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Validation master plans: progress of implementation within the pharmaceutical industry
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Content
VALIDATION MASTER PLANS:
PROGRESS OF IMPLEMENTATION WITHIN THE PHARMACEUTICAL
INDUSTRY
by
Clare Elser
A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE
May 2016
Copyright 2016 Clare Elser
2
DEDICATION
I dedicate my dissertation work to my family and many friends. A special feeling of
gratitude to my sons Alois Scott and Alec Scott, who stood by my side with
understanding and love. To my mom, Joan Riemer, whose words of encouragement and
faith in my quest allowed me to stay my course.
I also dedicate this to m many friends and colleagues who have supported me throughout
the process. A special thanks to JoAnn Pfeiffer who has been there with me throughout
the doctorate program as a mentor, a coach, and a friend.
3
ACKNOWLEDGEMENTS
There are people in life who are great influencers and believers in one’s success. This
person for me is Dr. Frances Richmond, who not only served as my advisor and
committee head, she supported me and encouraged me beyond what I had thought
possible.
The gift of generosity is one that I received from my committee. I wish to thank my
committee members, Dr. Michael Jamieson, Dr. Stan Louie, Dr. Daryl Davies, and Dr.
Eunjoo Pacifici for their expertise, encouragement and commitment of time throughout
this project.
Often times the simplest things in life appear to be the most difficult. I wish to thank
Randa Issa, Erin Chow and Deborah Lynne Schroyer whose support and management of
the doctoral program smoothed out the bumps and trenches I encountered along the way.
4
TABLE OF CONTENTS
DEDICATION .................................................................................................................... 2
ACKNOWLEDGEMENTS ................................................................................................ 3
TABLE OF CONTENTS .................................................................................................... 4
LIST OF TABLES .............................................................................................................. 8
LIST OF FIGURES ............................................................................................................ 9
ABSTRACT ...................................................................................................................... 12
CHAPTER 1. OVERVIEW ...................................................................................... 13
1.1 Introduction .................................................................................................. 13
1.2 Statement of the Problem ............................................................................. 16
1.3 Purpose of the Study .................................................................................... 17
1.4 Importance of the Study ............................................................................... 18
1.5 Limitations, Delimitations, Assumptions .................................................... 19
1.6 Organization of the Thesis ........................................................................... 20
CHAPTER 2. LITERATURE REVIEW .................................................................. 21
2.1 A Historical Perspective .............................................................................. 21
2.2 U.S. Drug Regulations ................................................................................. 25
2.2.1 Early Regulation ............................................................................. 25
2.2.2 Introduction of cGMPs ................................................................... 29
2.3 Refining cGMPs ........................................................................................... 32
2.3.1 Validation as a Quality Principle .................................................... 32
5
2.3.2 FDA Oversight of Process and Equipment Validation ................... 34
2.3.2.1 Early Stages ....................................................................... 34
2.3.2.2 Recent FDA initiatives ...................................................... 40
2.4 Implementing Effective Validation Programs ............................................. 42
2.4.1 Challenges of systematic process validation .................................. 43
2.4.2 International Efforts to Improve Validation Practice ..................... 46
2.5 The Validation Master Plan ......................................................................... 48
2.5.1 What is a validation master plan? ................................................... 48
2.5.2 Development and Implementation of Validation Master Plans ..... 52
2.6 Approaches to Research ............................................................................... 56
2.6.1 The Regulatory Triangle of Ayres and Braithwaite ....................... 57
2.6.2 The Quality Implementation Framework of Yusef and
Aspinwall ....................................................................................... 59
2.6.3 Organizational triangle framework of Guldenmund ...................... 60
2.6.4 High Reliability Organization Framework of Sullivan and
Beach .............................................................................................. 62
2.6.5 Risk Management Implementation Framework of Chan ............... 65
CHAPTER 3. METHODOLOGY ............................................................................ 68
3.1 Introduction .................................................................................................. 68
3.2 Survey Instrument Development ................................................................. 68
3.3 Survey Deployment and Analysis ................................................................ 69
6
3.3.1 Focus Group ................................................................................... 69
3.3.2 Survey Dissemination ..................................................................... 69
CHAPTER 4. RESULTS .......................................................................................... 72
4.1 Results of the Focus Group .......................................................................... 72
4.2 Analysis of the Survey Results .................................................................... 72
4.3 Profile of Respondents ................................................................................. 75
4.4 Profile of companies .................................................................................... 77
4.5 Status of Implementation of VMP ............................................................... 79
4.6 VMP Structure ............................................................................................. 81
4.7 Process to Maintain VMP ............................................................................ 84
4.8 Equipment Status ......................................................................................... 87
4.9 VMP Documentation System ...................................................................... 89
4.10 Project management and cultural considerations ......................................... 92
CHAPTER 5. DISCUSSION .................................................................................... 97
5.1 Consideration of Limitations, Delimitations, and Assumptions .................. 97
5.2 How mature are current VMP approaches? ............................................... 103
5.3 How do organizational capabilities affect VMP maturity? ........................ 104
5.3.1 Resources ...................................................................................... 105
5.3.2 Structure ....................................................................................... 106
5.3.3 Processes ....................................................................................... 107
5.3.4 Competence .................................................................................. 109
7
5.3.5 Culture .......................................................................................... 113
5.3.6 Memory ........................................................................................ 114
5.3.7 VMPs and Equipment Validation Planning ................................. 116
5.3.8 Conclusions .................................................................................. 117
REFERENCES ............................................................................................................... 119
APPENDIX A. DRAFT SURVEY ........................................................................... 133
APPENDIX B. FINAL SURVEY ............................................................................. 138
APPENDIX C. FOLLOW UP SURVEY .................................................................. 146
8
LIST OF TABLES
Table 1: VMP Sections ......................................................................................................50
Table 2: VMP Sources .......................................................................................................51
Table 3: Questionnaire Instrument: Breakdown of Areas of Inquiry ...............................68
Table 4: Questions to describe the profiles of the respondents and their
companies ..................................................................................................73
Table 5: Questions to explore implementation of the validation master plan at a
company .....................................................................................................73
Table 6: Questions to explore validation master plan structure, strategy, culture
and planning ...............................................................................................74
Table 7: Questions to explore the maintenance of validation master plans and
equipment status .........................................................................................75
9
LIST OF FIGURES
Figure 1: Validation as part of life cycle management ......................................................41
Figure 2: Pyramid of enforcement strategies extracted from Ayres and
Braithwaite .................................................................................................58
Figure 3: TQM conceptual implementation framework for small business ......................60
Figure 4: The organizational triangle .................................................................................61
Figure 5: The conceptual model for operational reliability ...............................................64
Figure 6: Research model for Medical Device Risk Management Implementation ..........65
Figure 7: “Select the best title that represents your position in the company.” .................76
Figure 8: “Which industry sector best describes your company?” ....................................78
Figure 9: “What is the size of your company in terms of number of employees?” ...........78
Figure 10: “To the best of your knowledge, how many drugs does your company
market?” .....................................................................................................78
Figure 11: “Select the geographic region that best describes the headquarter(s) of
your company.” ..........................................................................................79
Figure 12: Cross-tabulation of the geographic region that best describes the
headquarter(s) of your company against company size. ............................79
Figure 13: “How would you characterize the structure of your VMP?” ...........................80
Figure 14: “Does every site within your company have its own VMP?” ..........................80
Figure 15A: Cross-tabulation comparing companies’ geographic headquarters
and presence of some type of VMP. ..........................................................81
Figure 16: “Which of the following areas of activities is included in your
validation master plan?” ............................................................................82
10
Figure 17: “When your validation plan was put into effect who contributed to its
design?” ......................................................................................................83
Figure 18: Cross-tabulation of who contributed to its design and the company
size. ............................................................................................................83
Figure 19: “What is the most senior level of management required to review and
approve VMP?” .........................................................................................84
Figure 20: “How is the VMP updated for new product or facilities equipment,
excluding analytical equipment?” ..............................................................85
Figure 21: “How is the review of the validation program conducted?” ............................85
Figure 22: “What is the periodicity of review of the validation program?” ......................86
Figure 23: “How is the validation documentation retained?” ............................................87
Figure 24: “What is the retention period for validation documentation for
production and facilities equipment, excluding analytical
equipment?” ...............................................................................................87
Figure 25: “Our validation master plan is one system that is used to manage
equipment lifecycle” ..................................................................................88
Figure 26: “Our validation master plan describes equipment qualification and
validation standards” ..................................................................................89
Figure 27: “What is the period of time for which equipment is typically
considered validated?” ...............................................................................89
Figure 28: “Identify the administrative infrastructure that supports your holistic
validation program.” ..................................................................................90
11
Figure 29: “What is the retention period for validation documentation for
production and facilities equipment, excluding analytical
equipment?” ...............................................................................................91
Figure 30: Cross-tabulation of company utilization of paper based documents
systems .......................................................................................................91
Figure 31: “The validation master plan presents an overview of the entire
validation operation, its organizational structure, its content and
planning.” ...................................................................................................92
Figure 32: “The following questions deal with validation master plan.” ..........................93
Figure 33: Cultural and communication indicators related to the VMP ............................94
Figure 34: Cross-tabulation of culture of compliance and how it influences VMP
“evergreen” status. .....................................................................................94
Figure 35: Responses to general questions on the validation master plan. ........................95
Figure 36: Production and facilities equipment, excluding analytical equipment,
and the validation master plan. ..................................................................96
Figure 37: Slow adoption of leading-edge learning tools ................................................111
12
ABSTRACT
This paper presents the materials necessary for qualifying the researcher’s study in partial
fulfillment of the requirements for the Doctoral Degree of Regulatory Science at the
University of Southern California. The research that it describes examined the progress
of implementation of validation master plans (VMPs) in U.S. pharmaceutical companies
that manufacture and produce drug products in accordance with the U.S. FDA Good
Manufacturing Practice for Finished Pharmaceuticals. The study began with a literature
review to gain insight into the evolution of thinking with respect to manufacturing and
equipment validation and the current expectations regarding the implementation of
VMPs. It introduced a combined framework with a focus on behavior and capability that
was used to guide the analysis of the progress and problems that are perceived by
industry in the implementation of VMPs. A survey of 42 senior regulatory professionals
showed that VMPs are incorporated into the quality systems of most companies, but
those companies differ in their approaches to implementation. Small companies typically
employ centralized VMPs whereas larger companies commonly decentralize their VMPs
Both large and small companies most commonly use documentation systems that still
rely heavily on paper rather than electronic tools to organize and track validations
including validations of equipment. Their VMPs generally have established retention
policies that reduce the reliance of companies on the memories of individuals. Results
suggest that VMPs are commonly used in US companies even when such systems are not
mandated by US regulation.
13
CHAPTER 1. OVERVIEW
1.1 Introduction
The development of quality systems for pharmaceutical production has been seen as a
key element to ensure safe drugs for the public. Thus, regulatory guidelines in the US
have evolved and continue to be updated through regulatory revisions, in an attempt to
set a rigorous benchmark for manufacturing practices that takes account of evolving
scientific knowledge and industry trends. One important area of quality systems that has
recently received much attention is that called “process validation”. Process validation is
defined as a documented programme, which provides a high degree of assurance that a
specific process will consistently produce a product meeting its predetermined
specifications and quality attributes (U.S. Food and Drug Administration, 1987).
Validation requires a substantial effort to do well, so that the challenge for the
pharmaceutical industry is to streamline and/or simplify validation without sacrificing
product quality (Helle, Yliruusi, & Mannermaa, 2003).
The first formal requirements for process validation came as part of Good Manufacturing
Practices (GMPs) that were introduced in 1963. However, the industry appeared to be
confused about the requirements and specific methods for such validation and
implementation lagged. A series of patient injuries and deaths that then occurred because
of problems with sterile drug production led the FDA to provide more advice in the form
of an initial guidance, the Guideline on General Principles of Process Validation, in
1987. Since that time, FDA has integrated the concepts outlined in the guidelines into
their process inspections. However, such information appeared unable to prevent
14
recurring problems related to process validation. Numerous examples that illustrate a
failure to comply with the requirements for process validation were still evident in
warning letters and other documents describing deficiencies.
Although professional societies and regulators continued for the next two decades to
educate manufacturers about good validation practices, it took another two decades, until
2011, for the FDA to publish a revision to the 1987 Guideline on General Principles of
Process Validation (U.S. Food and Drug Administration, 1987, 2011). In this new
iteration, FDA identified that the old definition of process validation failed to specify that
validation was an activity required throughout the lifecycle of products and production
facilities. The definition was therefore revised:
Process validation is defined as the collection and evaluation of data,
from the process design stage through production, which establishes
scientific evidence that a process is capable of consistently delivering
quality products. (U.S. Food and Drug Administration, 2011)
At the same time, European regulators and industry groups also were in the process of
examining the way that validation activities were organized and concluded that changes
were needed. Amongst other initiatives, in 2001, the European Medicines Authority
(EMA) published an updated guidance for validation and qualification entitled Final
Version of Annex 15 to the EU Guide to Good Manufacturing Practice, published in
Eudralex Volume 4, Annex 15, to describe its expanded expectations for validation
(European Medicines Agency, 2001). In 2006, the World Health Organization (WHO)
added its perspective to validation by publishing Annex 4 Supplementary Guidelines on
Good Manufacturing Practices: Validation (WHO, 2006). Both introduced an important
15
new element in validation planning, called a Validation Master Plan (VMP). The intent
of a VMP was to provide as systematized approach to plan and track, in a single
comprehensive place, the wide range of validations required by different equipment and
processes associated with manufacturing activities.
The VMP is company specific; it documents a company’s own unique approaches to
meet the requirements for initial and ongoing validation and establishes monitoring and
assessment criteria for assuring that the equipment and processes maintain their validated
status after maintenance activities have been performed. Such documents cover a wide
variety of areas, so that identifying the status of implementation of validation in such a
plan is a very large undertaking. Thus when trying to understand if a company is
implementing such a plan and whether the plan is immature or advanced, it would make
sense to choose one area of the plan to examine deeply as an index area that might give
insight into how the plan is being carried out. In this research we are interested in the
state of implementation of VMPs, and in the way that it is used in one such index area,
that of equipment validation.
Production equipment varies from one site to another, so that no standard method can
dictate its quality management. Nevertheless, certain general requirements are in place
for equipment, to assure that a piece of equipment used to manufacture drugs is designed,
installed and maintained properly throughout its lifetime. Validation demands that each
piece of equipment goes through a set of evaluations related to its installation, operation,
and performance; these are generally called IQ, OQ, PQ (installation qualification,
operation qualification and performance qualification) steps. It also demands that
16
periodic maintenance is performed on that manufacturing equipment, because
maintenance, cleaning and general use may change the operation and performance status
from an originally validated state. This may lead to uncontrolled changes in the
validation status that can affect product quality and can lead to observations of
nonconformance when regulatory inspectors carry out their audits. Some of these
deficiencies have been and continue to be reflected in FDA warning letters and
complaints regarding drug quality.
1.2 Statement of the Problem
Regulatory agencies outside of the U.S. have recently required that companies develop a
VMP to govern their validation activities in a systematic and comprehensive way. Such a
requirement is not currently identified explicitly in U.S. regulations, but a VMP is a
sensible way to meet the expectations of the U.S. FDA for a systematic approach to
validation. Nevertheless, validation activities are a large amount of work for
manufacturers, and they may see the development of a VMP as one more onerous activity
that might increase their regulatory obligations and tie them to expensive activities in a
highly visible way. For example if such a document were to call out a particular activity
or test, then failure to carry out that activity would be considered by an inspector as a
failure of compliance. Thus, the VMP can be identified as a document that provides
opportunities for improvement but also challenges for development and implementation.
Little has been written about the prevailing views of industry with regard to the
implementation of VMPs in their facilities, particularly in the U.S. where such a
document is not mandatory. We do not know whether companies are implementing
17
VMPs consistently and whether the level of granularity is sufficiently deep to ensure full
coverage of all areas of validation. Further, if we use equipment validation as a probe to
better understand implementation, we do not know how equipment validation is currently
tied by companies into the VMP. For example it may be called out as a separate function
in that VMP (assuming that a VMP indeed even exists), or managed in some other way.
Further we do not know how attitudes and implementation vary from large companies,
where documentation may be considered more important to control a wide range of
validation tasks, to small companies, where resources may be limited and tasks may be
more circumscribed.
1.3 Purpose of the Study
In this thesis, the views of U.S. pharmaceutical companies on the use of VMPs were
explored. The study was carried out using exploratory survey methods to understand the
current progress and systems used by manufacturers to organize their validations,
including their equipment validations. The state of implementation was assessed
according to the Implementation Framework of Fixsen and colleagues (Fixsen, Blasé,
Naoom, & Wallace, 2009). The survey itself was guided by a combined framework to
assess behavior and capability suggested by Chan (2012). As part of this survey, I
attempted to characterize the role that a master validation plan plays in their quality
organizations. The extent and depth of inclusion of equipment validation were examined
in particular detail as a way to probe the level of comprehensiveness of the VMP by using
it as an example of one subset of activities contained in the VMP.
18
1.4 Importance of the Study
Drug product quality is important to assure drug safety and efficacy. Regulatory agencies
grant drug manufacturing licenses based upon the technology and processes that the
manufacturer describes thoroughly in its new drug applications (NDA) and assessed by
the regulatory agencies during pre-approval inspections. Patients rely on the drug
product, so that quality issues or drug shortages are detrimental to patient health. Thus, it
is essential that drug manufacturing is conducted in a way to ensure that the quality of the
drug product is maintained during the shelf life and life cycle of the drug. Downtime in
manufacturing such as that associated with equipment failure, unexpected maintenance or
non-compliance with regulatory inspections can compromise the ability to produce a drug
product. When no alternative drug product is available, such restrictions would have a
negative impact to patient supply. Thus an effective validation program is crucial to
company success and societal access to high-quality drugs. The VMP approach seems to
be recognized by experts as perhaps the best way to assure such a capable system.
However, before it is required as a regulatory expectation, it is important to understand
the strengths, weaknesses and constraints that companies see to implement this approach.
Such an understanding could inform future policy development in this area.
By understanding the role that is played by the VMP, I hope also to provide insight into
the current state of VMP implementation as part of a benchmarking exercise. Companies
need to understand if what they are doing constitutes best practices or even average
practice, so that they can judge the urgency of improvements in their systems. It also
helps companies with excellent practices to have more confidence that they are moving in
19
the right direction. Findings can be used as an educational tool for quality leaders in
companies with less developed systems.
1.5 Limitations, Delimitations, Assumptions
The study was delimited to evaluating the validation processes utilized by pharmaceutical
companies to maintain the integrity of their equipment in meeting 21 CFR 211 (U.S.
Food and Drug Administration, 1978). The study assumes that the companies whose
personnel were polled were manufacturing products requiring approval and licensing by
FDA. The respondents to the study were delimited to quality managers and subject
matter experts within the pharmaceutical industry who had an active role in reviewing
and applying validation methods to processes and equipment. Those individuals are
typically busy and often avoid participation in surveys such as this due to the personal
priorities that they set. Surveys are limited in the numbers of questions that they can ask,
and assume that answers will be given honestly. However it was not possible to check
the accuracy or veracity of the responses. Identification of an appropriate response pool
that represents the industry fairly is always a significant challenge, especially when
respondents are most likely to participate if they know me or the university. This may
have introduced bias in the types of companies that participated. Efforts were made to
recognize this bias by asking demographic questions that profiled the respondent pool.
The development of the survey may also have been handicapped by the relative
inexperience of the investigator with such methods. The use of a focus group helped to
increase the face validity of the survey but bias should always be kept in mind when
interpreting results.
20
Validation activities are required both for processes and equipment. However, this study
was delimited to equipment validation activities that are included in process validation,
and did not assess process validation or process controls more generally. The study
examined the validation of equipment, including utilities, essential to the manufacturing
process, but did not address computer validation or automation.
1.6 Organization of the Thesis
This dissertation is divided into five chapters. Chapter 1 provides an introduction to the
study including the problem statement, the purpose and importance of the study, and the
delimitations and limitations of the study. Chapter 2 provides the history of validation
and the evolution of GMPs for process and equipment validation. Chapter 3 outlines the
methods used to guide the analysis and rigorous oversight of the survey analysis. Chapter
4 presents findings from analysis of the survey results and provides additional insights
from text responses from participants. Chapter 5 discusses the results and their
implications.
21
CHAPTER 2. LITERATURE REVIEW
2.1 A Historical Perspective
The development of quality systems for pharmaceutical production has coevolved with
pharmaceutical compounding over the last 4000 years. Thus even in relatively early
societies, quality management in drug production appears to have been important.
Perhaps the first documentation of pharmacy “manufacturing” can be found in the
descriptions of compounding recipes and techniques documented by the Babylonians on
clay tablets in approximately 2600 B.C. The information on the clay tablets was used to
train new pharmacists on proven techniques related to pharmaceutical production, and
furnished an early example of sensitivity to quality management. Just a few hundred
years later, in 2000 B.C., the Chinese emperor, Shen Nung, investigated and documented
the medicinal use and formulations of over 300 herbs. In Egypt, around 1500 B.C.,
prescriptions were written on paper as a means to document consistent methods for
making a drug product. Pharmacies were housed in large production facilities where
formal roles were established for the personnel who gathered the raw materials or
prepared the prescriptions. The quality of the raw materials and the compounding
process was supervised by a head pharmacist (Bender, 2006).
The separation of pharmacists from physicians was a key step in the evolution of
compounding that led to the institution of the “apothecary” and the development of
specialized professionals and pharmaceutical approaches. Apothecaries first appeared as
small shops in the Middle East where prescriptions and other elixirs were sold alongside
confections and incense (Al-Ghazal, 2003). Apothecary-like pharmacies spread from the
22
Middle East into Europe during the Middle Ages. During the 15
th
century,
pharmaceutical formulations and processes were documented formally in official
technical guides that later became consolidated as pharmacopeia (Puett & Puett, 2009).
These books became reference materials for the more uniform training of pharmacists,
which at that time consisted of identifying appropriate raw materials, understanding the
nature of chemical reactions, and having expertise in techniques for extractions and
purifications to produce better medicines. It also required understanding the use of
appropriate equipment during processing and formulation. Early pharmacists most likely
made or commissioned equipment, and were likely to modify that equipment during
repairs according to the availability of spare parts. Changes were often made to permit
this equipment to “multitask” as new drug formulations were developed. In some cases
government- supported pharmacies that were able to scale up the volume of prescriptions
were in evidence. Nonetheless, these facilities appeared to use “bench scale” equipment
(Bender, 2006). They gained the ability to “mass” produce drugs simply by hiring more
personnel to perform the same formulation and purification steps in parallel.
More formalized methods that could be used to mass produce drug products appeared
first to develop not in compounding pharmacies but in dye and chemical industries.
However, companies such as Farbenfabriken vormals Friedrich, which eventually
became Bayer Healthcare, began to convert their dye production lines into
pharmaceutical production lines when it became apparent that more profit could be
gained by providing wholesale pharmaceuticals rather than chemicals in quantity (Bain,
2013).
23
By the early 1900s, the factory-based manufacture of drug products became quite well
established. Drugs were initially provided as simple elixirs, pills and capsules. The most
complex process at the time was to encapsulate finished drug products, a process that can
be recognized in early patents such as Patent #US001970396, Method of and Machine for
Making Capsules, in 1934 (Scherer, 1934). The process of making capsules was to create
the capsule shells manually by dipping molds in gelatin using a method and tooling
similar to that used to make taper candles. Precision and accuracy in capsule formation
relied primarily on the training of the craftsman, rather than the quality or type of tooling
or equipment being used for the process. Thus, large variations were observed and
expected. In many instances the operator or a local craftsman also made tools for
extrusion or forming the capsules. Repairs to the tools were typically performed locally
and most likely without the intervention of the original manufacturer (Fischer, 1905).
It was not until 1851, when Eli Whitney documented the template or pattern for rifles,
that inconsistencies in the features of tooling began to be identified as a problem worth
solving (Olson, 2006). Whitney’s templates allowed such consistent manufacture of
parts that the parts could be used interchangeably regardless of where they were
manufactured. A whole field of engineering developed around the need for tool
fabrication and standardization, including the design of interchangeable parts and the use
of tool path control via machine tools and jigs to establish a path of movement for a tool,
These improvements reduced the dependence on highly skilled handwork so that semi-
skilled or unskilled machine operators could then be employed during manufacturing
(Stobbs, 2001).
24
Improvements in the capabilities of equipment had the further important benefit that they
were able to facilitate mass production. Mass production improved the availability of
standardized tools and equipment for making drug products in both apothecaries and
factory settings. Catalogues became available that featured a range of easily ordered
equipment and tooling manufactured according to the standards of the time (Crellin &
Scott, 1970). Once an order was placed, factories could then manufacture and ship the
equipment, essentially providing an early version of what has come to be known as “off
the shelf” equipment. It seems that weights and measures were forged for balances and
scales as accessories or freestanding items, a necessary predicate for the calibration of
instruments.
The early tools and equipment utilized by pharmacists were chosen primarily to facilitate
processes that could then be carried out on an assembly line. The assembly line concept
streamlined manufacturing operations by reducing the number of movements that
laborers took and at the same time increasing the size of batch lots that could be released
to consumers (Ling, 2006). However, the particular way that drugs were developed, with
small investigational batches in advance of large commercial runs, called for new
approaches to manufacturing methods and operations. It required tools and equipment
capable of meeting “scale-up” requirements, that is, requirements for transferring a bench
scale process to production equipment capable of producing large volumes of finished
product. Improvements in manufacturing allowed large amounts of product to be
distributed more widely to patients than previously was possible. However, problems
associated with a single batch lot could then affect larger numbers of consumers, often
25
over a wider geographic territory. Thus it appears that some form of regulation with
respect to drug distribution and manufacture was required to ensure patient safety.
2.2 U.S. Drug Regulations
2.2.1 Early Regulation
Society quickly began to appreciate the potential dangers of poorly regulated drugs as the
prevalence and reliance on drug therapies increased during the 19th century. Awareness
was further heightened at the beginning of the twentieth century by a series of tragic
public safety incidents that translated the potential problems with unsafe drugs into vivid
reality. One particularly notable incident in 1901 was caused by a diphtheria antitoxin
derived from the blood serum of horses that was manufactured in local establishments
without effective quality controls (Podczeck & Jones, 2004). A crisis occurred when the
blood of a tetanus-infected milk-wagon horse named Jim contaminated batches of
vaccine, which was subsequently responsible for the deaths of 13 inoculated children.
The incidents caused public outcry and the subsequent enactment of one of the first drug
safety laws, the Biologics Control Act (U.S. Food and Drug Administration, 2009). An
important feature of this legislation was the fact that it relied on the interstate commerce
laws to justify implementation of federal legislation that could better ensure a centralized
approach to drug regulation.
The Biologics Control Act of 1902 was enacted to regulate the production of vaccines
and antitoxins. It perhaps constituted the first formalized effort to oversee the quality of
manufacturing, but was relatively narrow in scope, dealing only with the production of
biologic products. The Act required that manufacturing facilities hold production
26
licenses and undergo site inspection; the licenses could be revoked or suspended if the
manufacturing area failed inspection or if commercial distribution had to be halted to
protect public health. Production was to be supervised by a qualified scientist. Industry
was required to demonstrate that the facility and equipment were appropriate for the
manufacture and sale of vaccines and that hygienic measures were in place to reduce
contamination (Barkan, 1985).
However, vaccines that were specifically derived from animal sources were just one part
of the pharmaceutical universe. In the early 1900s, while Upton Sinclair's publications
detailed horrific conditions in the meat-packing industry (Sinclair, 1906), other
journalists exposed the false claims, harmful ingredients, and market manipulation of
nostrums- medicines “whose effectiveness is unproved and whose ingredients are usually
secret; a quack remedy and their producers” (Society of Toxicology, 2013). In response
to growing consumer concerns, State and Federal legislatures put into place laws to
regulate drug marketing. For example, in 1906, North Dakota promulgated a law where
…all medicines sold in that State except on physicians' prescriptions,
which contain chloral, ergot, morphine, opium, cocaine, bromine, iodine,
or any of their compounds or derivatives, or more than five per cent of
alcohol, must so state on the label.
A more comprehensive, federally based food and drug law known as the Pure Food Act
of 1906 (U.S. Food and Drug Administration, 1934) followed to prohibit interstate
commerce of adulterated and misbranded food and drugs (McDonald, 2002). The new
Act had a broader reach than the Biologics Act by expanding oversight to all drug
products. It aimed to prevent “the manufacture, sale, or transportation of adulterated or
27
misbranded or poisonous or deleterious foods, drugs, medicines, and liquors, and for
regulating traffic therein, and for other purposes”. Section 6 defined drugs as
…all medicines and preparations recognized in the United States
Pharmacopoeia or National Formulary for internal or external use, and
any substance or mixture of substances intended to be used for the cure,
mitigation, or prevention of disease of either man or other animals…(U.S.
Food and Drug Administration, 1934
The Act required that manufacturers submit to allowing the agency to take samples or
specimens of food and or drugs for examination to determine instances of adulteration
and or misbranding. Under the Act, manufacturers were required to provide a guarantee
signed by a party residing in the United States, who facilitated the purchase, to the effect
that the product was not adulterated or misbranded. It stated that the adulteration
requirements would apply to drugs that are sold under or by a name recognized in the
United States Pharmacopoeia or National Formulary provided that no drug defined in the
United States Pharmacopoeia or National Formulary is considered if the standard of
strength, quality, or purity is plainly stated upon the bottle, box, or other container.
Secondly, the strength or purity does not fall below the professed standard or quality
under which it is sold.
An important element that was introduced by the Pure Foods Act was that of traceability.
Manufacturers were required to obtain a license, to assure traceability of drug products
back to the source of manufacture. The license required that the manufacturer describe
their facilities and the equipment used in manufacturing processes, and these could be
subject to inspection. Thus the legislation provided early evidence of requirements for
quality and equipment oversight. However, at this time, the equipment was not
28
specifically standardized for use in the pharmaceutical industry. It was often adapted
from the dairy and dye making industries, and was primarily designed to reduce the
number of laborers required to manufacture goods and increased output. Equipment
mimicked traditional activities performed by tools and laborers (McDonald, 2002).
The 1906 Food and Drug Act was a first step to assure the regulation of drugs but its
language was relatively weak with respect to drug safety and efficacy. To challenge
problematic manufacturers, FDA was required to prove fraud by the drug manufacturer
for drugs that failed to meet the consumers’ expectations. This flaw was clearly in
evidence in 1937 when a major public health problem challenged the effectiveness of the
Act at that time. Massengill distributed a new antibiotic formulation called Elixir
Sulfanilamide that it advertised for "all conditions in which the hemolytic streptococci
appear." This elixir contained diethylene glycol, a chemical analogue of antifreeze that
causes liver and kidney toxicity (Willrich, 2011). The documented deaths of 107 people,
including many children, provided a policy window to enable the passage of the Federal
Food, Drug, and Cosmetic Act (FD&C Act) in 1938. The FD&C Act was best known for
its focus on increasing oversight of drug safety, by requiring that all drugs be tested for
safety prior to marketing, and the results be submitted to the FDA in a new drug
application (NDA). In addition to safety, the Act empowered the agency to perform
authorized factory inspections, opening the door for stronger manufacturing oversight of
drugs and biologics (Society of Toxicology, 2013).
The strength of the new FD&C Act and its associated regulations were soon to be tested,
by a challenge that began in December 1940, when the Winthrop Chemical Company of
29
New York put on the market sulfathiazole tablets contaminated with phenobarbital.
Hundreds of deaths and injuries resulted. FDA's investigation into Winthrop's
sulfathiazole production and the agency's subsequent ability to retrieve the distributed
drug brought to light several deficiencies related to manufacturing methods and recall
capability (Lezotte, 2014). FDA then initiated major modifications to the regulatory
requirements for manufacturing and quality controls. These changes to the regulations
established the initial Good Manufacturing Practices (GMPs) (Immel, 2008). However,
several years passed before the GMPs evolved into the regulations with which we are
familiar today.
2.2.2 Introduction of cGMPs
Perhaps the most important landmark in the regulation of U.S. pharmaceutical
manufacturing came in the 1950s. The environment was ripe for change when a major
crisis appeared in the form of thalidomide, a drug that had already been approved for
marketing in Europe as a sedative, on the basis of a relatively modest dossier of safety
information. Its uncontrolled use in pregnant women for morning sickness resulted in the
births of many babies with a previously rare birth defect, phocomelia, which exhibited as
a pronounced shortening of limbs as well as other anomalies (Carpenter, 2010). In
reaction, Senators Kefauver and Harris introduced a bill that gave more authority to the
FDA, so that better control could be exercised over the safety and efficacy of a drug prior
to its approval. The successful adoption of the Kafauver-Harris Amendments (Drug
Amendments of 1962) allowed the FDA to update a number of regulations and in so
doing, to establish a more robust set of GMP requirements for drug manufacturers. These
revisions included the requirement to consider current technologies and trends in the
30
manufacture of finished drugs. The importance of current practices as part of the drug
manufacturing regulation was emphasized by placing a “c” denoting “current” in the
acronym, cGMP (U.S. Food and Drug Administration, 2015).
The introduction of GMPs gave the FDA the explicit authority to regulate a variety of
elements in the manufacturing environment, including the equipment used in drug
manufacture. As part of these requirements, equipment had to be designed for its
intended use and installed according to the instructions of original equipment
manufacturer. This approach was consistent with the initial steps that are now part of
equipment qualification and are considered as “validation”. Manufacturers were required
not only to list the equipment used to manufacture a drug product in their licensed
facility, as they were previously. They were also required to demonstrate that the
equipment performed as designed. Thus, equipment management now came more
explicitly under the oversight of the FDA during facility inspections. The revised
regulations stated:
Equipment used for the manufacture, processing, packaging, labeling,
holding or control of drugs shall be maintained in a clean and orderly
manner and shall be of suitable design, size and construction and location
in relation to surroundings to facilitate maintenance and operation for its
intended purpose.
and
…the regulations permit the use of precision automated mechanical or
electronic equipment in the production of drugs when adequate inspection
and checking procedures are used to assure proper performance…(U.S.
Food and Drug Administration, 1978)
31
No longer was proper design and installation enough to assure that equipment was
performing properly. The regulation required focus on the adequacy of equipment to
perform the function for which it was intended. Systematic and periodic checks were
required, to be documented in maintenance schedules to assure that the equipment
continued to meet its performance standards over time. Manufacturers were also
obligated to evaluate the functionality and precision of electronics and sophisticated
automation systems that were embedded in equipment. The cGMPs required “adequate”
inspection and checking procedures; however manufacturers were given little guidance
on defining “adequate”.
The FDA set out to implement its newly obtained authorities by instituting a new
assurance program, called the Drug Product Quality Assurance Program (WHO_TRS,
2006). In this program the FDA undertook to conduct sampling and testing of finished
batches of drugs that were obtained from the manufacturer. The FDA program focused
on the risk associated with an individual product. Risk profiles for different products
were constructed to select batches to be evaluated based upon the importance of the drug
in terms of its clinical significance and sales volume. Legal action was taken when non-
conforming batches were identified; drug manufacturing facilities were then inspected
and re-inspected until they could prove to be in compliance.
The Drug Product Quality Assurance Program attempted to assure better quality by
assuring process uniformity and consistency. Equipment inspections as part of the
conformity assessment were still relatively superficial with respect to the level of control
that was considered to be adequate under this program. Since the cGMP rules already
32
required equipment to demonstrate adequate performance, the safety concerns posed by
equipment were considered low risk. Equipment records were reviewed as part of the
audit to ensure that the equipment was appropriate for its intended use and was cleaned to
prevent contamination, but equipment qualification and validation were not typically
viewed as key activities to assure or impact quality (WHO, 2006).
2.3 Refining cGMPs
2.3.1 Validation as a Quality Principle
The management of manufacturing methods and equipment became a target of further
regulation in the 1970s, again driven by public health issues. Principal amongst these
initiatives was the identification of multiple cases of nonsocomial septecemia in 1970 –
1971, that could be traced to contaminated infusion products manufactured by Abbott.
The contamination of these products appeared to occur because Abbott made a change to
the materials used in the packaging of the infusion solutions without reassessing the
ability of the existing sterilization process and equipment to yield a sterile product when
contained in the changed packaging. A root cause was subsequently identified from
different manufacturers. In those investigations, FDA found significant problems of
content uniformity as a result of poorly controlled manufacturing processes.
Manufacturers of parenteral drugs were challenged by investigation of the sterile
processes. These manufacturers made an assumption without verification through
validation and qualification that the existing process and equipment would continue to
provide a sterile product regardless of changes to the packaging materials (Mackel, Maki,
Anderson, Rhame, & Bennet, 1975).
33
Sensitized by sterility failures, FDA investigated other clinical complaints associated
with the failure of products packaging. FDA increased their scope to include complaints
related to non-sterile products even though quality control programs were in place and
products purportedly passed criteria associated with sterility testing. FDA performed
inspections of these manufacturing establishments and found that the manufacturing
processes lacked controls sufficient to demonstrate that the products were sterile. The
inspection results caused the FDA to reassess their expectations and guidance with regard
to quality assurance and process validation. The changing perspective was captured by
FDA in a paper entitled “Design for Quality” written by Ted Byers, an FDA Director, in
1970 (Neha & Seema, 2013). Mr. Byers attempted to describe best practices for
maintaining process consistency and quality that included taking a systematic approach to
validation. Recommendations that were to be considered by industry were that
manufacturers use a system of process validation that paid close attention to the adequacy
of production processes when producing parenteral drugs (Parthasarathy & Priya, 2013).
To demonstrate process control, manufacturers were advised to use validation approaches
in which process variables were assessed systematically, by instituting testing protocols
that would yield data on process variability. The recommended validation activities
included the assessment of raw materials entering the manufacturing process and the
requirements to specify the operating parameters of the process (Houson, 2011).
At the outset, most pharmaceutical companies viewed validation as important primarily
for assuring the adequacy of sterilization processes for large volume parenteral products
like those that had caused problems for Abbott. Despite its introduction as a more
34
generalized regulatory requirement, the standardized use of validation took several years
to become part of mainstream practice. Originally, pharmaceutical firms followed a
retrospective approach in which a deviant result was observed, investigated and
documented in a study report. It took time for validation activities to evolve into the
format that appears to be widely used today. In this approach, validation is performed as
a prospective method in which a validation protocol with a hypothesis and pass-fail
criteria is developed, a plan for execution includes three repeated batch runs, and a
summary report is written that contains the documented observations with conclusions
regarding the adequacy of the process.
2.3.2 FDA Oversight of Process and Equipment Validation
2.3.2.1 Early Stages
Apparent from the literature was the common view that process validation was essential
to improve process control, in order to reduce the occurrence of problematic processes,
i.e., processes that cannot produce a consistent product meeting predetermined
specifications and quality attributes. However, the extent and content of acceptable
process validation initiatives were not clear to many. By the late 1980s the increased
attention to validation led industry to request that FDA clarify its expectations with
respect to validation programs. In response, FDA published guidance for industry in a
document titled 52 FR 17638, Guideline on General Principles of Process Validation
(U.S. Food and Drug Administration, 2011). The new guidance was intended to provide a
more consistent message regarding expectations of process validation by providing better
definitions of essential terminology and a better description of the way in which such
validation should be conducted. In the guidance, FDA indicated that existing regulatory
35
language in 21 CFR Parts 210, 211 and 820, the more general cGMP guidance for drugs
and medical devices respectively, was already appropriate to meet the more specialized
needs of validation. The guidance attempted to ensure consistency by encouraging
industry to leverage better design, engineering and qualification practices. It emphasized
the importance of documenting systematic evidence showing that the process would yield
a product meeting expectations laid out by its specifications and quality requirements.
The early guidance was also attentive to the role of equipment and the effect that its
variability could have on a process. It explicitly identified the need to consider
equipment, as a part of process validation by assuring that equipment “is capable of
operating consistently within established limits and tolerances” (U.S. Food and Drug
Administration, 1987). However, at this early stage of defining process validation, the
suggestions again focused on the initial stage at which equipment was introduced into the
process. The guidance described how manufacturers should qualify and document the
installation, operation and performance of equipment to demonstrate its suitability for the
proposed process. However, relatively little attention was paid to the continued
performance of the equipment as an important variable that could affect the ongoing
consistency of the process. The guidance cited just above, was largely silent on evolving
needs to maintain the equipment in a validated state as the equipment aged and the
processes evolved over time.
A challenge for many pharmaceutical firms at the time when the process validation
guidance was published was the relative immaturity of the whole field of equipment
management. Manufacturers found it difficult to identify suitable guidelines to assure
36
that equipment was fit for use. Equipment standards specific for the pharmaceutical
industry were limited in number. Companies were then forced to use existing standards
that were often developed for other industry sectors. Principal amongst these types of
standards were those written by the European Committee for Standardization (CEN),
American Standard for Testing and Materials (ASTM), and 3A Sanitary Standards (3-A
Sanitary Standards, 2014) the latter used in the dairy industry. This adoption of standards
from other industries was perhaps to be expected because many of the equipment
management issues faced by the pharmaceutical industry were similar to those in other
sectors. For example, the dairy industry, like the pharmaceutical industry, uses large
quantities of water in its manufacturing processes and must protect and sanitize its
equipment after potential exposure to biological contaminants. Unsurprisingly, then, the
3A Sanitary Standards written for the dairy industry contained applicable best practices
appropriate for pharmaceutical equipment management as well (Schmidt & Erickson,
2005).
Nevertheless, the reliance on standards from other industries had its limits. After the
publication of the FDA guidance in 1987, industry took a major step toward
standardizing pharmaceutical design, engineering and qualification in 1989 by seeking a
more focused set of standardized equipment requirements for the pharmaceutical
industry. To this end, the industry initiated discussions with the American Society of
Mechanical Engineers (ASME), and more particularly, the ASME Council on Codes and
Standards, to develop a standard for pharmaceutical equipment. The project was
approved by the Council; its scope was to include the design, materials of construction,
37
inspection, testing of vessels, piping, and related accessories such as pumps, valves, and
fittings for use in the biopharmaceutical industry. The ASME standard was published in
1997 and referenced existing standards that were applicable to pharmaceutical equipment
design and fabrication (Henon, 1997).
Attention to process validation continued through the 1990s, and provided quality experts
with more experience and expertise in systematizing process validation. This activity
resulted in numerous publications and textbooks [e.g. Pharmaceutical Process Validation,
Second Edition: Drugs and the Pharmaceutical Sciences (Berry & Nash, 1993);
Statistical Design and Analysis in Pharmaceutical Science: Validation, Process Controls,
and Stability Statistics (Chow & Liu, 1995); Pharmaceutical Equipment Validation: The
Ultimate Qualification Guidebook (Cloud, 1998)] that amplified the concepts and
procedures advocated by FDA’s original short guidance document. Further, input from
the FDA continued to come, not in the form of additional formalized guidance
documents, but rather from the more individualized and informal collection of “case law”
developing from FDA inspectional observations.
FDA exercises its authority over marketed products by performing inspections of
facilities to establish compliance with the relevant regulations. Its publicly available
inspectional findings can be a rich source of information on FDA thinking at the time of
the inspections. When, during an inspection, the inspectors observe instances that, in their
judgment, constitute violations of the Food Drug and Cosmetic (FD&C) Act, a
description of the deficiencies will be issued in a document known as an “FDA Form
483” letter. Typically these observations specify conditions or practices that they view to
38
contravene acceptable GMP practices or pose a potential adulteration hazard to the drug
product. Firms then respond to the FDA Form 483 observations in writing with their
corrective action plans. This collection of 483 observations that can be obtained under
Freedom of Information Act (FOIA) can assist manufacturers to identify the boundaries
that separate compliance from noncompliance with respect to process validation, amongst
other issues. Further, when corrective actions fail to resolve inspectional observations or
when the FDA is compelled to act more aggressively to protect public health, the FDA
issues a different form of letter, called a “Warning Letter”, to communicate its
requirements for immediate corrective action (Allport-Settle, 2005). These warning
letters are even easier to find because they are posted on the FDA website
(http://www.fda.gov/iceci/enforcementactions/WarningLetters/default.htm). Inspectional
observations in these warning letters often include deficiencies in equipment qualification
and validation.
To illustrate the potential value of this database for industry experts and quality
researchers, I conducted a review of warning letters from 1996 to 2000. One type of
violation that was identified repeatedly in these warning letters was associated with
deficient equipment practices. For example, the FDA identified several instances, in 5 of
33 reviewed warning letters, where autoclaves were not validated. The autoclaves in
these instances were used for sterilization processes that ironically were very similar to
the sterilization processes that provided the driving force for FDA to focus its efforts on
improvement of validation a decade earlier. In a number of warning letters, industry
appeared to be unable to present inspectors with documentation demonstrating that the
39
equipment was qualified and validated for the processes. Examples include the warning
letters to Bristol Myers Barceloneta, Inc., 1997, Elan Corporation, 1997, and Solvay
Pharmaceuticals B.V., shown below.
You have no documentation of Installation Qualification/ Operation
Qualification in accordance with 21 CFR 211.63 for several pieces of
equipment used in the manufacture of drug product… Bristol Myers
Barceloneta, Inc. (Jones, 1997).
You failed to properly validate the dissolution testing equipment. There
was no raw data available for the installation qualification/operation
qualification (IQ/OQ) for three of the spectrophotometers used in
dissolution testing. Qualification data could also not be found for system
[XXX] and Systems [XXX] were placed into service prior to execution of
IQ/OQ protocols [XXX] Elan Corporation (Graham, 1997).
Validation of the autoclave, used to sterilize equipment, stoppers and filled
syringes, is inadequate in that: a. The worst case load configuration has
not been established. b. There were no written procedures to describe load
configurations. c. A minimum sterilization time of minutes was required
for each autoclave cycle, however, the autoclave timer was not calibrated
in order to assure accuracy…Solvay Pharmaceuticals B.V. (Famulare,
1999).
Warning letter observations during this time also cited unacceptable process variability
that was often improperly monitored and controlled because of inadequate validation.
Examples include the following:
Failure to establish and follow adequate controls to monitor and validate
manufacturing processes that may be responsible for causing variability
in in-process materials and the drug product…, Gemini Pharmaceuticals,
Inc.(Aveta, 1997).
Manufacturing process validation was found to be inadequate for the
following products, in that, portions of batches were rejected that did not
meet predetermined specifications… Purepac Pharmaceutical
Co.(Ellsworth, 1997).
40
Failure to validate the performance of the manufacturing process may be
responsible for causing variability in the characteristics of interim
materials and drug products… LNK International, Inc. (Aveta, 1997).
Inadequate validation was often identified by FDA partially as a result of equipment
being employed in situations or used for functions beyond the boundaries of its original
intended use (Ulatowski, 2009).
2.3.2.2 Recent FDA initiatives
It took another two decades, until 2011, for the FDA to publish a revision to the 1987
Guideline on General Principles of Process Validation (U.S. Food and Drug
Administration, 2011). In this new iteration, FDA amended its definition of process
validation to the following:
Process validation is defined as the collection and evaluation of data,
from the process design stage through production, which establishes
scientific evidence that a process is capable of consistently delivering
quality products. (U.S. Food and Drug Administration, 2011)
This clarification in terminology communicated the intent of FDA to view process
validation as an ongoing activity. It also signaled the FDA’s resolve to treat the
validation of equipment not as a one-time event at the time of installation, but as an
activity to be assessed throughout the lifecycle of the equipment.
The update of the 1987 validation guidance by FDA shifted validation activities from a
“documentation” exercise to an exercise of life cycle management. As described by
Calnan and colleagues (Calnan, Redmond, & O'Neill, 2009) the validation life cycle can
be viewed as a continuous loop (Figure 1).
41
Figure 1: Validation as part of life cycle management
Validation modified from Calnan and colleagues (Calnan, Redmond, & O'Neill, 2009)
The basic concepts in the new revision were consonant with international standards that
had been put in place by the International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance, Q8
Pharmaceutical Development, Q9 Quality Risk Management, and Q10, Pharmaceutical
Quality System, all of which advocated the benefits of lifecycle monitoring and controls.
These documents advocated blending quality management principles and quality systems
with risk based approaches as the foundation for validation. The analysis of risk was
Phase 1
Process Design
Phase 2: Process Qualification
Phase 3
Continuous Process
Verification
42
considered important to focus the attention of the quality manager onto areas of most
significant concern. Better priority setting could come from reviewing inspection trends
and compliance activities, monitoring of manufacturing operations continuously and
incorporating benchmarking into management decision-making processes. By increasing
the visibility of their commitment to validation management, FDA and ICH appeared to
be aligned in communicating to the pharmaceutical industry that more systematic,
ongoing validation programs would be expected in future (U.S. Food and Drug
Administration, 2012).
2.4 Implementing Effective Validation Programs
Effective validation programs have the capacity to impact significantly the quality of
drugs. Today’s effective validation programs are expected to demonstrate that quality,
safety and efficacy are designed into the product throughout its lifecycle. In-process
testing and final inspection are used as inputs to the validation process as a way to
monitor the effectiveness of the validated state, and thus to show that the manufacturing
process is capable of producing products that meet specifications consistently as a result
of operating under validated manufacturing conditions.
However, developing and implementing a systematic validation program is not trivial.
Appropriate program design depends on having information and experience about the
sources of variation and their impact on the product as operations are scaled up from
development to commercial production. As part of that validation, a focus on equipment
becomes important during the initial process design, to ensure that the procedures and
associated equipment have the capabilities to operate in a reproducible manner. Once the
43
process is well understood, a protocol can be developed to collect, document and analyze
of data related to process capability and stability. This protocol is designed to evaluate
the critical attributes and parameters of the process and the risks introduced if the process
or equipment is changed. It includes key metrics to assess the extent and nature of
variability. The protocol should also address the effects of process stops and starts. The
results of this testing are then used to establish scientifically driven process controls that
can confine product variability within acceptable limits. Results of the executed protocol
and the subsequent conclusions and controls are documented in a summary report.
It is not enough for a single person to write a protocol. The protocol must be reviewed
and approved by functional areas responsible for technical implementation of the process,
and also must be reviewed by the quality assurance division of the company to assure that
the protocol meets GMP requirements. These same functional areas should then assess
the summary report. If the validation establishes that the system can be held in an
adequate state of control, a review board signs to signify its approval of the validation,
and the process is implemented. As part of today’s standards for life cycle evaluation, key
processes are also reviewed on a periodic basis to be sure that the process stays within its
expected tolerances and limits over time.
2.4.1 Challenges of systematic process validation
A major limitation often seen in early efforts to conduct validation activities is the
tendency to focus on assuring compliance with regulations rather than understanding
process failures and anomalies at a more mechanistic level. Regulatory requirements with
respect to validation appear often to be pursued with reluctance because of the costs and
44
time commitments associated with the activities. Validation activities can interfere with
regularly scheduled production activities resulting in a loss of productivity, and require
the deployment of extensive technical resources to draft protocols, plan activities, provide
oversight and analyze data.
Life cycle approaches to validation can challenge the ability of a company to maintain
operational flexibility, because they rely on continuous monitoring as opposed to periodic
demonstrations of control (Long, Baseman, & Henkels, 2011). Process changes can also
pose concerns. If a process is locked without sufficient understanding of its robustness
and its critical parameters, any deviation to the process will be viewed as a worrisome
challenge that might cause the process to fail in an unpredictable way. Any change will
therefore need to be accompanied by revalidation. Significant changes to the facilities,
equipment, or processes that might improve the quality of the product or production cycle
are then often avoided unnecessarily because the consequences of the change cannot be
easily anticipated and the needed revalidation activities would be difficult and costly. An
unfortunate response to such a challenge is to minimize the impact of the change by
conducting pro forma risk assessments, to avoid the established triggers for reassessment
of the validated state. The absence of sufficient review then could introduce uncontrolled
variability whose potential impact is insufficiently explored and characterized.
Another challenge posed by validation relates to the difficulty of implementing the
validation protocols without unexpected problems. It is a rare validation project that
does not experience a single validation deviation, defined as “an error or failure that
occurs during validation” (Katz & Campbell, 2012). Deviations are classified into
45
simple, non-critical or critical based upon their impact to the outcome of the validation
(O'Keefe, 2013). Simple deviations typically include documentation or protocol errors,
such as typographical mistakes or problems of clarity or inconsistency, usually
discovered prior to execution. Simple deviations can include relatively small problems of
little consequence during a testing protocol. For example, accidentally unplugging of a
piece of equipment identified for use in the protocol might cause a temporary loss of
power at a time when the equipment is not actually being used for the validation exercise.
These types of deviations usually have no impact on the results of the validation and
therefore present no real risk to the validation process or outcome.
Non-critical deviations include errors in the content of the protocol or execution of the
validation that have no impact on the key metrics or results of the validation. The
classification of these deviations is differentiated from “simple errors” because the errors
are normally discovered during or after the execution of the validation protocol.
Examples may include situations in which operators conduct the validation without
adequate training on the equipment or where the use of the equipment is unexpectedly
interrupted during the actual conduct of the validation. In such instances, an assessment
must be performed and documented to determine if the deviation has any impact on the
conclusions of the validation.
Critical deviations are the most serious and do impact the validation; these errors may be
discovered during or after execution of the protocol. As an example, this type of
deviation might include the execution of the testing protocol on equipment that fails to
meet the established acceptance criteria for its qualification. Classification of a deviation
46
as critical also requires that an assessment is performed and documented to determine the
extent of the impact (O'Keefe, 2013).
As the pharmaceutical industry embraces validation and applies more rigorous and
formalized methods for its assessment, areas or systems are commonly identified that can
be validated as subgroups of activities. This subdivision allows for equipment to be
validated to some extent independently, so that equipment qualification can be
approached as a set of activities separate from, but subordinate to, process qualification.
Equipment qualification can then be subdivided further into activities related to
equipment installation, to assure that equipment is suitable for use at the time of its initial
introduction, and to equipment operation, to assure that the equipment stays in a state of
operational effectiveness.
2.4.2 International Efforts to Improve Validation Practice
From the review provided to this point in the dissertation, a reader interested in the
evolution of process validation would be forgiven for thinking that all of the important
activities related to process validation were happening in the U.S. Concurrent with the
activities of the FDA, however, have been important discussions and guidance from
entities outside of the US at both the international and European levels. One significant
piece of work, published in 1998, by the International Society for Pharmaceutical
Engineering (ISPE), in collaboration with FDA (ISPE, 2009). This work, entitled ISPE
Baseline® Guide, Vol. 2: Oral Solid Dosage Forms (First Edition) elaborated on FDA’s
1987 guidance. It emphasized the importance of a systematic approach to process
47
validation. However, as an international group without the capability to pass laws, its
recommendations were developed to guide rather than to legislate change (WHO, 2013).
At the same time, the European Union was working to define practices and develop
legislation for managing validation. In contrast to FDA, the European Union integrates
the thinking of a number of member states and promulgates regulations to be integrated
into country-specific legislation. In 2001, the European Medicines Authority (EMA)
published an updated guidance for validation and qualification titled Final Version of
Annex 15 to the EU Guide to Good Manufacturing Practice, published in Eudralex
Volume 4, Annex 15, to describe its expanded expectations for validation (European
Commission, 2015). This work appears to have been influenced strongly by previous
activities of two groups, the Pharmaceutical Inspection Convention and Pharmaceutical
Inspection Co-operation Scheme, these groups have combined their efforts in a blended
organization called Pharmaceutical Inspection Cooperation Scheme, or PIC/s. The goal
of this group, with members from several regulatory agencies as well as industry, has
been to harmonize standards and quality systems associated with Good Management
Practices (GMP) and the development and manufacture of drug products. Eudralex
incorporated by reference the PIC/s guidance, PI-006-03 Recommendation on Validation
Master Plan Installation and Operational Qualification Non-Sterile Process Validation
Cleaning Validation (PIC/S, 2012).
In 2006, the World Health Organization (WHO) added its perspective to validation by
publishing Annex 4 Supplementary Guidelines on Good Manufacturing Practices:
Validation (WHO_TRS, 2006). Its guidelines did not focus on specific processes or
48
products such as sterile product manufacturing, as did the European guide. Instead it
attempted to support firms to create plans for validation that would ensure regulatory
compliance as well as product quality more systematically.
All of the significant documents that dealt with validation identified above discussed an
important new element in validation planning, called a Validation Master Plan (VMP).
The ISPE Baseline® Guide, described above, appears to have introduced the concept of a
VMP, based on the PIC/s guidance, PI-006-03, which identified the VMP as a central
element in organizing validation activities (PIC/S, 2012). The WHO document, in Annex
4, identified the VMP as one element on its list of documents that it recommended to
manufacturers in order to provide confidence that products are manufactured consistently
in accordance with their specifications.
2.5 The Validation Master Plan
2.5.1 What is a validation master plan?
A VMP is a high-level document that spells out a framework for validation activities in a
manufacturing environment. Its definitions in various documents are similar:
A document that summarizes the firm’s overall philosophy, intentions, and
approach to be used for establishing process adequacy [including]
validation activities relating to critical technical operations, relevant to
product and process controls within a firm” [and more specifically]
qualification of critical manufacturing and control equipment. (Health
Science Authority, 2013a)
A document providing information on the company’s validation work
programme. It should define details of and timescales for the validation
work to be performed. Responsibilities relating to the plan should be
stated (PIC/S, 2012).
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The VMP is a document that describes how and when the validation
program will be executed in a facility….the VMP defines the areas and
systems to be validated and provides a written programme for achieving
and maintaining a qualified facility with validated processes (Saghee,
2012).
Of all of the many sources that now discuss VMPs, the Singaporean Regulatory Guidance
is particularly interesting because it identifies the format and content of such a document
through the eyes of a regulatory authority. The Singaporean guidance is granular, in that
it specifies elements to be included in a VMP: a description of the organizational
structure of all validation activities, descriptions of the plant and processes, lists of
products, and specific considerations of individual processes and systems to be validated.
The requirements for validation include specific initiatives to assure equipment
qualification as well as process qualification that are organized according to a specified
plan and schedule. Validation activities are expected to have protocols that document key
acceptance criteria. The VMP is expected to be part of the controlled document library
and change controls are needed to update the document regularly to maintain currency.
The broad expectations for the VMP identified above are similar to those outlined in
other documents, and are listed in Table 1. Table 2 identifies a number of authoritative
sources from which such descriptions can be obtained. However, reference to a VMP is
common in newer regulations of emerging countries as well, including those of China
and Singapore.
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Table 1: VMP Sections
VALIDATION SECTION DESCRIPTION
Validation policy A description of the facility and
manufactured products whose validation
requirements are defined under the plan. For
new products or facilities, a clear definition
of what is not included.
Organizational roles & responsibilities A definition of the roles and responsibilities
of department and project core team
members, identifying who is accountable for
decisions and deliverables.
Summary of scope A definition of products, processes, and
facilities within the scope of the plan, and a
description of each.
Strategy Strategy of how equipment, products and
processes, and facilities will be validated, and
a rationale for each strategy. A definition of
test methods, test coverage, tools and
techniques, statistical techniques, and use of
compliance standards be included.
Documents and deliverables This section may include all validation
activities that have currently been performed,
as well as a schedule of planned activities.
For new facilities or projects, this section
should include all of the deliverables that are
required by the validation strategy.
Acceptance criteria A definition of the criteria that must be met to
consider the product, process, or facility
within scope of the plan validated and fit for
its intended use.
Change control The VMP should reference or contain aspects
of how the effort will maintain configuration
management, traceability, modifications to
plan, entry criteria to testing, retesting, data
collection, and issue reporting and resolution.
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Table 2: VMP Sources
AGENCY DOCUMENT TITLE DATE
HAS (Singapore) Regulatory Guidance, Preparation of Validation
Master Plan
January 2013
FDA Facilities Utilities and Equipment, GMP, GMP
– Qualification, Special Edition
2013
PIC/s Validation Master Plan Installation and
Operational Qualification Non-Sterile Process
Validation Cleaning Validation PI006-3
2007
World Health
Organization
WHO Technical Report Series, No 937, 2006,
Annex 4, Supplementary Guidelines in Good
Manufacturing Practices: Validation
2006
ISPE Baseline® Guide, Vol. 2: Oral Solid Dosage
Forms (First Edition)
1998
As can be seen from Table 2, there is no comparable document that explicitly calls for a
VMP in the U.S. regulations. Nonetheless, the use of such a document would be
compatible with, and indeed enhance compliance with, the recommendations embodied
in the 2011 Guidance for Industry Process Validation: General Principles and Practices.
As explained earlier, that U.S. guidance recommended a systematic, ongoing approach to
validation during which data is collected across the product life cycle from development
to commercial manufacturing. The VMP could thus serve as an umbrella plan to
facilitate the collection and compilation of the required validation plans associated with a
complex set of projects and facilities into a single controlled document.
The use of a VMP imposes a useful discipline onto validation activities. As a master
document, it can provide a framework for a manufacturer’s validation program, by
providing the details and timelines associated with the work to be performed and the roles
and responsibilities of the personnel implementing the plan. It also may serve as a source
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that specifies relevant applicable requirements, regulations, and testing standards
associated with the various validation activities. As a controlled document, the VMP
would require version control, and would assure that its contents are reviewed at regular
intervals. As a result, the VMP is viewed by many as an essential component to an
overall compliance program because of its role as a central repository for validation
reports and status that may be consulted when assessing the company’s state of
compliance (WHO, 2006).
2.5.2 Development and Implementation of Validation Master Plans
There are many benefits to having a VMP. The obvious area in which benefits might be
recognized is in assuring compliance. The VMP provides a structured approach to
organize testing across the product life cycle. It also provides a means to document
justifications for strategies to prove that products will continue to meet acceptance
criteria based on design and risk considerations. It can be integrated with the company's
quality system to ensure that the ultimate requirements for health care professionals and
patients are met consistently. By defining clear validation parameters and processes, the
VMP reduces ambiguities and misinterpretations concerning the desired validation
program, and establishes concrete timelines to implement them. A VMP can incorporate
engineering models and novel experimental designs to provide scientifically sound and
statistically valid test results that not only validate parameters but also validate
interactions between parameters. As a result, these models improve the robustness of
testing and define boundaries and quality attributes of products to complement the
objectives of a robust compliance program.
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In addition to enhancing compliance, the goal of a well-designed validation plan is to
support and strengthen process capabilities rather than to hinder their development. The
use of a controlled document to plan and memorialize validation helps to optimize the
transfer of new products from research and development (R&D) into commercial
manufacturing or the transfer of manufacturing operations from one location to another
(Ciesliga, 2009). When a well-defined VMP is constructed as a business process, it can
reduce costs, improve compliance, give visibility to higher-risk processes, limit risk,
improve speed to market, and achieve harmonization across products and international
requirements and practices.
A VMP is easiest to create when it is prepared for a new facility so that the essential
elements in the newly crafted documents and procedures can be captured to facilitate the
VMP planning (Weber, 2013). As a living document, the processes and timelines can
then be modified going forward. For existing facilities the development of VMP is more
complicated because a post hoc assessment of validation activities is required to establish
what has already been accomplished and what vulnerabilities still remain. With respect to
equipment, for example, vulnerabilities can be assessed by evaluating a range of
indicators, such as the age of equipment, deviations and out of specification (OOS)
history, maintenance down time due to unplanned events, audit observations, personnel
training and feedback, and review of past validation activities.
VMPs will vary in their structure and content from one company to another. They will
likely be more extensive in larger companies with multiple product lines especially when
those lines are complex. Thus, the successful execution of a VMP is often challenging. It
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requires thoughtful planning by individuals well-versed in the management of the
complex processes and facilities under evaluation. Considerable expertise and effort is
needed to prioritize activities and to set realistic target dates that will ensure the timely
completion of validation activities. These activities include preparation of protocols,
document review and rework, and scheduling of reviews and approvals. Project timelines
will set limits on when production activities can commence or undergo an interruption,
and such interruptions must be taken into account when a company plans to meet its
delivery expectations (Health Canada, 2009).
What might constitute best practices for implementing a successful VMP? One element
that has been repeatedly identified is the need for leadership from senior management
whose commitment to compliance extends to providing financial, personnel and technical
resources for VMP activities. One recommended approach is to establish a matrix
organization or task force that crosses company sectors. This task force would be
responsible for assisting top management in making VMP policy decisions and informing
top management of progress and problems. Together the group would strategize the best
approaches to implement the VMP, would select key business performance indicators to
measure the implementation, and would review the progress of the implementation effort
(Haider, 2001).
Another important element to ensure that the VMP can be executed is a having a means
to ensure the support of key stakeholders who will carry out the activities in the VMP.
Key stakeholders will include personnel from as Engineering / Technical Operations,
Manufacturing, Quality Control, Quality Assurance and Validation departments. The
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stakeholders may also include personnel from information technologies (IT) who must
support activities such as preventive maintenance and calibration of certain types of
electronic or computerized equipment if this is a separate function from Engineering.
The requirements for executing a VMP can be a great cause of concern for many
companies. They may be concerned about the level of effort that is revealed when all of
the validation needs are brought together, and may resist such a systematic and
challenging organizational approach that can lay bare inadequacies in their systems
(Mitu, 2012).
Clearly there are both opportunities and challenges posed by the implementation of a
VMP. However, little has been written about the prevailing views of industry on the
adoption of this approach, particularly in the U.S. where such a document is not
mandatory. We do not know whether companies are implementing VMPs consistently
and whether the level of granularity is sufficiently deep to ensure full coverage of all
areas of validation. Further, at the more granular level, we do not know how equipment
validation is tied into the VMP, whether it is called out as a separate function in that
VMP (assuming that a VMP indeed even exists), or whether it is managed in some other
way. Further we do not know how attitudes and implementation vary from large
companies, where documentation may be considered more important to control a wide
range of validation tasks, to small companies, where resources may be limited and tasks
may be more circumscribed. Thus in this thesis, the views of U.S. pharmaceutical
companies on the use of VMPs will be explored. As part of this investigation, the extent
and depth of inclusion of equipment validation will be examined as a way to probe the
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level of comprehensiveness of the VMP by using it as an example of one subset of
activities contained in the VMP.
2.6 Approaches to Research
It is clear that validation is regarded by the regulatory agencies as an essential component
in manufacturing, to assure product quality, safety and efficacy. We know much about
regulatory expectations regarding VMPs from instructional documents such as standards
and regulatory guidance, and we know a little about its implementation from anecdotal
evidence provided by trade- journal articles or conference presentations (e.g., Ofni
Systems, 2014). However, none of these sources gives a systematic examination of
industry views regarding the usefulness and challenges of developing a VMP. Further,
very little is written about the degree to which these same companies are implementing a
VMP. Thus, the goal of this research is to obtain more information on the level of VMP
implementation from a selection of U.S. pharmaceutical manufacturers using survey
method (Buchanan & Hvizdak, 2009).
Two ways of developing the data set and making determinations about its meaning were
used as we construct the survey. First, information was gathered to characterize the level
of implementation of a VMP. To do this, the conceptual framework of Fixsen and
coworkers (Fixsen, Blase, Naoom, & Wallace, 2009) was be used to define three stages
of implementation:
Paper implementation: new policies and procedures are developed with the hope
of leading to innovation. In this case, the implementation process does not
develop any further—the paper records provide a plan for implementation, but
full implementation is not achieved.
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Process implementation: not only is paper implementation in evidence but new
operating procedures are attempted, as evidenced by training sessions, changes
in protocol, and the presence of supervision; however, all of these may not lead
to actual changes or benefits.
Performance implementation: new operating procedures are implemented in
such a way that they actually change outputs and create benefits to consumers or
users.
Second, the survey explored a range of issues related to the challenges associated with
implementing a VMP. In order to examine the universe of elements that can impact the
success of implementation a second conceptual framework was used to assure that
questions regarding areas of strength and weakness are explored systematically.
Questions were asked about the implementation of the VMP at a high level, and then
about one area that should be represented in the VMP, that of equipment validation. The
deeper examination of the status of equipment validation was seen to provide one
example to evaluate in more detail the depth of commitment to the requirements for
validation activities.
Several frameworks have been proposed to characterize elements important to success
that were surveyed to select an approach to the characterization of challenges.
2.6.1 The Regulatory Triangle of Ayres and Braithwaite
Ayres and Braithwaite attempted to systematize the ways to ensure compliance with
quality standards by trying to understand whether the decision of a company to comply
with a given requirement was related to its tolerance for risk. Risks increased as
companies were able less and less to comply with a set of standards prescribed by a
governing body, usually a governmental authority, because increasing levels of non-
compliance introduced risk of higher financial and or criminal penalties. Ayres and
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Braithwaite described this relationship in a model that was illustrated, as a regulatory
pyramid based upon the level of penalty required eliciting compliant behavior (Figure 2)
(Ayers & Braithwaite, 1992).
Figure 2: Pyramid of enforcement strategies extracted from Ayres and Braithwaite
Reproduced with permission from Ayers & Braithwaite
The pyramid structure is based upon the assumption that most companies are represented
in the heavy base of the pyramid because they are persuaded to comply with regulations
without overt threat of punishment. The middle and top of the triangle are areas of risk
for companies with poorer practices. They need more formalized methods to assure
compliance. At the apex would be positioned the very small number of companies for
which License Revocation becomes essential to ensure compliance.
As stated earlier, the VMP is a regulatory requirement of a number of global regulatory
authorities and thus might seem to be appropriately studied using a framework that tries
to gain insight into methods to assure compliance. This model could be used in
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evaluating a company's implementation of a VMP if its views on risks associated with
non-compliance were to be the only question of interest. It could be used for example to
study whether the requirements for the VMP in Europe provide as stronger motivating
force to assure the use of a VMP than would be the case in the U.S. where FDA does not
specifically require companies to have a VMP. In this study, however, we are proposing
a different set of questions that deal more with implementation than with motivation.
Thus the Compliance Pyramid as developed by Ayres and Braithwaite seemed to be an
insufficient framework for this study.
2.6.2 The Quality Implementation Framework of Yusef and Aspinwall
A search for frameworks that better describe implementation led to the work of Yusef
and Aspinwall who were concerned about capturing areas considered key for the
successful implementation of total quality management (TQM) within an organization
(Yusef & Aspinwall, 2000). They were looking specifically to develop a framework that
could assist small companies in the automotive industry to develop systems that were not
overly complex. The key elements that they viewed as important s are depicted in Figure
3 and include: quality initiatives; general methodologies; and a coordinating body.
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Figure 3: TQM conceptual implementation framework for small business
Extracted with permission from Yusef and Aspinwall, 2000
Yusef and Aspinwall felt that each of these key areas must be considered when planning
the implementation of quality programs across an organization. This framework appears
to have some relevance to what we are trying to do in this study, in which we want to
understand whether the necessary elements are in place to facilitate implementation.
The framework might be valuable if the research questions were only related to
organizational capabilities. However, the framework has limitations related to that fact
that its primary focus is on planning for quality system implementation but not assessing
the status of implementation as it goes forward.
2.6.3 Organizational triangle framework of Guldenmund
The model developed by Guldenmund attempts to relate organizational capacity for any
initiative, in their particular case to risk management, to three factors:, resources,
processes and culture (Guldenmund, 2010). The relationship between these three factors
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is shown in Figure 3. Guldenmund describes each of the factors contributing to his
triangle as follows.
Organizational Structure
Organizational structure can be defined as “the division of authority,
responsibility, and duties among members of an organization.”
Structure is primarily the formal framework of an organization, that is,
how the work is done and by whom. From the point of view of
management, an efficient structure facilitates both effective coordination
and communication.
Processes
Processes are the patterns of activity taking place throughout an
organization, often divided into three levels: the primary processes, which
deal with the main output(s) of an organization; the secondary processes,
which support the primary ones, for example, management, quality
control; and the tertiary processes, for example, formulations of policies
and strategies, designed to drive and support both the primary and
secondary processes.
Culture
Culture is often understood to be the basic assumptions, the underlying
tacit convictions of an organization (Guldenmund, 2010).
Figure 4: The organizational triangle
Reproduced with permission from (Guldenmund, 2010)
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Aspects of this framework may be suitable to assure that the survey covers these
important factors that contribute to successful implementation of a VMP. The limitations
of this framework may relate to the fact that it was developed to understand the way that
a company deals with implementing a successful risk management program. It does not
include certain other variables associated with the complexities of implementing highly
technical projects. The implementation of the VMP requires technical skills that seem
not to be reflected sufficiently in a model that emphasizes behaviors. The model touches
only indirectly on the needs for specific capabilities and resources for addressing
technical issues. It requires the assumption that an effective culture would be predicated
on the availability of appropriate resources. Nevertheless, its attributes are at least
partially useful and could be complimented by the additional framework below.
2.6.4 High Reliability Organization Framework of Sullivan and Beach
A fifth framework that may have advantages for this study is that proposed by Sullivan
& Beach, to evaluate organizational approaches to implement and manage highly
technical projects such as those associated with management information systems.
Complex projects tend to have lengthy implementation times, require a significant level
of resources, and have substantial commitment from management that span the entirety
of an organization (Sullivan & Beach, 2009). The framework focuses on the ability of a
highly functioning organization to manage complex projects successfully.
Sullivan and Beach proposed that the capabilities of an organization are imprinted
through its culture. Developing an effective culture is particularly important in
organizations that they term as highly reliable organizations (HRO). These are typically
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organizations where success depends upon the tight control of tasks and systems to avoid
catastrophic outcomes. The more sophisticated the systems the greater the risks that the
organization will fail to meet the organizational objectives. Thus the success of such
organizations depends on their ability to manage and avoid risks. In such organizations
Sullivan and Beach defined a set of characteristics that they felt were necessary
organizational capabilities to accomplish an objective. Reliability is listed as a higher
priority than profit and includes the effectiveness of performance and communication as
key characteristics as well. Organizations whose priority is reliability understand the link
between resources and capabilities and how this supports expectations. It is relatively
simple to use their focus on risk and reliability as a base for a focus on quality systems
that ultimately share overlapping aims.
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Figure 5: The conceptual model for operational reliability
Extracted with permission from Sullivan & Beach, 2009
With adequate resources, an organization is capable of accomplishing complex projects.
As more resources are committed to a project the expectations increase. Thus, if
resources or competence do not exist, are limited in nature or reduced from previous
necessary levels, then quality would be expected to decline. The limitation within this
framework is its heavy focus on risk associated with implementation of technical projects
without acknowledging fully the role of organizational support and behavior emphasized
by Guldenmund.
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2.6.5 Risk Management Implementation Framework of Chan
Both the models of Guldemund (2010) and Sullivan and Beach (2009) offer elements that
would seem to be important for the successful implementation of any project, and seem
relevant to the research proposed here. This view seems to be consistent with the work of
Chan (2012) who blended the two approaches in his research on implementation of risk
management, as shown in Figure 4. It seems that a good framework to use in this
research would be a synthesis of the work of Guldenmund and Sullivan & Beach in the
same manner as that adopted by Chan (Chan, 2012). However, I will attempt to
repurpose that framework to assess the extent of VMP readiness implementation in
pharmaceutical companies rather than their approach to risk management.
Figure 6: Research model for Medical Device Risk Management Implementation
Research model for extracted with permission from Chan, 2012
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The Chan model blends capability and behavior as complementary components for
whose nature can affect the implementation of complex technical programs such as that
of implementing a VMP. Support for his contention that the elements covered all of the
areas important areas that are key to risk management came from an analysis of causes of
risk management disasters; the root causes of a studied set of disasters could be
completely described within one or more elements of the framework. However, Chan
added another element not represented in the two listed above, that of corporate memory,
that he also considered key to the success of risk management programs. It would seem
logical to include this element as part of the framework for the present research. Quality
programs like risk management programs are tied to the lengthy life cycles of medical
products and must be carried out by a workforce that is turning over quite rapidly, so that
the risk of lost knowledge during these turnovers is high. Chan’s study suggests the
combined framework would cover areas of importance in implementing successful
programs based upon risk. The limitation of this study is that this was developed for the
specific study of risk management and has not been tested for its generalized ability to
meet the needs of quality programs. Further, it assumes robustness for all stages of a
product life cycle is comparable to the stages involved in risk management.
In this study I was interested in learning the degree to which companies have
implemented a VMP, and the challenges that they have faced as part of that effort. By
using the combined framework suggested by Chan, it appeared possible to assess more
systematically the status of VMP implementation in a range of U.S. companies who may
or may not have yet attempted to use a VMP in their quality systems. We found that it
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provided a more structured way of assuring that survey questions directed at a company
covered a number of areas deemed central for effective program implementation.
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CHAPTER 3. METHODOLOGY
3.1 Introduction
This exploratory research study was conducted to assess the implementation stages of
VMPs within an organization. The method used was an online survey instrument to gain
a more comprehensive picture of VMP implementation within the pharmaceutical
industry.
3.2 Survey Instrument Development
The maturity of the VMPs examined in companies was assessed using a survey tool
structured by reference to the stages of implementation described by Fixsen and
coworkers (Fixsen, Blase, Naoom, & Wallace, 2009). Questions were developed first to
assess the demographics of the respondents and to ask preliminary questions regarding
their views on the importance of a VMP and the general state of implementation of the
VMP within their quality and continuous improvement systems of their company as
shown in Table 3.
Table 3: Questionnaire Instrument: Breakdown of Areas of Inquiry
No. Areas of Inquiry
1 Professional profiles of individual respondents
2 Impact of VMP to organization
3
Stage of implementation and integration with continuous improvement
programs
4
Challenges to implementation, with reference to the framework of Chan
(2012)
The largest number of questions was concentrated on the fourth area identified in Table
3. These questions explored areas in which the companies found the greatest challenges
with regard to the various areas proposed in the Chan (2012) framework. Questions of
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yes/no, multiple-choice and Likert formats were developed and the data compiled
identified trends in the topical areas identified in the survey. Questions with open-ended
responses were included to gather more detailed information that could be used to gain a
deeper insight into views identified by the primary questions.
3.3 Survey Deployment and Analysis
3.3.1 Focus Group
A focus group was convened to examine and discuss the quality of the survey questions
prior to distribution of the survey. The focus group was comprised of the following
representatives: four (3) in academia (University of Southern California) including my
advisor, two (2) in industry, (1) consultant, and two (2) peers in the area of quality and or
compliance who have worked in the pharmaceutical industry within the past 3 years.
Four (4) of the participants in the focus group also had a good understanding of the
survey methodology, whereas others had a deep knowledge of the technical aspects of
validation master planning. The focus group met prior to the implementation of the
survey for approximately 90 minutes in the Regulatory Science conference room. A
web-enabled exchange platform (WebEx, webex.com) was used to allow four (4) of the
participants to communicate from a distant location. Any suggestions or comments
arising from this meeting were documented and used to amend the survey.
3.3.2 Survey Dissemination
The target population for the survey were individuals who have worked in the quality
field either in a company or as a consultant to a company over the last 5 years, and whose
manufacturing operations must be compliant with U.S. GMP rules under 21 CFR 210 and
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211. Included were individuals known to the investigator and associates, as well as
individuals identified using a snowball method, individuals giving presentations or
participating at quality meetings, and individuals who are members in U.S. quality
societies. An emailed letter was sent to each potential respondent to seek their
participation in the survey. Individuals who were not known to the investigators were
asked whether they are familiar with pharmaceutical equipment qualification and
validation under U.S. cGMPs. Participants were assured that no specific data regarding
the identity of the companies or organizations would be published should this work result
in publication even though I would know their identities. No remuneration was provided
to encourage participation, but the respondents were promised a summary of the results
after the survey had been analyzed.
Once the respondent identified that he or she is interested in participating, a second email
was sent with the link to the survey. Participants who identified that Qualtrics survey was
not received were instructed to view their “spam” folder or were resent the survey,
sometimes to a different web address. The number of respondents was compared to the
number of surveys distributed in order to establish the response rate. The target for this
survey was chosen to be 40 surveys in which the respondents have answered more than
75% of the questions. The survey instrument was administered using the Qualtrics web-
based survey platform (www.qualtrics.com). Participant responses to the survey was
tracked and reminders sent to participants when 2 weeks passed without survey response.
The collected data was analyzed after participants had completed the on-line survey.
Qualtrics was utilized to complete simple statistical analysis of the raw data. At that time
it became clear that two questions in the principal survey asked for a single answer but
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the respondents felt that more than one answer should have been permitted. A second
survey with just these two questions was developed in a way that would permit multiple
choices and this additional survey was resent to the participants. Of the previously
participating pool, twenty-one (21) responded also to the second survey.
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CHAPTER 4. RESULTS
4.1 Results of the Focus Group
The role of the focus group, to discuss the appropriateness of the survey questions for the
targeted subpopulation, was explained by me during in a 90 minute meeting attended by
participants, either face to face or by videoconference, on January 15, 2015 at the
University of Southern California, International Center for Regulatory Science.
Discussion then focused on the applicability and clarity of each survey question in the
draft survey that was distributed to participants in advance. The focus group agreed that
the inclusion and exclusion criteria for respondents were appropriate for the topic under
study. They suggested that the approach to demographics be modified from focusing on
the survey respondent to gaining insight into the company itself. The focus group
recommended additional questions that might expand insights into not only the
implementation of the VMP but also into company culture and commitment to
compliance and quality systems. Questions were modified and or added based upon the
focus group guidance as shown in Appendix A that contains the draft, final and follow up
survey.
4.2 Analysis of the Survey Results
The responses to the survey are analyzed in eleven sections. The survey questions are
listed in Table 4, 5, 6 and where they are grouped together for purposes of analysis. Table
4, sections 4.3 – 4.4 outline the profiles of the respondents and the companies employing
them. Table 5, sections 4.5 – 4.6 describe responses to questions regarding the
implementation status of validation master plans within a company. Table 6, sections
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4.10 – 4.14 consider the opinions of the validation master plan structure, strategy, culture
and planning. Table 7, sections 4.7 – 4.9 describe responses to questions on the
maintenance of validation master plans.
Table 4: Questions to describe the profiles of the respondents and their companies
Section Questionnaire Items
4.3 Profile of respondents 1. Select the best title that represents your position in the company:
4.4 Profile of companies 2. Which industry sector best describes your company?
3. What is the size of your company in terms of number of employees?
4. Select the geographic region that best describes the headquarter(s) of
your company:
5. To the best of your knowledge, how many drugs does your company
market?
Table 5: Questions to explore implementation of the validation master plan at a
company
Section Questionnaire Items
4.5 Status of implementation
of a validation master plan
6. Does your company have any form of validation master plan?
7. How would you characterize the structure of your validation master
plan (VMP)?
8. Does every site in your company have its own validation master
plan?
4.6 Structure of the validation
master plan
9. Which of the following areas of activity are included in your
validation master plan?
10. What is the most senior level of management required to review
and approve the validation master plan?
11. When your validation master plan was put into effect, who
contributed to the design?
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Table 6: Questions to explore validation master plan structure, strategy, culture and
planning
Section Questionnaire items
4.10 Views on structure 12.1 Our validation master plan includes rigorous timelines for activities
12.2 Our validation master plan is developed and implemented utilizing a
multidisciplinary approach
12.3 Our validation master plan has its own approved budget.
12.4 Our validation master plan clearly communicates a defined
structure.
4.11 Views on strategy 13.1 VMP objectives are included in company strategic planning.
13.2 Site specific goals include VMP goals.
13.3 Our quality department establishes the VMP goals.
13.4 Our company VMP goals are incorporated into each employee
performance plan.
13.5 Our VMP specifies job functions and their oversight responsibilities
and accountabilities.
4.12 Views on culture 14.1 Senior management communicates the goals of the VMP to each
employee.
14.2 I am familiar with my company’s VMP.
14.3 My company emphasizes culture “beyond” compliance.
14.4 My company utilizes the VMP as a foundation for operational
efficiencies.
14.5 Our validation master plan is updated each time equipment
validation status is changed.
4.13 Views on planning 15.1 Our validation master plan has input from the marketing group.
15.2 Our validation master plan is reviewed during updates to the
applicable regulatory requirements.
15.3 Our validation master plan aligns with the validation requirements
for each of the countries where products are distributed.
15.5 Our validation master plan references other equipment standards
such as environmental permits and OSHA standards.
4.14 Views on equipment
17.1 I feel that the current process for managing equipment serves as the
gatekeeper to ensure new production and facilities equipment, excluding
analytical equipment, is added to the validation master plan.
17.2 I feel that the validation master plan is maintained in an ‘evergreen”
status ready for inspection and audit.
17.3 I feel that compliance with production and facilities equipment
validation regulations, excluding analytical equipment, is a priority for
the organization.
17.4 I feel that the production and facilities equipment list, excluding
analytical equipment, in the validation master plan is up to date and
current.
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Table 7: Questions to explore the maintenance of validation master plans and
equipment status
Section Questionnaire items
4.7 Process to maintain
validation master plans
16. How is the validation master plan updated for new product or
facilities equipment, excluding analytical equipment?
26. How is the review of the validation master plan conducted?
27. What is the periodicity for review of the validation program?
28. How is the validation program documentation retained?
29. What is the retention period for validation documentation for
production and facilities equipment, excluding analytical equipment?
4.8 Equipment status 12.5 Our validation master plan is one system that is used to manage
equipment lifecycle.
15.4 Our validation master plan describes equipment qualification and
validation standards.
25. What period of time for which equipment is typically considered to
be validated?
4.9 VMP documentation
systems
18. Identify the administrative infrastructure that supports your holistic
validation program.
19. If you primarily utilize a paper based system how would you
describe the type of documentation?
20. If your company developed software to govern its validation
program requirements it would be best described as:
21. Is your system compliant with FDA Part 11, Computer System
Validation?
22. We use the following Enterprise Resource System:
23. Is your system compliant with FDA Part 11, Computer System
Validation?
24. Does your Enterprise Resource Planning system include a module
for Preventative Maintenance / Maintenance activities?
4.3 Profile of Respondents
The survey was sent to 71 quality professionals associated with 52 pharmaceutical
companies. Forty-two responses were received, representing a response rate of 59%.
Most commonly, the respondents (15/42, 36%) were Directors. The proportions of
Senior Managers and Vice Presidents or above were equal (10/42, or 24% in each
category). A small number of “others” also were included (Figure 7).
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Figure 7: “Select the best title that represents your position in the company.”
Other (Please specify)
Consultant Quality Manager
Retired Associate
Product Quality
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4.4 Profile of companies
Most respondents (21/41, 51%) were associated with companies that manufactured
innovative drugs, and a further 10/41 (24%) were associated with companies that
manufactured biologics. A modest proportion of respondents (7/41, 17%) represented
manufacturers of medical devices (including In Vitro Devices (IVDs)) (Fig. 8).
Respondents were distributed throughout companies of all size categories from very
small to very large (Fig 9). The spectrum of product lines appeared to reflect this
diversity. Approximately half of the represented companies manufactured more than 21
drugs (19/40, 48%), whereas a little more than a quarter (11/40, 28%) manufactured only
1-5 drugs. Several of the respondents (5/40, 13%) did not know the number of drug
products produced by their company (Fig 10). The headquarters for most companies
(27/42, 64%) were located in the United States (U.S.); a smaller number of companies
were headquartered in Europe (11/42, 26%) or Asia (3/42, 7%) (Fig. 11). A cross-
tabulation was prepared revealing that 16/27 (59%) responses for headquarters in the U.S.
were companies with employees total under 1000 employees, whereas most companies
with headquarters in Europe were larger and only two (2) companies had under 1000
employees (Fig. 12).
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Figure 8: “Which industry sector best describes your company?”
Figure 9: “What is the size of your company in terms of number of employees?”
Figure 10: “To the best of your knowledge, how many drugs does your company
market?”
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Figure 11: “Select the geographic region that best describes the headquarter(s) of
your company.”
Figure 12: Cross-tabulation of the geographic region that best describes the
headquarter(s) of your company against company size.
4.5 Status of Implementation of VMP
Validation master plans appear to be well established as a quality approach. Most
respondents (36/42, 86%) indicated that their company had some form of VMP. Further,
25 of the 42 respondents could answer detailed questions to characterize their plans.
These characterizations revealed a mix of approaches between decentralized plans
(10/25, 40%), centralized plans (6/25, 24%) and plans that were a combination of both
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(9/25, 36%) (Fig 13). Of those companies whose response indicated that VMPs were
developed in a decentralized fashion, 14/25 or 60% relied on implementation at the site
level rather than at a centralized organizational level (Fig 14). A cross-tabulation was
prepared revealing that regardless of size of geographic location of the headquarters,
companies indicated that there was some sort of VMP at their company (Fig. 15A), but
smaller companies typically had centralized VMPs whereas larger companies had
decentralized VMPs (Fig. 15B).
Figure 13: “How would you characterize the structure of your VMP?”
Figure 14: “Does every site within your company have its own VMP?”
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Figure 15A: Cross-tabulation comparing companies’ geographic headquarters and
presence of some type of VMP.
NOTE: Total represents survey respondents taking into consideration any type of VMP.
Figure 15B: Cross-tabulation comparing company size with VMP structure
approach: centralized or decentralized.
NOTE: Total represents a subset of the survey respondents who responded yes to initial question.
4.6 VMP Structure
Validation master plans were identified to have many components. In the original
survey, this diversity could not be captured adequately because the question exploring
these components did not allow multiple selections. Because this question was considered
important to the survey, the same participants were resurveyed to obtain more complete
answers about the multiple elements that were contained in their VMPs. Respondents
typically identified that the VMP included most of the listed items, including Maintaining
the Validated State (17/20, 85%), Validation Deliverables (15/20, 75%), Validation
Activity Timelines (15/20, 75%), and Validation Strategy (18/20, 90%) (Fig 16).
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In that same second survey, respondents were allowed to choose multiple answers to a
subsequent question about who most commonly compiled the VMP. All of the
respondents to this question identified that the VMP was compiled by Site specific
internal employees (20/20, 100%), but many also used contractors or employees from
other sites (Fig 17). Cross tabulation of these results showed that companies with 1000
employees or more included contractors in their design of VMP (Fig. 18). Once a VMP
was authored, the review and approval of VMP was identified by most respondents to
take place at a senior management level, with the responsibility assigned wither to the
Vice President or above (12/25, 48%) or the Director (10/25, 40%) (Fig 19).
Figure 16: “Which of the following areas of activities is included in your validation
master plan?”
Other (Please specify)
Management responsibilities
To be clear, the documents checked above would be referenced via hyperlink – the VMP
would not contain the actual documents as attachments.
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Figure 17: “When your validation plan was put into effect who contributed to its
design?”
Figure 18: Cross-tabulation of who contributed to its design and the company size.
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Figure 19: “What is the most senior level of management required to review and
approve VMP?”
4.7 Process to Maintain VMP
An ongoing program, such as one that includes a VMP, should be updated and reviewed
periodically as a maintenance function. Different mechanisms are potentially available to
maintain a VMP when changes to the facilities or equipment are made, but most
respondents identified that their company used a change control process as the primary
mechanism (20/25, 80%) (Fig 20). Review of the validation program on a periodic basis
seems to be performed as a paper-based exercise by about half of the respondents (14/29,
48%), with the remaining responses split evenly between the review process being
conducted electronically (4/29, 14%) or as part of department or management review
exercises (4/29, 14%) (Fig 21). Typically the review occurs annually (18/29, 62%) (Fig
22) but some respondents identified intervals of up to 5 years or based on milestones. A
few respondents added comments to this question, and these are abbreviated as well in
Figure 22.
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Figure 20: “How is the VMP updated for new product or facilities equipment,
excluding analytical equipment?”
Figure 21: “How is the review of the validation program conducted?”
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Figure 22: “What is the periodicity of review of the validation program?”
Other
Site dependent Two years
Based on milestones Unknown
Unknown
Validation documentation is maintained as a controlled document by most respondents
(25/29, 86%) (Fig 23). However, retention periods of those documents varied; for
equipment documentation specifically, the most common response was “for the life of the
equipment” (13/29, 45%) (Fig 24), but practices included a 5-10 year retention period, a
period of 3+ years added beyond the life of the equipment or a variable length of
retention depending on the conditions. Interestingly, seven of the 29 respondents to this
question did not know the answer.
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Figure 23: “How is the validation documentation retained?”
Figure 24: “What is the retention period for validation documentation for
production and facilities equipment, excluding analytical
equipment?”
Other
Life of product + 3 years Treated as part of the production record, so
depends on product specifics and corporate
document retention policy
4.8 Equipment Status
Validation is an ongoing process in which evidence is accumulated and synthesized to
demonstrate that equipment and processes remain consistent with the expectations
identified during initial qualification activities. The VMP describes the equipment
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standards required to demonstrate validation. As shown in Fig 25, most respondents
(14/24, 58%) identified that management of equipment lifecycle was included as a
system under the VMP but several did not agree that it was included (7/24, 29%).
Almost unanimously the respondents noted that the VMP houses the qualifications and
standards for equipment validation (23/25, 92%) (Fig 26). When asked about the period
for time for which facility (i.e., water systems, pumps) and production equipment
(manufacturing equipment but not analytical equipment) was considered to be validated,
Most respondents indicated that that production equipment was considered to be
validated for up to one (1) year (10/13, 77%). Facilities equipment, according to
respondents, more commonly fell into the three (3) year category (7/12, 58%). It is not
known if this three (3) year cycle is related to equipment maintenance recommendations
or a companies’ understanding of equipment functionality (Fig 27).
Figure 25: “Our validation master plan is one system that is used to manage
equipment lifecycle”
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Figure 26: “Our validation master plan describes equipment qualification and
validation standards”
Figure 27: “What is the period of time for which equipment is typically considered
validated?”
4.9 VMP Documentation System
Good manufacturing practice (GMP) requires that the pharmaceutical manufacturer
maintain proper documentation and records. Respondents indicated that the
documentation system primarily used to support the validation program is paper-based
(17/30, 57%). Only a few respondents appeared to hold their validation-program
documentation within an Enterprise Management System (2/30, 7%), but a few others
reported some combination as a text response to the category “Other” (Fig 28).
Companies with paper-based systems always (17/17, 100%) relied on procedures and
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forms to administer the program. Respondents using electronic systems sometimes
developed their own software (2/18, 11%) but more commonly used vendor-supplied
systems or combinations of systems (see other, Figure 29). Enterprise Management
Systems utilized by the companies surveyed here were usually based on SAP (Systems,
Applications & Products) (9/13, 69%) that were always noted to comply with FDA Part
11, Computer System Validation. All of the respondents utilizing SAP also claimed to
have its Preventative Maintenance / Maintenance module (13/18, 72%). Retention
periods for the documentation was most commonly held for the lifetime of the equipment
(13/29, 45%) (Fig 29). A cross-tabulation of some of these questions against company
size showed that even large companies appeared still to use paper-based systems (Fig.
30).
Figure 28: “Identify the administrative infrastructure that supports your holistic
validation program.”
Other
EPR and PLM (Agile) Company document management database
Paper, and ERP Agile PLM
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Figure 29: “What is the retention period for validation documentation for
production and facilities equipment, excluding analytical
equipment?”
Number
Figure 30: Cross-tabulation of company utilization of paper based documents
systems
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4.10 Project management and cultural considerations
A Validation Master Plan is a document that not only establishes procedures but also can
summarize the overall philosophy, intentions and approach for validation activities, and
thus reflect a company’s culture. Respondents were asked several questions that were
intended to capture some of the project-management approaches to VMP activities, as
shown in Figure 31. Typically, respondents believed that their companies were using a
multidisciplinary approach and that this approach clearly communicated a defined
structure. However only about half of the respondents, (12/25, 48%) identified that the
VMP contained timeline of activities and only about half identified that the VMP is used
to manage equipment lifecycle (13/25, 52%). Few companies (5/22, 23%) appeared to
have a specified budget allocated for the VMP (Fig 31).
Figure 31: “The validation master plan presents an overview of the entire validation
operation, its organizational structure, its content and planning.”
The majority of respondents suggested that the strategy associated with VMP included
incorporation of roles and responsibilities, site and quality department goals, and
oversight approaches. How roles and responsibilities are executed is influenced by
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cultural norms. Respondents identified that establishing goals is part of the company’s
VMP strategy. However many respondents neither disagreed nor agreed or did not know
whether VMP goals were included in company strategic planning (17/25, 72%) or were
part of employee goals (18/25, 72%) (Fig 32).
Figure 32: “The following questions deal with validation master plan.”
A set of statements was provided to gain more insight into the culture of the VMP
process (Fig. 33). Most respondents felt that they were familiar with the VMP (20/25,
80%) and that the culture of maintaining a VMP “beyond” compliance was prevalent in
their organizations (16/25, 64%). Nevertheless, only a minority of respondents (7/25,
28%) appeared to agree that VMP goals were communicated; most (18/25, 72%) neither
disagreed nor agreed, or did not know. The most variation in opinions was expressed
over two items, whether the VMP drives efficiencies (agree or strongly agree, 13/25,
52%; disagree or strongly disagree, 5/25, 20%), and whether the VMP was updated for
VMPs are included in company’s
strategic planning
Site specific goals include VMP goals
Our QA dept establishes VMP goals
VMP goals are incorporated in
employee performance plans
Our VMP specifies job functions with
responsibilities and accountabilities
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equipment (agreed or strongly agreed, 11/25, 44%, disagreed or strongly disagreed, 9/25,
36%). A cross-tabulation shows that a culture of compliance has a positive impact with a
VMP that is kept in an “evergreen” state (15/25, 60%) (Fig. 34).
Figure 33: Cultural and communication indicators related to the VMP
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Figure 34: Cross-tabulation of culture of compliance and how it influences VMP
“evergreen” status.
General questions were also asked about the way that other standards and requirements as
well as groups outside of quality and their influence to guide the development of the
VMP (Fig. 35). Most respondents agreed or strongly agreed (23/25, 92%) that regulatory
requirements and external standards were referenced in the VMP. Most respondents
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(21/23, 91%) further identified that the VMP was developed with attention to the
alignment of activities that would be needed to meet the needs of multiple countries.
However, most disagreed or strongly disagreed that input was sought outside of quality,
(18/24, 75%), especially in the area of the marketing department, a group that often times
represents the voice of the customer, when compiling a VMP. About half of the
respondents (11/22, 50%) acknowledged that other equipment standards such as OSHA
standards were included in the VMP (Fig. 35). When asked about VMP document
maintenance, respondents agreed that the VMP is kept in an “evergreen” status (20/25,
80%) (Fig. 36). Respondents also shared that the VMP document houses facilities and
production related equipment (17/25, 68%), which seems to support the attention to
managing the VMP in an “evergreen” status as stated earlier (Fig. 36).
Figure 35: Responses to general questions on the validation master plan.
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Figure 36: Production and facilities equipment, excluding analytical equipment, and
the validation master plan.
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CHAPTER 5. DISCUSSION
Manufacturers of drug products have long struggled with the challenges of ensuring
quality, safety and efficacy under conditions of mass production. The development of
quality systems for pharmaceutical production has been seen as a key element to ensure
safe drugs for the public. Today industry engages in validating the drug manufacturing
process and qualifying its attendant equipment as a method of assuring control over
variability that might affect critical parameters and attributes. The goal of the present
research was to look at the presence and nature of the validation master plan, including its
equipment validation and qualification standards within the pharmaceutical industry in an
attempt to understand how validation requirements are incorporated into a company’s
overall quality system and practices. Results suggested that most companies are
incorporating VMPs as a framework for validation activities. However, at this early
stage, it is perhaps not surprising that approaches varied across companies of different
sizes and resource depths.
5.1 Consideration of Limitations, Delimitations, and Assumptions
A key consideration in the design of an investigation such as that identified here is
whether to use a survey methodology or another means to gain insight into the questions
of interest. A survey was selected as a way to collect data for the research because of its
better utility to reach a broad pool of respondents located throughout the United States
and in some cases at international locations. This geographic spread would make it
expensive and perhaps even time-prohibitive to interview each of the respondents.
Interviews by telephone might be an alternative option to a face-to-face interview, but
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research shows that respondents are becoming averse to telephone interviews in response
to the increasing number of telemarketing and sales calls to which they have been
subjected (Draugalis, Coons, & Plaza, 2008). The survey also has the additional
advantage that it allows respondents to participate anonymously. It is therefore less likely
that responses will be influenced by the cues or opinions of the interviewer, as is often
pointed out by the methodological literature (Buchanan & Bryman, 2007).
The strength of a survey in part depends on its ability to capture sufficient salient
information about the topic under study. In this work, the survey instrument was based
upon the combined framework suggested by Chan that blended capability and behavior as
complementary components whose nature can affect the implementation of complex
technical programs such as that of implementing a VMP (Chan, 2012). Chan’s model
was repurposed, however, to assess the extent of VMP readiness in pharmaceutical
companies rather than to assess the approaches to risk management in medical device
companies in its earlier application. Nevertheless, Chan’s framework appeared well
suited to encourage a more systematic approach to the development of questions relating
to diverse elements of company practice and culture that could affect the implementation
of a VMP.
In the present study, the survey was distributed electronically, in order to ensure that most
respondents were given the survey at the same point in time, in a way that conserved
resources such as paper and transport costs, and eliminated the need to travel. These
advantages have been identified elsewhere (Buchanan & Bryman, 2007), and are
important reasons why electronic surveys using electronic tools such as Qualtrics are so
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popular. However, electronic methods also have weaknesses that must be managed to the
extent possible. Security constraints imposed by companies on their electronic
communications blocked many surveys from the e-mail “inbox” of the potential
recipients. Some respondents identified that they later found the email with the attached
survey tool in a “spam” folder, but others may have missed the email because they did
not check for it there. Thus it is not possible to be sure how many potential respondents
failed to respond because the survey did not arrive as intended. Nevertheless, the
response rate in this survey was relatively good compared to other electronic surveys in
the past (Buchanan & Bryman, 2007; Starr, 2012). Further, the point of information
saturation was felt to be reached and the addition of more respondents was viewed as
likely to yield diminishing returns (Baker, Brick, Bates, Battaglia, Couper, Dever, Gile,
& Tourangeau, 2015).
One very useful feature of the electronic survey was found to be its flexibility to use
multiple question styles and formats. By allowing the respondents to make selections
from sets of listed choices, it was relatively straightforward to carry out simple analytics
even on this relatively small sample of responses. Nevertheless some of the limitations
of multiple-choice questions must also be borne in mind. Likert-type rating scales are
known to insert a level of ambiguity by offering a neutral choice of “neither agree or
disagree”, that could reflect either no opinion or a neutral opinion (Alwin, 2013). In
order to reduce this problem, the researcher used questions that addressed similar topics;
for example, exploration that a company had a culture “beyond compliance”, in Question
14.3, was aligned with a question about whether a company maintained its VMP in an
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“evergreen” state, audit / inspection ready, in Question17.2. Experimental work on
question format has also shown that questions with an odd number of choices tend to
steer the respondent towards middle response as their answer (Taylor, 2015). The
addition of a “do not know’ option typically increased the choices to an even number, but
it is not clear whether the symmetry of the positive and negative response choices in this
study was influential in helping respondents to avoid this steering effect. Question
complexity, as reflected by syntax, word length and frequency and sentence length will
also affect the readability of survey questions, and could have an impact to the results of
a survey (Lenzner, 2013). For this reason, the use of a focus group was viewed to be
helpful in assuring the “face” validity of the survey questions, as has been done by others
(Nassar-McMillan, Wyer, Olivre-Hoyo, & Ryder-Burge, 2010; Storm, 2013). However,
even well-constructed multiple choice questions have been criticized in the past as
providing a relatively limited insight, compared to the richer information that might be
contributed if the respondents were to be interviewed (Dialsingh, 2008). To some extent,
comments boxes appeared effective at gathering additional information more typical of
the deeper answers that might be gathered in an interview. Nevertheless, an exploratory
study such as this may need to be the initiating point for deeper research with other, less
constrained methodologies.
Although survey methods allow much more flexibility to reach an intended audience, the
actual effectiveness of that outreach depends on the nature of its sampling plan (Jansen,
2010). It was clear from the outset that an exploratory survey such as this would require
certain delimitations so that results would not be confounded by too many variables.
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Important, for example, is assuring that the respondents know enough about this
relatively specialized topic. It was therefore important to utilize the researcher’s network
to define the research population in order to avoid the inclusion of uninterested or ill-
informed individuals who might fail to complete the survey or provide misleading
answers that might skew the results (Baruch & Holtom, 2008).
The survey was also delimited by focusing it on a particular snapshot of time and a
constrained topic, that of FDA cGMP regulations for the manufacture of pharmaceutical
products. This may limit the usefulness of the data to generalize results to other types of
medical products. In particular, the temptation exists to broaden the interpretation of
these views to the device industry where validation planning is also an important part of
manufacture. However, it may be a stretch to make this leap. The medical device
regulations have been developed and amended extensively over the last three decades, by
a different and relatively autonomous Center in the FDA from that setting rules for
pharmaceutical products (U.S. Food and Drug Administration, 2009). Those expanded
regulations had a stronger focus on validation activities and control systems that had to be
implemented at an earlier time in product development as part of “design control”
activities (Rados, 2006). Follow up research on validation practices and VMP
implementation for medical devices and or combination products might add some depth
and breadth to understanding broader “best” and “current” practices in other parts of the
medical products industry. If these practices were to be more mature, they might provide
“lessons learned” to the pharmaceutical industry for whom such approaches have only be
implemented widely in the last 10 years.
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One objective of the present study was to gain preliminary information about the use of
VMPs across companies of varying sizes. Previous research on the sizes of
pharmaceutical companies in the U.S. is hard to find. However, Barbadora identifies that
very small companies are much more numerous than midsized companies, a pattern that
was reflected in the distribution of large and small companies in our sample (Barbadora,
2012). Benson also identifies that large companies make up 41% of the revenue within
the U.S. pharmaceutical industry; however, this group contains only 12 companies
(Benson, 2015; Grom, 2006). These observations suggest that the sampling of
respondents in this study over-represents large companies. However, this enrichment is
perhaps not surprising because large companies have several manufacturing sites, and
therefore have a disproportionate number of quality experts with experience in VMP
implementation. It might also reflect the fact that I have previous professional experience
mainly in large companies and my contact lists are most likely to include individuals with
similar backgrounds. However, it is not at this point clear whether the differences in the
backgrounds of the respondents was a serious problem for the interpretation of the
results, particularly because cross-tabulation methods could be used to sort and compare
the responses of respondents from companies of different sizes.
Finally, responses of respondents may also vary depending on geographic location.
Companies with stronger global or European activities are more likely to be required to
have a VMP, because specific regulations are in place to require such a VMP in other
countries but not in the U.S. (Health Science Authority, 2013b; WHO, 2006).
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To avoid overlooking the possibility that differences in the responses of participants
might be related to some aspect of company location, this information was also gathered
and used to sub-stratify answers based on based on the location of company headquarters.
By cross-tabulating the views of 27 respondents with headquarters in the U.S. against 15
had headquarters outside the U.S., it is possible to see if strong differences existed as seen
in Chapter 4, Figure 12. However, in a survey of this size, statistical comparisons lack
the power necessary to make any definitive conclusions about similarities and differences
with regard to these modest differences, especially when many of these companies do
business in both constituencies.
5.2 How mature are current VMP approaches?
In this study, we suggested using an approach suggested by Fixsen’s model of
implementation (described in chapter 2) to examine the implementation maturity of
VMPs. The results showed that across the industry, VMPs were present in almost all
companies. Further, cross-tabulations suggested that the location of the company
headquarters had little influence on the adoption of VMPs. These results were surprising.
Literature leading up to this study suggested that VMPs were mandatory in many
countries including the countries of the EU, but were not required in the U.S. (Ahir,
Singh, Yadav, Patel, & Poyahari, 2014). This led us to postulate that regulatory
requirements might be a significant driver for implementation of a VMP and might be
reflected in a lower rate of adoption in the U.S. Thus the fact that most U.S. companies
were making the commitment to carry out this activity suggested a greater degree of
adoption than might have been expected.
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It might be argued that the presence of a VMP does not mean that the VMP is mature in
its design and implementation (Ofni Systems, 2014). This exploratory study was not
designed to ascertain the level of sophistication of VMPs across the industry. However,
the data that were gathered did suggest that the VMPs of most companies had attributes
of a fairly advanced system. For example, most companies reported that they had paper
or electronic documentation in place to base their VMP. The implementation of
documentation such as standardized procedures and work processes is a hallmark of at
least reaching the stage of paper implementation, as identified by Fixsen. Respondents
also noted that documentation was reviewed regularly and updated through conventional
change control mechanisms and regular review; this would further suggest that the
system was at the stage of process implementation. The final stage of implementation
identified by Fixsen, that of performance implementation, is more difficult to assess from
the responses here. Fixsen defines performance implementation as the use of new
operating procedures in such a way that they actually change outputs and create benefits
to users. That at least some companies are at this stage is suggested best by a question in
which the large majority of companies agreed, “My company utilizes the VMP as a basis
for operational efficiencies”. Nevertheless, it would be useful to evaluate more
systematically where the VMP is seen to have contributed greatest value, and how
companies have specialized their systems to improve that value.
5.3 How do organizational capabilities affect VMP maturity?
The survey instrument was based upon the combined framework suggested by Chan,
blending capability and behavior as complementary components that can affect the
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implementation of a complex technical program such as that of implementing a VMP.
The six areas identified in this framework are used as a way to decompose and discuss
some of the more interesting observations in this study.
5.3.1 Resources
VMPs are resource intensive. As stated by PIC/S (2007) while recommending principles
to govern validation master plans:
Validation studies are costly as they require time of highly specialised
personnel and expensive technology.
Yet resources are precious, and are particularly limited in many small companies, as had
been noted in previous literature (Dixon, Gates, Kapur, Seabury, & Talley, 2006). In
those small companies, we might anticipate that resources would be focused on activities
crucial for future development and survival. Small companies might therefore be
reluctant to invest in VMP development. Further, a VMP is not required under the FDA
regulations so a small company that is not yet making a marketed product, or one serving
only a US market, would be less likely to need a VMP than a large multinational
producing drugs for Europe where such a VMP is required (Stevans & Pawlik, 2009).
We might then expect that the use of VMPs would be reported more frequently by large
companies with more resources to focus on this activity. However, differences between
large and small companies were quite small, as reflected by the fact that only two
companies of modest size (200-499 employees) and no very small companies (< 200
employees) had no form of VMP as seen in the cross-tabulation in Ch. 4, Fig 15B. Why
might this be? It could be that the development of a VMP for a small company is a
relatively straightforward activity when the extent of production is modest. In a smaller
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company, often a small team makes only one or two products at a single site, or may even
outsource these products and re-label them prior to sale. Thus the VMP would be
relatively easy to implements because it would include the validation of only a small
number of processes and items of equipment. It may be that small companies find the
VMP to be a convenient way to systematize their quality activities and find that its value
makes investment of resources worthwhile. However, this conjecture would need to be
validated by additional research, perhaps by interviewing individuals in such companies.
5.3.2 Structure
An interesting difference that appeared obvious when the results of large and small
companies were sub-stratified was the finding (question 10) that small companies
adopted a centralized system of VMPs whereas large companies typically had a
decentralized structure or combination of centralized and decentralized approaches as
seen in the cross-tabulation in Ch. 4 Fig 15B. It is not surprising that the VMPs of small
companies are centralized. As identified above, small companies typically do not have
multiple sites, so that activities have no choice but to be centralized. A streamlined,
centralized approach is easier for small companies, whose smaller teams can
communicate more easily and can engage more easily in a systematic, companywide plan
(Boundless, 2015).
The situation is different for larger companies. Large companies may have more
resources to bring to bear on a VMP strategy but they also have a bigger problem to
solve. In large multinational companies organizational systems such as VMPs are much
more complicated. The large company might prefer a centralized strategy that would
107
give greater control over the strategy and a more homogenous set of procedures and
oversight mechanisms at each of its sites. However, the business environment seems to
make such centralization difficult. Large companies acquire and divest subsidiaries very
frequently. Recent mergers and acquisitions within the pharmaceutical industry have
created great diversity and complexity in the structural features and cultures of larger
companies (Baines, 2010). Among these complexities is the need to satisfy multinational
regulatory obligations related to quality programs that can be located in different
countries (Handoo, Arora, Khera, Nandi, & Sahu, 2012). In those sites, often inherited
from an acquisition, quality systems and VMPs, if present, are different in form and
detailed requirements. Thus, it may be difficult to bring multiple sites making multiple
products into a harmonized singular VMP. A decentralized or mixed approach to their
VMPs might be the only practical option.
5.3.3 Processes
The results in this study suggested that well-developed processes are in place to support
the VMP in most companies. These extend from the establishment of VMPs to their
review and maintenance. The fact that robust processes might be present is not
surprising. FDA introduced process validation requirements into the cGMPs (21 CFR
211) as early as 1978 and two decades later, in 1987, published its Guideline on General
Principles of Process Validation (U.S. Food and Drug Administration, 1987). The most
recent guidance document, titled Process Validation: General Principles and Practices,
somewhat surprisingly, did not explicitly call for a VMP. However, it certainly identified
the need for a procedurally based system for
108
…the collection and evaluation of data, from the process design stage
through commercial production, which establishes scientific evidence that
a process is capable of consistently delivering quality product. Process
validation involves a series of activities taking place over the lifecycle of
the product and process. (Process Validation: General Principles and
Practices).
Given the emphasis in other countries on a VMP, it would seem a small step to develop a
VMP as an umbrella to collect the processes and procedures already well-embedded in a
typical quality system that meets the above requirements.
To be consistent with quality systems into which they are embedded, VMPs have certain
defined features that are included in the regulatory standards and guidance. Many of
these features were identified in the survey responses such as procedures, training,
timelines, communication and structure (Question 15). Further, companies have shared
through the survey that VMP is updated and maintained in a manner similar to that of any
other quality system, by utilizing change control, technical transfers and asset control
(Question 19). However, the survey did not assess whether or not companies followed
certain specific regulatory standards or guidance when creating a VMP and identifying
the features to be included. It may be helpful to understand if the industry is following
guidance such as that published by WHO or if some other specific regulatory standard
required as part of their compliance program for a specific country or constituency.
The robustness and successful execution of a VMP are necessarily linked to the maturity
of a company’s quality system. Therefore it was not a surprise that a majority of
companies have tied their VMP into their controlled documentation system consistent
with GMP requirements (Question 22 – 28). It would also be expected that good
documentation practices would assure that critical documentation is maintained, and that
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record retention periods are specified (Question 33). All of these results lead us to believe
that the VMP efforts in most companies are highly structured and meet most of the high-
level expectations of regulatory guidance.
5.3.4 Competence
Competence in an organization has two levels. First is that of its employees. Employee
competence is defined as
…a cluster of related abilities, commitments, knowledge, and skills that enable a
person (or an organization) to act effectively in a job or situation (N.A., 2014a)
The survey responses suggest that companies must have employees with at least some
level of competence to develop and implement a VMP. Regardless of the size of the
company, internal employees were identified as taking a role in designing the VMP and
in most cases in taking full responsibility for it without the use of outside experts. In
those few instances where contractors or consultants supported the development of the
VMP, internal employees were also engaged in the process. Typically this latter pattern
was seen in large companies, where the complications of multiple centers and product
lines may profit from a higher level of engagement by experts as seen in the cross-
tabulation in Ch. 4, Fig. 18.
What could not be gauged in this study was the depth of competence of the internal
individuals and of the consultants who interacted with them. It would be interesting in
future to explore the roles and responsibilities of the internal employees and consultants
to better understand the depth of their knowledge and experience related to VMPs. It
would further be interesting to understand how they acquired this knowledge because this
110
material is not generally taught in schools of engineering or science. As these companies
design and implement VMPs it would be useful to discover whether there are specific
regulatory standards or guidance that are being used most commonly as a basis for the
developmental activities and whether they view that the knowledge that they have related
to the implementation of a VMP is sufficient to do a truly effective job of that
implementation. Keeping a professional workforce competent with a rapidly changing set
of requirements is a challenging undertaking that requires the use of a variety of tools, not
only through its internal knowledge management system (Dieng, Corby, Giboin, &
Ribiere, 1999) but also the judicious use of training opportunities, professional
development meetings and internet offerings. However, as suggested by Bersin and
colleagues when studying employee training, companies are slow to embrace alternative
methods to corporate learning, such as online coursework, mobile learning or videos and
simulations (Fig. 37), relying instead on presentations and apprenticeship approaches
(Bersin, Haims, Pelster, & van der Vyver, 2014). Thus it is currently not clear how the
development of new methodologies such as this one are introduced and fostered in most
companies, to identify best practices for this type of education. This area would seem to
be a fertile field for future research.
111
Figure 37: Slow adoption of leading-edge learning tools
Permission to reproduce from (Bersin, Haims, Pelster, & van der Vyver, 2014)
The second type of competence that appears commonly in the literature is that of the
corporate body as an entity. Corporate competence is defined as
...a unique ability that a company acquires from its founders or develops
and that cannot be easily imitated. Core competencies are what give a
company one or more competitive advantages, in creating and
delivering value to its customers in its chosen field (N.A., 2014b).…
Corporate competence is foundational to company strategy and is part of a company’s
competitive edge (Prahalad & Hamel, 1990). The ability to meet quality requirements is
well-known to be an important aspect of corporate competence, because failure to meet at
least the minimum requirements will result in a number of negative consequences ranging
from warning letters to embargoes and import restrictions that reduce the ability of
companies to compete in the marketplace. Obvious examples of this challenge are
112
recently seen for Dr. Reddy’s and Ranbaxy corporations, where quality issues have
greatly impacted their ability to sell product in the U.S. (Palmer, 2015). However, once a
state of compliance with regulations is reached, is there an advantage to going “beyond
compliance”? It was interesting that many respondents identified that they had a quality
culture “beyond compliance”. However, at this point in time, it is not clear whether
having a even a superb quality system would reap many benefits compared to just an
adequate quality system. As pointed out by Medina and Richmond (2015) in a recent
study of quality metrics, the market for pharmaceutical products in a “one-sided incentive
structure”.
The GMP regulations for pharmaceuticals establish minimum
requirements to ensure that products are safe and effective but do not
provide an incentive for manufacturers to go beyond that minimum
benchmark and strive for excellence in quality (Medina & Richmond,
2015).
Perhaps, then, it is not unexpected to find that many respondents, especially those in
smaller companies, did not see their VMP as included in company strategic planning or
as having goals that are incorporated into each employee performance plan.
In future, however, this situation might change. FDA is considering the expansion of a
risk-based ranking system for pharmaceutical companies that might give certain
competitive benefits, such as reduced inspectional oversight that is costly and distracting
for companies. Further, it has been debated whether such rankings could expand to a
publicly available rating system in which quality could become a differentiating feature
that might influence drug purchase, especially from high-volume customers such as
formularies. In that case, corporate competencies related to quality capabilities, including
113
the effective design and execution of a VMP, might have positive financial and
reputational implications to increase a company’s competitive edge compared to of
competitors.
5.3.5 Culture
As noted above, companies grow and change as a result of their own business successes
as well as their acquisitions and partnerships. These changes not only affect the structure
of an organization but also its culture. In the pharmaceutical arena, the importance of a
“quality culture” has been repeatedly emphasized both by the leadership of the Food and
Drug Administration and by professionals in quality circles (Stegemann, 2015). That this
concept is also important to most manufacturers is reflected here in the fact that only a
minority of companies disagreed with the view that their company had a culture beyond
compliance. This appeared to be coupled with a significant involvement of senior
management in the review of the VMP and the presence of change control mechanisms to
map changes in the VMP once developed. All of these elements suggest a system that
appreciates the type of best practices that form the basis for a quality culture, at least to
the extent possible to judge for the types of questions in this study.
However, it has proven difficult to gauge the “quality” of a quality culture in any
satisfactory way, despite its perceived importance as a driver for effective practice.
Uydess and Meyers (2011) have highlighted several important features of a quality
culture that range from communicating effectively regarding quality objectives and
policies, to including quality expectations in the roles defined for individuals within the
organization, to providing leadership and establishing an environment that breeds trust
114
and collaboration (Uydess & Meyers, 2011). The results of the survey suggest that most
of the companies considered in this survey were making efforts to assure such a quality
culture. For example, many utilized a multidisciplinary approach to VMP development
and implementation, with well-defined structures and communication channels. These
efforts would seem to encourage a positive culture for VMP implementation and
maintenance, as was also suggested by the fact that most felt their VMP to be in an
“evergreen” state.
At the same time, one challenge to creating a holistic quality culture may be presented by
the need to communicate a commitment to quality and compliance across many sites with
decentralized VMPs and possibly other aspects of quality systems. Companies that have
international operations and employees with differences in languages and local cultural
norms will be more difficult to entrain into a single cultural mindset. It will be then more
difficult to establish effective communication strategies (Meyer, 2015) that would foster
shared assumptions and norms. It would be interesting in future to explore how VMPs
are perceived and managed in those companies that did not believe or were not sure if
they had a quality culture, compared to those that did. It would be further interesting to
know if international companies express different views than small companies on the
ways that a quality culture must be developed.
5.3.6 Memory
An important element in establishing effective quality systems such as VMPs in the
longer term is the ability to build on past knowledge. As stated by Uydess and Meyers
(Uydess & Meyers, 2011), it is important in a quality culture that
115
the organization institutionalizes a process for capturing, analyzing, and
incorporating lessons learned from past successes and failures
The VMP is one of the useful ways of ensuring corporate memory by acting as a
framework for integrating documentation (Doherty, 2014). Having an integrated
collection of documented processes and practices that can then be reviewed and updated
periodically and retained in accordance with a policy is a best practice in managing
knowledge. As pointed out by Kuhn and Abecker (Kuhn & Abecker, 1997) in their
review of mechanisms to improve corporate memory,
Highly paid workers spend much of their time looking for needed
information…essential know-how is available in the heads of only a few
employees…delays and suboptimal product quality result from insufficient
flow of information (Kuhn & Abecker, 1997)
It seemed apparent from the answers to questions regarding the maintenance and review
of the VMP that documentary assets are being retained in a way that will provide a
significant legacy. It will allow the company to revisit previous practices in cases of
quality issues, and to trend progress toward the harmonization and incorporation of best
practices into its quality activities.
The specifics of how documents are managed and retained do seem to vary across
companies. One observation of interest was the finding that companies do not all set up
their VMPs with similar platforms; some respondents had paper-based systems and
others were moving to electronic systems. This observation suggests that the current
trends to “go paperless” still have not been fully embraced. It was not unexpected that
small companies with few products might base their systems on paper, but it was also
apparent that paper-based systems are also being used in some large companies with
116
many products. The reasons for the continued use of paper-based systems in the face of
current trends to “go paperless” would be worth exploring. It may be that electronic
systems are still expensive and difficult to make compliant with FDA requirements for
electronic records and signatures, and that this pattern will change in the next decade.
This type of change may assist the effective use of the VMP as a source of “memory”
that is searchable and easy to access compared to paper-based systems.
5.3.7 VMPs and Equipment Validation Planning
Because surveys are limited in scope and restrict the number of questions that can
reasonably be asked, I selected equipment as a focal point to assess one aspect of VMP
implementation in some detail. The group of respondents in this survey almost all
identified that equipment qualification activities were integrated into the VMP. Although
the management of equipment might be performed outside of the VMP, the VMP was
identified as the structure for maintaining equipment standards and associated regulatory
requirements, and for assuring the organizational commitment to implementing and
maintaining this system across the equipment lifecycle. As a result the VMP appears in
most companies to be the repository housing regulatory expectations for equipment. That
the VMP often housed not only GMP requirements but also OSHA requirements and
other equipment related standards suggested that it has become the holistic manager for
equipment. In other words, many companies have embraced the VMP as a gatekeeper for
equipment that establishes timelines for maintenance and tracks alterations and deviations
in equipment management though a change control system. It is also the place to revisit
when installing new equipment or making modifications to manufacturing areas.
117
The VMP would seem to be evolving from simply another organizing principle for
quality into a key tool to frame activities related to regulatory surveillance. Certainly in
the EU, the VMP is considered to play this central role, as reflected in its Annex 15
update for its EU guidelines for Good Manufacturing Practices (European Commission,
2015). The recommendations with regard to equipment come early in the document,
before the recommendations for other types of validation such as process validation, and
discuss in detail what should be included for the entire life cycle of the equipment from
its user requirements and design qualification to its installation, operational and
performance qualification. As stated by Miller, “The site VMP is often one of the first
documents to be reviewed in a regulatory agency audit”, serving not only as an archive
but as a overarching plan to define policies and commitments with respect to equipment
management (Miller, 2008).
5.3.8 Conclusions
Although VMPs are not identified explicitly in any guidance document of the U.S.FDA
(Miller, 2008), it seems clear from this survey that companies are almost universally
familiar with the concept and in fact have advanced considerably in the use of this high-
level document to structure their quality activities. If FDA were to make such a program
a formal requirement in future, most companies would probably find that they are already
well on their way to having such a plan in place. This state of readiness may in part
come from the fact that VMPs are required by many regulatory agencies elsewhere, some
of which spell out the contents of the VMP is considerable detail. However, despite this
apparently positive picture, caution should be exercised in believing that the detailed
implementation of the VMP makes validation quality issues go away. Surveys of
118
warning letters from the FDA document the fact that in 2014 19/39 Warning Letters
issued with regard to cGMP problems highlighted validation or validation related topics
(U.S. Food and Drug Administration, 2014).
Table 8: U.S. FDA 2014 Warning Letter Summary
WARNING LETTER CATEGORY NUMBER PERCENTAGE
ISSUED 198 29%
NOT ISSUED 484 70%
cGMP / QSR OR FINISHED PRODUCT 39 20% (issued)
cGMP / QSR OR FINISHED PRODUCT with
validation citation
19 10% (issued)
TOTAL as of December 2015 682 NA
NOTE: Warning Letters are issued once it has been determined that certain FDA
compliance criteria has been met.
Thus further investigation is needed to identify whether companies that already appear to
derive value from such an organized framework would be comfortable with having the
VMP as a formal regulatory requirement in the U.S. and whether its use will over time
drive down the number of inconsistencies and failures that often plague the
pharmaceutical industry.
119
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APPENDIX A. DRAFT SURVEY
A Validation Master Plan outlines the principles involved in the qualification of a facility,
defining the areas and systems to be validated, and provides a written program for
achieving and maintaining a qualified facility.
134
The following set of questions is to gain an understanding of the implementation of validation
master plans at your company.
135
136
137
138
APPENDIX B. FINAL SURVEY
139
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APPENDIX C. FOLLOW UP SURVEY
Abstract (if available)
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Elser, Clare
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Validation master plans: progress of implementation within the pharmaceutical industry
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School of Pharmacy
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Doctor of Regulatory Science
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02/22/2016
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