a number
of public health crises, such as the meningitis outbreak caused when NECC laboratories
supplied purportedly ‘sterile’ steroid injections contaminated with fungus or bacteria that
caused the deaths of dozens of patients (Sutton, 2013). As worrying were the examples
of outright fraud rather than just poor practice. For example, a Kansas City-based
pharmacist in 2001 was discovered to have adulterated 72 different drugs, including
many oncology medications, to increase profits. According to estimates, the pharmacist
diluted approximately 98,000 prescriptions for 4,200 patients over an 11-year time period

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(Gudeman et al., 2013). After the 2012 meningitis outbreak, FDA rewrote the rules for
compounding pharmacies, by designating those pharmacies that compounded for groups
of patients as registered outsourcing facilities and identifying heightened GMP
requirements for them (Sutton, 2013).
The rules for compounding pharmacies seemed to serve as a starting point for
similar requirements in PET GMP facilities. However, as chapter 2 identified, few safety
concerns had been identified in PET GMP facilities (Hung, 2001) so the need for such
rules to heighten safety were not so clear. Thus, it seemed important to ask whether
respondents believed that the original intent of the regulations would, in fact, result in
material improvements to the industry. The fact that respondents did see value is
promising. Some of these benefits have been identified elsewhere. Notably, the GMPs
should provide a common set of expectations to control product quality and thus to
increase credibility (Sutton, 2013), and should reduce risks to patient safety by increasing
drug stability, purity, potency, and sterility (Foehr, 2014).
5.6 Predicted impact of the GMP regulations
At the outset of this study, the available literature seemed to suggest that the new
and more stringent Current Good Manufacturing Practices for PET drug products would
challenge academia and industry and might cause some centers to cease their operations.
It is therefore interesting that the responses in this survey appeared more tempered than I
might have expected. Most respondents expressed the view that the new PET cGMP
requirements would not hamper the development of novel PET radiopharmaceuticals.
The reasons behind this more moderate view than previously expressed in the literature
are not so clear. It may be that the experience of implementing GMPs proved to be more

121
manageable than the facility’s management had feared at the time that the regulations
were introduced. At the same time, results introduce a cautionary note related to the
effects of the higher costs of GMP compliance. In particular, it is worth to consider the
views of the respondents that the costs would be unlikely to cause the closure of
commercial PET pharmacies but would lead to the closure of many academic
manufacturing facilities. Notably, respondents on average felt that facilities would have
to produce about 12 ANDA approved PET drug doses daily to break even. At the same
time, the median production rate of doses in the surveyed facilities was only 12. Low
levels of production are typical of academic facilities, whereas commercial radio
pharmacies make hundreds of doses each day (Callahan, 1996). Thus, the larger facilities
are less vulnerable when faced with new and expensive regulatory requirements.
However, academic sites have one advantage and area of opportunity. Their connection
to an academic medical center allows the in-house facility to charge more for the
individual doses because the cost can be contained within the overall reimbursement
envelope for the PET scans. Those reimbursement rates are significantly higher than
would be allowed if a hospital were to bill the insurer for the PET radiopharmaceutical
doses alone (Conti et al., 1994). Without this type of symbiosis, it would be much more
difficult for academic sites to survive the costly demands of new PET cGMP
requirements.
Given the sensitivity to costs of regulatory compliance, the results here may have
significant lessons for future situations in which regulatory requirements of different
types are added. For example, FDA has currently introduced requirements for submitting
INDs and ANDAs electronically. All ANDA, NDA, and BLA submissions must be

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submitted using an eCTD format on May 15, 2017. Further, INDs from commercial
manufacturers must be submitted electronically by May 15, 2018, although non-
commercial IND submissions would still be exempt (Food and Drug Administration,
2017c). In a presentation at the 2016 SNMMI annual meeting, held in San Diego, CA,
(Yokell & Hanebach, 2016) discussed the implications of this change. They noted that
electronic submissions would facilitate faster and more efficient reviews by FDA.
However, in arguments reminiscent of those used when GMPS were introduced, they
noted that such a requirement would create challenges for most small facilities. On
average, they estimated that sites must submit 8-10 filings per year per drug. To satisfy
this new mandate, groups would have to implement either an in-house eCTD solution or
outsource submissions to a third-party group. For an in-house system, they estimated
costs for infrastructure of more than 200,000 dollars, for annual maintenance nearly
50,000 dollars and for a regulatory specialist, 70-90,000 dollars per year. They suggested
that small facilities may find it cost-prohibitive to purchase and implement sophisticated
eCTD publishing software, and to hire qualified regulatory and IT personnel to oversee
these submissions (Yokell & Hanebach, 2016).
Another presentation by Zigler (2016) at the SNMMI annual meeting discussed
the impact of GMPs on market outlook. They note that the production of
radiopharmaceuticals is under significant pricing pressure. Figure 35 illustrates how
profit margin from dose prices have decreased over the years under pressure from rapid
price decreases by commercial radiopharmacies and requirements to cover the costs
incurred to assure regulatory compliance. Both factors can markedly reduce profits

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margins (Callahan, 1996). It will be interesting to see how these two factors affect drug
prices in the future. Denault and colleagues (2008) express this concern well:
Although non-GMP biological products have similar cost structures to
traditional manufacturing products, CGMP-compliant facilities often have
distinctive cost-drivers. All things considered, costs will undoubtedly
increase in the future due to increasingly higher regulatory requirements,
and companies will need to carefully assess their overall process to
properly understand all related costs (Denault et al., 2008).

Figure 35: Challenges of Market Sustainability (Zigler, 2016)

It is also important to note that based on market evaluation and conversations with
industry leaders, it was determined that a large number of commercial PET
radiopharmacies have closed multiple sites across the nation. With the introduction of
PET cGMPs, a provision for drug application fees was also introduced for commercial
entities. This additional cost, combined with higher costs of ensuring on-site GMP
compliance and the shrinking dose prices are some potential factors that could be leading
to these site closures. This would be another area of evaluation in future years, based on

124
additional quantitative data. Unlike commercial entities, academic PET centers are
exempt from FDA application fees due to the hardship it would cause these facilities.
However, there are other positive trends to evaluate based on recent FDA PET
drug approvals. In the beginning of this study, I summarized a list of six FDA approved
PET radiopharmaceuticals. Since then, the FDA has approved four additional drugs
(listed in Table 15). The list of approved PET drugs has grown significantly since the
introduction of PET cGMPs and the initiation of this study in 2014. This indicates a
positive trend towards the development of new PET radiopharmaceuticals. Contrary to
the perception of PET cGMPs as potential regulatory barriers, these findings demonstrate
the utility and importance of these regulations for the development of new PET
radiopharmaceuticals.

Table 15: FDA Approved PET Radiopharmaceuticals (post 2014)
PET Radiopharmaceutical Approved Indications
Fluorine-18 florbetaben Indicated for PET imaging of the brain to estimate β amyloid neuritic
plaque density in adult patients with cognitive impairment who are being
evaluated for Alzheimer’s disease (AD) or other causes of cognitive
decline
Fluorine-18 flucicovine

A radioactive diagnostic agent indicated for PET imaging in men with
suspected prostate cancer recurrence based on elevated blood prostate
specific antigen (PSA) levels following prior treatment
Fluorine-18 flutemetamol

Indicated for PET imaging of the brain to estimate β amyloid neuritic
plaque density in adult patients with cognitive impairment who are being
evaluated for Alzheimer’s disease (AD) or other causes of cognitive
decline
Gallium-68 dotatate A radioactive diagnostic agent indicated for use with PET for localization
of somatostatin receptor positive neuroendocrine tumors (NETs) in adult
and pediatric patients

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It would be interesting to follow up with a similar study in another 3-5 years to
evaluate the effects that are experienced by FDA regulated sites when they reach more
mature stages of PET cGMP implementation and have been subjected to FDA audits. In
a study of regulatory reform related to orphan products, Redington identified three goals
that should be recognized when evaluating the regulatory change: to relieve patient
suffering by improving therapeutic options either by increasing product safety or
efficacy; to increase patient access to needed therapies; and to assure a “fair playing
field” for different types of companies (Redington, 2009). In the present situation, it
would seem the regulations have primarily focused on the first of these three goals with
relatively less consideration of the others. What the present results seem to be saying is
that the regulations will likely improve the quality of the product and thus may
potentially improve patient outcomes (provide relief), but may actually decrease access,
if some facilities must close. If those closures are primarily experienced only by the
smaller academic facilities, the third goal is not met, because the negative consequences
are shared unequally, by allowing larger facilities to be more competitive than small
ones. FDA and imaging societies could help minimize these negative effects by
providing more help to the smaller facilities to reduce the difficulties and costs, for
example. Reducing the burden of these smaller facilities without compromising quality
can be achieved through direct collaboration with these important stakeholders.

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APPENDIX A ……
Comparison of USP 823 vs Part 212 (Personnel & Resources)-Adopted from
Zigler, S. and Taylor, N. (2012, June). FDA audits and inspections for PET: A personal
perspective. Pathways: The Clinical Trials Network Newsletter.
Chapter <823> FDA Part 212
Responsible personnel: designated,
qualified & trained staff shall be
responsible for ensuring that procedure
verification; compounding & quality
control activities are carried out & properly
completed by qualified & trained personnel.
Sufficient personnel with necessary
education, background, training &
experience to perform their assigned
function.
Sterilization & Sterility Assurance
1. Training in aseptic technique
2. Training in proper garbing & gloving
3. Observation of personnel
Personnel Qualifications
1. Appropriate education, training &
experience
2. Trained in GMP
3. Ongoing training for new procedures
4. File for each employee (CV, degree
certificates, certificates of training)
Comparison of USP 823 vs Part 212 (Quality Assurance)
Chapter <823> FDA Part 212
1. Control of Components, Materials &
Supplies
2. Compounding Procedure Verification
• Written acceptance criteria for
identity, purity & quality of each
PET drug

1. PET drug meets required quality &
purity
2. Materials: examine & approve or reject
components
3. Specifications & processes: approve or
reject before implementation
4. Production records: review production
record to determine whether errors
have occurred, investigate and take
action
5. Quality assurance: establish & follow
written QA procedures

138
Comparison of USP 823 vs Part 212 (Facilities & Equipment)
Chapter 823 FDA Part 212
Sterilization & Sterility Assurance
1. Facilities: work area for compounding,
must be clean
2. Compounding Equipment &
Components
• Equipment used to prepare PET
drugs
• Properly cleaned & stored to
maintain cleanliness
• May be processed to remove
endotoxin
• Recommended purchase sterile
vials, syringes, transfer sets &
filters from qualified suppliers
• Components may be sterilized

1. Facilities: adequate to ensure orderly
handling, prevention of mix-ups &
prevention of contamination
2. Equipment procedures:
• Clean
• Suitable for intended purpose
• Properly installed, maintained &
capable of producing valid results
• Document activities
3. Equipment construction &
maintenance: not reactive, additive or
absorptive to alter the PET drug

139
Comparison of USP 823 vs Part 212 (Control of Components, Container &
Closures)
Chapter <823> FDA Part 212
PET RPh Compounding for Human Use
1. Ensure the correct identity of
components
Control of Components, Materials and
Supplies
1. Establish written specifications
• Identity, purity & quality of
components
• Appropriate storage
2. Log-in each lot of shipments of
components
3. Determine each batch of components
in compliance with written
specifications
4. Store components in controlled access
area according to established
conditions.
1. Written procedures
2. Written specifications
3. Examination & testing
4. Components to be handled and stored
to prevent contamination, mix-ups &
deterioration
5. Keep a record

140
Comparison of USP 823 vs Part 212 (Production & Process Controls)
Chapter <823> FDA Part 212
Compounding Procedure Verification
1. Written & verified procedures for
compounding each PET RP
2. A written record must be maintained
for each batch
Sterilization & Sterility Assurance
3. Aseptic Hood
• Microbiological testing performed
periodically (e.g., weekly)
• Swab or contact plates
• Settle plate/dynamic air sampler
• Airborne nonviable less frequent
4. Aseptic Technique
• Process simulations
5. Qualification of Filtration Process
6. Quality Control
For each batch of PET RP perform
membrane filter integrity test
immediately after filtration.

1. Written control Procedures: document
all key process parameters are
controlled & deviations are justified
2. Master production & control records
3. Batch production & control record
created for each new batch
4. Area & Equipment checks
5. In-process materials controls
6. Microbiological control on Aseptic
Processing & Sterilizing Filtration
7. Qualification for Aseptic Processing
Media fills
8. Sterilizing Filtration
• Integrity testing of membrane
filters should always be
performed post filtration (e.g..
bubble-point test)
Environmental & Personnel Monitoring
• Conduct during sterility testing &
critical aseptic manipulation
• Use swabs or contact plates for
surfaces
• Settling plates or dynamic air
samplers for air quality

141
Comparison of USP 823 vs Part 212 (Laboratory Controls)
Chapter <823> FDA Part 212
Quality Control
1. Written QC procedures
2. Verification of QC equipment and
procedures used
3. System suitability testing
4. Check correct operation on scheduled
basis (system suitability)
5. Dose Calibrators: applicable tests
1. Written procedures
2. Established specifications & standards
3. Analytic methods, sensitive, specific &
reproducible
4. Materials
5. Equipment suitable for purpose
6. Equipment maintenance
7. Complete record of all data

Comparison of USP 823 vs Part 212 (Stability)
Chapter <823> FDA Part 212
Stability Testing & Expiration Dating
1. Establish written specifications for the
expiration dating and storage of PET
drug
2. Analyze 3 batches for stability &
specific activity
3. Sample PET drug, at each time point
from the original container specified
for storing the product
4. Must meet all acceptance criteria at
expiry

1. Establish written stability testing
program

2. Program used to establish storage
conditions and expiration time

142
Comparison of USP 823 vs Part 212 (Finished Drug Product Controls and
Acceptance)

Chapter <823> FDA Part 212
Control of Components, Materials &
Supplies
1. Written specifications for identity,
purity & quality of each PET drug
Quality Control
2. Establish in writing QC tests to be
performed, the analytical procedures
and acceptance criteria, pre or post
release.
3. Establish written QC procedures
4. Conduct verification testing of
equipment & procedures
1. Establish specifications for each PET
drug
2. Test Procedures
3. Before release assure each batch or
sub-batch conforms to specifications
(except sterility)
4. Sterility testing
1. Must be started within 30 hours
after completion of production.
Time-limit may be exceeded but
must demonstrate longer period
does not adversely affect the
sample

Comparison of USP 823 vs Part 212 (What actions must I take if a batch of PET
drug product does not conform to specifications?

Chapter <823> FDA Part 212
Quality Control
1. Accept or reject PET RP based on the
conformity of QC tests results with
established acceptance criteria.
2. Investigate unacceptable QC test
results and document the outcome of
such investigations.
1. Must have written procedures
2. Reject nonconforming product and
segregate the PET drug product
3. Investigate and document the process
4. Take corrective action to prevent
recurrence
5. Reprocess PET drug according to
written procedures, and finished
product must meet specifications

143
Comparison of USP 823 vs Part 212 (Labeling)
USP <823> FDA Part 212
1. Label all subdivided components used
2. Label final PET RP container prior to starting
1. PET drug name and lot number
2. Fully label final container or dispensing-
administration assembly such as,
3. Identity of PET RP
4. Added substances
5. Lot number
6. Required warning & symbols
7. Total radioactivity & concentration
Suitably packaged and labeled to
protected from adulteration,
contamination and damage

144
APPENDIX B ……..
SURVEY INSTRUMENT, PRE-FOCUS GROUP, JULY 28,2015

145

146

147

148

149

150

151

152
APPENDIX C …..
SURVEY INSTRUMENT, POST FOCUS GROUP-LAUNCHED ON MARCH 14, 2016
This survey contains questions that will elicit important data regarding PET cGMP
implementation. The results of this data will be used for a doctoral thesis in regulatory
science at the University of Southern California, and may be submitted for publication.
Your participation is vital to the success of this research project and we appreciate your
time and contribution in completing this survey. This data will be kept confidential and
all results will exclude any personal information.

Q1 Where are you employed?
 University/Hospital (1)
 Commercial Operation (2)
 Federal Government (3)
 Other (4) ____________________

Q32 How big is your operation (based on batches released in a day)?
 1-2 (1)
 3-5 (2)
 6-10 (3)
 Over 10 (4)

Q2 I am currently employed as a....(please choose answer that fits most accurately)
 Chemist/Technician (1)
 Radiopharmacist (2)
 Administrator (3)
 Cyclotron Operator/Engineer (4)
 Regulatory/Quality Specialist (5)
 Other (6) ____________________

153
Q3 I have been involved in the environment of PET radiopharmaceutical production for...
 0-2 years (1)
 3-5 years (2)
 6-10 years (3)
 Over 10 years (4)
 No involvement (5)
If No involvement Is Selected, Then Skip To End of Block

Q4 I spend the following percentage of time in the following PET cGMP activities...

Less Then
20% (1)
21-40% (2) 41-60% (3) 61-80% (4)
81-100%
(5)
Cyclotron operations
(1)
    
Chemistry synthesis
(2)
    
QA/QC for product
release (3)
    
Development of
manufacturing/quality
documentation (4)
    
Management of
regulatory submission
(ANDA, NDA, IND,
etc.) (5)
    
Other (7)     

Q5 My main role related to the implementation of PET cGMP activities is...(choose all
that apply)

 Administrative (1)
 Technical (2)
 Regulatory (3)
 Other (4) ____________________

154
Q6 Which statement below best describes the state of cGMP (21 CFR Part 212)
implementation at your facility?

 We are learning and exploring options (1)
 We have secured resources (2)
 We have started to hire necessary staff but have not put into place the documented
systems (3)
 We are writing controlled documentation/procedures and training staff (5)
 We have been audited by the FDA (4)
 We have a fully functional cGMP facility (7)

Q7 We are interested in the degree to which you have implemented quality systems in
your operations. Which of the stages below best characterizes the progress of your
activities in the following areas?

______ Assessing PET facility needs (1)
______ Evaluating cGMP requirements (2)
______ Examining potential barriers to implementing requirements (3)
______ Assessing organizational resources (4)

Below we are interested in the approach of your ORGANIZATION with regard to the
implementation of GMPs.

Q8 Which of the following choices identify the current state of hiring to implement PET
cGMP activities at your facility?

 We must still hire more staff (1)
 Current staffing is adequate but lacks GMP expertise (2)
 Current staffing is adequate and has GMP expertise (5)
 We successfully hired new staff with GMP expertise (6)

155
Q9 Which of the following choices identify the current state of training to implement
PET cGMP activities?

 We are still training staff and without problems (2)
 All staff are adequately trained (3)
 We are having difficulty in training staff (Please also comment on why below) (4)
____________________

Q10 Which of the following choices best identifies the interactions that you will or have
had with industry leaders or consultants in respect to PET cGMPs?

 We are evaluating available options with regard to potential consultants (1)
 We have hired or engaged with appropriate consultants (2)
 Our facility has become fully operational with the aid of outside consultants (3)
 Our facility has become fully operational and did not require the help of consultants
(4)
 Our facility is not operational and no resources have been allocated to hire outside
expertise (5)

Q11 If consultants were obtained, what were they hired to do? Choose all that apply.
 Assist in writing regulatory documents (1)
 Train staff (2)
 Help implement PET cGMPs (3)
 Develop needs assessment (4)
 Auditing facilities/process (6)
 Construction (7)
 Other (5) ____________________

Q12 Which of the following choices best describes the current status of facility upgrades
or renovations for PET cGMP compliance?

 We are evaluating needs and costs (1)
 We are in the design phase (2)
 We are in the construction phase (3)
 Our facility is fully commissioned and operational (4)
 Our existing facility did not require any upgrades or renovations (5)
 Do not know (6)

156
Q13 Which of the following choices best describes the current status of equipment
acquisition for PET cGMP compliance?

 We are identifying resources for equipment acquisition (1)
 We have ordered all necessary equipment but have not installed it (2)
 We are in the process of installing and validating needed equipment (5)
 New equipment has been fully installed and validated (3)
 Existing equipment was adequate and fully functional (4)
 Do not know (8)

Q14 Describe the expertise of your group to develop your own standardized cGMP
documentation for the following: categories below.

Standard Operating
Procedures (All
cGMP operations)
(1)
Drug Applications
(NDA, ANDA, IND,
RDRC) (2)
Training Materials
(Staff and Equipment
Qualification) (3)
We can write all of
the necessary
documentation in-
house (4)
  
We can write only
part of the
documentation in
house (5)
  
We can write very
little of the
documentation in
house (6)
  

157
Q15 In your opinion, which of the following aspects of cGMP requirements do you
believe to be implemented at your PET cGMP facility at a level sufficient to pass an FDA
audit? Check all that apply.

 Modifying SOPs (1)
 IQ/OQ/PQ of equipment & facilities (2)
 Preparation and Submission of FDA regulatory applications (ANDA/NDA) (3)
 Advanced training for staff (4)
 Annual or quarterly audits (6)
 QA/QC validation activities implemented on a prescribed schedule (5)
 None of the above (7) ____________________

Q16 Please estimate to the best of your ability the costs that have been associated with
bringing your facility into compliance with PET cGMP requirements.

0-50K
(3)
51-
100K
(4)
101-
200K
(5)
201-
500K
(2)
Over 1
million
(1)
No
additional
cost (6)
Cannot
say (7)
Facilities
improvements (1)
      
Equipment
acquisition/upgrade
(2)
      
Hiring and training
of additional staff
(3)
      
Investment in
consultants (4)
      
Process Validations
(5)
      
Equipment
Validations (6)
      

158
Q17 How challenging have you found the following potential obstacles for your PET
cGMP implementation?

Very
difficult
(6)
Difficult
(1)
Somewhat
Difficult
(2)
Neutral
(3)
Somewhat
Easy (4)
Easy
(5)
Cannot
say (7)
Lack of
internal
organizational
resources (1)
      
Writing and
submitting PET
Drug
Applications
(3)
      
Financial
resources (4)
      
Finding/hiring
knowledgeable
staff (5)
      

159
Q18 Please describe how satisfied your organization is with the role of the FDA feedback
and support in the following areas of interest.

Very
Dissatisfied
(1)
Dissatisfied
(2)
Neutral
(3)
Satisfied
(4)
Very
Satisfied
(5)
Cannot
comment
(6)
Review of PET
drug
submissions
(12)
     
Support/clarity
of
communications
(11)
     
Experience of
FDA staff (13)
     
Opportunities
for dialogue (14)
     
Adequacy and
consistency of
standards (15)
     

Q19 Please rank the importance of the following organizational resources to affect your
ability to comply with implementation of GMPs

______ Adequate funding (1)
______ Adequate staffing (2)
______ Appropriate facilities and equipment (3)
______ Training and coaching (4)

Q20 Do you have further comments to share about challenges to GMP implementation?

160
Q21 How useful would it be to your organization if the following were available from the
PET community or FDA?

Very
Useful
(1)
Useful
(2)
Neutral
(3)
Unimportant
(4)
Very
Unimportant
(5)
Cannot
comment
(6)
Standardized
PET Drug
Applications
(1)
     
Standardized
PET cGMP
Facility SOPs
(2)
     
Funding
Opportunities
for PET cGMP
activities (3)
     
Annual
Training for
FDA/PET Drug
Manufacturers
(4)
     

161
Q22 Would your organization be likely to adopt standardized templates in the following
areas if they were available for free?

Very
Likely (1)
Likely (2)
Undecided
(3)
Unlikely
(4)
Very
Unlikely
(5)
Cannot
comment
(6)
Standardized
PET Drug
Applications
(1)
     
Standardized
Facility SOPs
(2)
     
Standardized
Training
Material (3)
     

Q23 Would your organization be likely to adopt standardized templates in the following
areas if they were available for a fee (below 50K)?

Very
Unlikely
(1)
Unlikely
(2)
Undecided
(3)
Likely (4)
Very
Likely (5)
Cannot
comment
(6)
Standardized
PET Drug
Applications
(1)
     
Standardized
Facility SOPs
(2)
     
Standardized
Training
Material (3)
     

162
Q24 In your opinion how many ANDA approved PET drug doses would have to be
produced daily to break even?

Q25 If you cannot write all of the documentation in house, on whom do you rely for
assistance?

Q26 Will the new PET cGMP hamper the development of novel PET
Radiopharmaceuticals?

 Yes (1)
 No (2)
 No opinion (3)
 Other (4) ____________________

163
Q27 What is your view on the following statements? Check all that apply.

Strongly
Agree (1)
Agree
(2)
Disagree
(3)
Strongly
Disagree
(4)
No
opinion
(5)
Cannot
answer
(6)
PET cGMPs are
unnecessary and cost
prohibitive (1)
     
PET cGMPs are
necessary and
important for quality
patient care (2)
     
The cost of
implementing PET
cGMPs will lead to
the closure of many
commercial PET
pharmacies (4)
     
PET cGMPs will
improve the safety
and quality of PET
radiopharmaceuticals
(6)
     
PET cGMPs will lead
to the closure of
many academic
based PET
manufacturing
facilities (7)
     

Q28 What has been your biggest unforeseen challenge in PET cGMP implementation?

Q29 What advice or comment would you provide for stakeholders or other groups that
are involved in PET cGMP implementation?

Abstract (if available)

Abstract The application of positron emission tomography (PET) radiopharmaceuticals has been an important area of expertise for academic medical centers. However, the ability of these centers to contribute to the evolution of this important technology will hinge on their ability to satisfy new regulatory requirements, perhaps the most challenging of which are the new FDA regulations that govern current Good Manufacturing Practices (cGMPs) for radiopharmaceuticals. This study explored the challenges and opportunities presented for academic centers by requirements to implement cGMPs in their facilities. A novel survey instrument was developed, critiqued by a focus group of highly reputable imaging leaders and then disseminated to imaging experts. Results provided insight into the views of those individuals with regard to the potential of these changes to facilitate or hamper the development of innovative PET drugs. The results showed that most PET cGMP facilities viewed their sites as mature in implementation of PET cGMPs. However, a more in depth review of FDA audits and overall number of FDA inspections indicates an opposing view of maturation. Our findings indicated that cost of implementing PET cGMPs were significant

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Asset Metadata

Creator Dagliyan, Grant (author)

Core Title Implementation of good manufacturing practice regulations for positron emission tomography radiopharmaceuticals: challenges and opportunities perceived by imaging thought leaders

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 02/15/2018

Defense Date 11/29/2017

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

Tag 21 CFR 212,academic hospitals,ammonia,ANDA,CFR 212,cGMP,compounding,cyclotron,eCTD,FDA,FDA inspection,FDG,good manufacturing practices,implementation framework,IND,medical imaging,naf,OAI-PMH Harvest,PET radiopharmaceuticals,positron emission tomography,QA,QC,radiopharmaceuticals,radiopharmacy,RDRC,regulatory affairs,USP 823

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Conti, Peter (committee member), Jamieson, Michael (committee member), MacKay, Andrew (committee member)

Creator Email dagliyan@med.usc.edu,dagliyangrant@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-476976

Unique identifier UC11266669

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Legacy Identifier etd-DagliyanGr-6047.pdf

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Document Type Dissertation

Rights Dagliyan, Grant

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

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