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Current practices in pharmaceutical container closure development

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Current practices in pharmaceutical container closure development

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CURRENT PRACTICES IN PHARMACEUTICAL
CONTAINER CLOSURE DEVELOPMENT

by
Duane L. Mauzey

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 2012

Copyright 2012 Duane L. Mauzey

ii
Dedication
This dissertation is dedicated to Frances Richmond, Ph.D., Director of the Regulatory
Science Program in the School of Pharmacy at the University of Southern California, without
whose constant help and encouragement this dissertation could not have been completed. And to
my wife Kathie, without whose support I never would have started down this path, nor completed
the journey. Lastly, to my manager, Loren Wagner, M.S.(R.S.), whose constant support for the
USC Regulatory Science Program made this accomplishment possible.

iii
Acknowledgements
I would like to acknowledge the help and encouragement of the first cohort of the DRSc
program in the Regulatory Science Program. It has been an exceptional journey due to such good
comrades in regulatory science. I would also like to acknowledge the help and support of the
staff of the Regulatory Science Program, Kathy, Christine, Julie, Erin, and Kim, for smoothing
out some of the bumps along the way. And, the help of Mike Jamieson, DRSc, has been most
appreciated in the last phase of this journey. Lastly, I would like to thank Teodora for her help
with the final manuscript. The help of friends and colleagues has made the journey that much
more pleasant, my cup floweth over, and I am deeply grateful to all. Lastly, but very importantly,
I would like to thank Edward Smith, Ph.D., and Iris Rice, both of the Parenteral Drug Association
(PDA), for their excellent help in moving the survey instrument through the PDA and out to
members of the PDA Packaging Science Interest Group whose responses make up a large portion
of this dissertation.

iv
Table of Contents
Dedication ii

Acknowledgements iii

List of Tables vi

List of Figures vii

Abstract x

Chapter 1: Overview of the Study 1
1.1 Introduction 1
1.2 Statement of the Problem 4
1.3 Purpose of the Study 4
1.4 Importance of the Study 5
1.5 Limitations, Delimitations and Assumptions 7
Delimitations 7
Assumptions 8
Limitations 8
1.6 Definitions, from ICH Q1A(R2) (ICH 2003) 9

Chapter 2: Literature Review 11
2.1 Introduction 11
2.2 Evolution of Packaging Regulations 14
2.3 The Current State of Guidance Documents 17
Principal Guidance Documents 17
Content of Key Guidance Documents 21
Content of ICH guidelines 27
Role of the Pharmacopeia 28
Concerns about Regulatory Guidance 32
2.4 Recent Initiatives to Improve Extractables/Leachables Testing 34
2.5 Synthesis of the Literature 37

Chapter 3: Methodology 40
3.1 Introduction 40
Overview 40
Development of the Survey Instrument 40
3.2 Preliminary Survey Reviews 41
PDA Packaging Science Interest Group (PSIG) 41
PDA Scientific Advisory Board (SAB) 41
3.3 Sample and Population 42
3.4 Data Collection and Analysis 42

v
Chapter 4: Results 44
4.1 Survey Review, Validation and Distribution 44
4.2 Analysis of Survey Results 45
Background of Survey Respondents 45
Primary Container Closure Qualification 48
Extractables and Leachables in Shipping Materials 53
Drug Delivery Devices and Drug Master Files 54
Extractables and Leachables General Studies 56
Product Recalls and Marketing Approval Delays 59
Adequacy of Guidance and Compendial Documents for Testing 61
Comments on the Survey Instrument 68

Chapter 5: Discussion 70
5.1 Consideration of Methods 72
Delimitations 72
Limitations 74
5.2 Consideration of Results 75
Recalls and Marketing Approval Delays 82
Guidance Documents and Compendial Information 82
5.3 Future Directions and Recommendations 86

Bibliography 88

Appendices:
Appendix A: The Survey Instrument 93
Appendix B: The Survey Results 106

vi
List of Tables
Table 1: Comparison of FDA, EMA, and ICH Guidances for Container Closures 18
Table 2: Japanese Container Closure Regulatory Information 20
Table 3: Summary of Compendial Sources of Container Closure Information 30
Table 4: JPXV Chapters and their Corresponding USP and Ph Eur Chapters 32
Table 5: Comments from the Survey Instrument, Question 23 69

vii
List of Figures
Figure 1: Explanation of “degree of concern” concept enunciated by FDA with respect
to packaging materials. Reproduced from Guidance for Industry: Container
Closure Systems for Packing Human Drugs and Biologics (FDA 1999). 24
Figure 2: Table from FDA guidance to show the level of detail suggested for package
testing. Reproduced from Guidance for Industry: Container Closure
Systems for Packing Human Drugs and Biologics (FDA 1999). 25
Figure 3: Explanation of short-forms in Table 2. From Guidance for Industry:
Container Closure Systems for Packing Human Drugs and Biologics (FDA
1999). 26
Figure 4: Question 1: Do you consult for/manufacture/market products in a field that
the FDA regulates? Check all that apply. 46
Figure 5: Question 2: If you deal with devices, please indicate which class(es) of
devices that you market. Check all that apply. 47
Figure 6: Question 3: If you deal with pharmaceutical products, please identify which
types of primary container closure systems that you use. The primary
container closure is that part of the container closure and any associated
packaging that has direct physical contact with the drug product. Check all
that apply. 48
Figure 7: Question 4: Does your company perform primary stability studies of your
drug product in the proposed marketing configuration for the primary
container closure system? 49
Figure 8: Question 5: Does your company conduct studies to establish the integrity of
the primary container closure system in lieu of sterility testing? 50
Figure 9: Question 6: Does your company conduct studies to establish the level of
protection from moisture for the drug product in the primary container
closure system? 51
Figure 10: Question 7: Does your company conduct studies to establish the potential for
adsorption of the drug product to the primary container closure system
container? 52

viii
Figure 11: Question 8: Does your company conduct studies to establish the justification
for use of materials for the secondary packaging system with the primary
container closure system? 53
Figure 12: Question 9: Do you conduct studies on container leachables for drug product
interaction with shipping materials other than the primary and secondary
container closure system? 54
Figure 13: Question 10: Does your company conduct studies to establish the accuracy
and reproducibility of drug product delivery devices that are part of the
primary container closure system? 55
Figure 14: Question 11: Does your company use packaging drug master files (Type III
DMF) to support your submission dossier for your drug product? 56
Figure 15: Question 12: Do you conduct studies on container extractables for drug
product interaction with the primary container closure system? 56
Figure 16: Question 13: Do you include the primary container closure leachables as
part of primary stability testing protocols? 58
Figure 17: Question 14: Do you monitor leachables as part of ongoing commercial
stability? 59
Figure 18: Question 15: Have you ever had a drug product recall due to container
leachables? 59
Figure 19: Question 16: Have you ever had a marketing application delayed due to a
packaging issue such as extractables and/or leachables? 60
Figure 20: Question 17: Do you conduct studies to establish the safety of materials of
construction of the primary container closure system? 61
Figure 21: Question 18: Which of the following statements best describes your feelings
about the adequacy of the guidance documents from FDA for
extractable/leachable testing? 62
Figure 22: Question 19: How do you feel about the adequacy of the USP and/or Ph Eur)
compendial chapters for extractable/leachables testing? 64
Figure 23: Question 20: Which of the following documents do you use routinely? 65

ix
Figure 24: Question 21: If you lost access to one document, which document would be
the one that would have the greatest impact on your extractable/leachable
program? The choices are: 66
Figure 25: Question 22: Please choose the best answer to describe your feelings about
each of these documents. 68

x
Abstract
Container closure development for drug products has undergone significant evolution
within the last 10 years. However, the information available to guide manufacturers in the design
and testing of container closures is relatively limited. The FDA Guidance for Industry on
Container Closure Systems for Packaging of Human Drugs and Biologicals is more than 12 years
old. Other, more recent, guidance documents written by the International Conference on
Harmonization provide added insight regarding the evaluation of container closures. Further, a
modest number of pharmacopoeial requirements and regional regulations have been written that
relate to container closures for pharmaceutical products. However, it is not clear whether this
collection of documents is sufficient to capture current industry best practices, and whether
scientists responsible for container closure development are satisfied with the level of guidance
provided by these regulatory documents.
In this study, a literature review was combined with a survey of current practices and
views of scientists responsible for developing and testing container closures. The literature
showed that current industry practices extend beyond the current requirements of the regulatory
paradigm. It further suggested that testing of extractables and leachables is regarded as an area in
which more guidance may be needed. The survey that focused on extractables and leachables
testing further identified substantial variation in the practices of industry scientists. The majority
of scientists identified that the FDA Guidance document written in 1999 has the greatest impact
on their testing programs but that this document is inadequate and in need of revision. Survey
results further suggested that many of the other available documents are not sufficiently broad to
meet the needs of many scientists. Taken together, the data lead to a recommendation that the
FDA guidance document of 1999 be prioritized for revision in the near future.

1
Chapter 1: Overview of the Study
1.1 Introduction
In the pharmaceutical industry, a marketed drug product is more than the tablet dispensed
to the patient; it includes the container that is considered an integral part of the product. The
importance of the container relates to its role in maintaining the safety of the drug product beyond
the factory floor. Thus, much attention must be directed at ensuring that the container closure
system is effective to ensure the drug’s purity and quality. Proof of this capability is part of the
regulatory submission to obtain marketing approval for the drug product. Testing to show
suitability of the container closure system must be conducted and data must be reviewed by the
United States (US) Food and Drug Administration (FDA) prior to marketing. Further, any
change in the container closure system must be reported to the FDA in order to maintain market
approved status.
Nevertheless, information is limited with respect to expectations for managing container
closure systems from a regulatory perspective. The primary and most systematic guideline in the
US is the FDA “Guidance for Industry on Container Closure Systems for Packaging Human
Drugs and Biologicals.” Published in May, 1999 (FDA 1999), it is now more than a decade old.
The other most commonly consulted guidance documents on the subject of container closures are
four more specific documents from the International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH). However, these
documents address specific aspects of drug development and manufacturing quality and make
relatively limited contributions to the topic of container closure evaluation. ICH Q1A(R2) (ICH
2003) covers drug substance and drug product stability testing. With regard to container closure
systems, Q1A(R2) merely states that stability testing for both the drug substance and the drug

2
product must be performed in the final proposed packaging, or its equivalent. ICH Q1B (ICH
1996) is limited in its scope to the requirements for testing photo-stability under defined
conditions, and identifies that this testing must include both the primary and secondary container
closure, where appropriate. ICH Q6 (ICH 2000) describes the requirements for specifications and
testing of drug substances and drug products, and includes the need for specifications of the
primary container closure system as part of the requirements. ICH Q8(R2) (ICH 2009) is titled
“Q8 Pharmaceutical Development.” It mentions container closures by briefly discussing
considerations for the development of container closure systems and largely replicates advice that
is summarized in a much abbreviated fashion from the 1999 FDA Guidance. ICH Q8(R2) also
describes a requirement for data on precision and accuracy for drug delivery devices when a part
of the container closure system. Some additional information can be found in international
regulatory guidance documents and compendial references, particularly the Pharmacopeiae of
different countries or regions. These Pharmacopeiae deal with certain specific aspects of
container closure analysis and management, and are discussed below in detail in Chapter 2.
The importance of having current and comprehensive regulatory guidance documents on
container closures relates to the role of these documents in defining not only current best
practices but also minimally acceptable practices from a regulatory perspective. Regulatory
agencies are oversight bodies whose rules are used to police companies that are failing to produce
product under current Good Manufacturing Practices, often short-formed as “cGMPs.” The small
“c” signifies “current” and reflects the fact that manufacturers are expected to remain up-to-date
in their knowledge of manufacturing practices and operate according to acceptable standards, as
defined in 21 CFR 210 (CFR 2010). Products that are not produced under adequate cGMP
conditions are considered adulterated. Being found to be an adulterated product is problematic
from a business as well as quality perspective, because it may affect the ability of the company to

3
market its products, and may result in financial and other forms of penalties levied by the FDA.
In addition, it can affect the ability of a company to protect itself from legal liability if consumers
who take the product are injured by problems that can be traced to the manufacturing practices of
the company. Thus, it is very important that guidance documents on particular subjects such as
container closure systems provide industry with up-to-date and accurate information on what is
currently considered to be appropriate measures to comply with Good Manufacturing Practices,
as stated in 21 CFR 210.2 (CFR 2010):
The regulations set forth in this part and in parts 211 through 226 of the chapter contain
the minimum current good manufacturing practice for the methods to be used in, and the
facilities or controls to be used for, the manufacture, processing, packing, or holding of a
drug to assure that such drug meets the requirements of the act as to safety, and has the
identity and strength and meets the quality and purity characteristics that it purports or is
represented to possess.
If little information is available concerning the development and testing of container
closure systems as part of regulatory guidance documents, how else can the manufacturer obtain
information about best practices? A range of additional literature can be found on specific topics
related to container closures in peer reviewed journals and the non-peer reviewed trade press over
the past decade. Further, a public-private collaboration under the auspices of the Product Quality
Research Institute (PQRI) (PQRI 2006; Norwood, Paskiet et al. 2008) has produced a very
detailed set of recommendations to update certain regulatory requirements and make them more
tractable from a risk management perspective, but these recommendations are designed only for a
specific subset of drugs delivered by inhalation. All of this literature has provided valuable
additional information about such topics such as container closure extractables and leachables
that should be of value to manufacturers. However, it is not available easily in a central
integrated resource. Manufacturers are therefore left with some insecurity about whether the
approaches they are taking are the best ways to ensure high quality and regulatory acceptability.

4
1.2 Statement of the Problem
The development and management of pharmaceutical container closure systems is
challenging because few guidance documents are available to assist the pharmaceutical
manufacturer. There is a relative paucity of regulatory guidance that delineates what is, or should
be, current practice for pharmaceutical container closure development and most of the formal
guidance from the US regulatory agency is now quite old. Nonetheless, the significant number of
journal articles in this field of study suggest that changes in container closure development may
have occurred since the May 1999 FDA Guidance (FDA 1999), possibly due to implementation
of ICH Q1A(R2) (ICH 2003) and ICH Q8(R2) (ICH 2009) and the increase in scientific and
technological capabilities related to materials-science and analytical capabilities. This new
literature may suggest that the regulatory guidances are out-of-date and need to be revised.
However, current thinking on this topic from the scientists and engineers responsible for this area
of activity has not been surveyed. At the same time, current practices by some companies appear
from anecdotal evidence to fall below the standard of regulatory expectations but it is not clear
whether this is due to the failure of the companies to adhere to the limited guidance already
available or whether the information that is available is insufficient or outdated.
1.3 Purpose of the Study
The purpose of this study is to assess current views and practices relating to container
closure validation in the pharmaceutical industry. The study probes this question by reviewing
primarily on the adequacy of guidance relating to leachables and extractables that appear to be of
particularly great concern because of the serious safety implications consequent to drug product
contamination. The study aims to examine current trends and industry best practices in container
closure development using two primary approaches. First, a synthesis of published information

5
concerned with container closure development will be the basis for a preliminary description of
current guidance and practice for drug-product container closure development. This review of the
literature will provide a more detailed overview of the regulatory guidance as a basis for
consideration of current best practices. It will further identify whether published literature in
academic and trade journals portray the current guidance materials as adequate or whether gaps or
insufficiencies exist.
However, reviewing the literature by itself may not give an adequate picture of the views
of thought leaders in the area of container closure development regarding the current practices of
the industry and the adequacy of current guidance documents. Such questions can be addressed
by surveying the current views and practices of pharmaceutical companies willing to share
information on their best practices. Therefore, a literature review combined with a survey of
current practice should provide a beginning attempt to triangulate current practices used by the
pharmaceutical industry to develop and test container closures for drug product marketing
applications to the US FDA.
1.4 Importance of the Study
Recent studies indicate that the cost of developing a new drug product and bringing it to
market is very high from the viewpoint of both money and time. Estimates for the cost of drug
development range from about $800 million to about $1.2 billion dollars depending on the types
of drugs under consideration and the dates at which the analyses were conducted (DeMasi,
Hansen et al. 2003; DiMasi 2008). The time frame for this development typically ranges from 10
to 12 years (DeMasi, Hansen et al. 2003). Because such enormous investments are needed, about
7 out of 10 drugs brought to market are unable to recover their developmental costs. As a
consequence, many pharmaceutical companies focus their primary efforts on “block-buster”

6
drugs that can ensure the flow of funding needed for the growth and survival of the company. A
block-buster drug product typically will generate over $1 billion in sales per year. If we assume a
figure of $1.2 billion in sales per year, and divide by 12 for the number of months in a calendar
year, we can estimate that a block-buster drug is worth about $100 million per month in sales.
Therefore, any delay in the launch of the drug product will cost the pharmaceutical company
$100 million per month of delay.
Many chemistry, manufacturing, and control (CMC) issues can be questioned by the
FDA and result in a delay of marketing approval of the drug product. One of those areas of
potential concern is that of the adequacy of the container closure system. If one or more elements
of the container closure system do not pass regulatory scrutiny, the drug approval can be delayed,
often by months, while the deficiency is remediated. If, for example, the delay were to be on the
order of six months, the regulatory deficiency associated with the container closure could cost the
company as much as $600 million in lost sales. As a consequence, it is essential that the
container closure developmental process be complete without appearing as an element on the
critical path during the development phase, and then be able to pass a regulatory audit/inspection
without incurring questions that could delay approval. As an example, Johnson and Johnson’s
McNeil business unit experienced a loss in sales of $900 million in the year 2010 from product
recalls, which included recalls that involved a leachable impurity in certain drug products
resulting from contaminated shipping pallets, as reported by the Wall Street Journal (Recall
2011). A review of the adequacy of guidance materials for container closure development and
validation would assist the pharmaceutical industry to complete the container closure portion of
their developmental activities with some assurance that reviews by the FDA will not be unduly
lengthened by potential deficiencies in this area. The present study would help to identify where
weaknesses in the system exist with regard to the testing of extractables and leachables, so that

7
appropriate strategies can be developed to improve the efficiency and effectiveness of container
closure testing and validation. It would further provide information of value to regulatory
agencies charged with maintaining up-to-date regulatory information about areas in which
revision of available materials would be beneficial to stakeholders.
1.5 Limitations, Delimitations and Assumptions
Delimitations
This research is delimited to the pharmaceutical sector, and more specifically, to
companies that are marketing products in the US. Within these companies, current practices were
explored as seen through the eyes of a subset of individuals who hold middle to senior
management positions and who have an expertise in chemistry and manufacturing controls.
Thus, the survey conducted in this study may not sample uniformly from regulatory professionals
in general. Nevertheless, this delimitation was considered to be necessary because expertise in
containers and closures is typically confined to individuals with a specialized knowledge in fields
of chemistry and manufacturing controls. Extending the survey to individuals outside of these
areas might result in opinions that are not so well-grounded in expert knowledge. However, such
exclusions risk problems of external validity, if the responses of the more expert individuals
examined here do not represent the whole population of regulatory affairs professionals or if
some aspect of particular knowledge is better represented in other parts of the company.
The examination of regulatory guidance is also primarily focused on US requirements,
although global standards were examined as part of this review. The study is further delimited in
time to the year of 2011. It is clear that standards will change with time and with the introduction
of new guidance materials, so this study provides a date-stamped benchmark against which later
studies of the same issues could be evaluated through additional examinations.

8
Assumptions
It is assumed for the purposes of this research paper that the literature is adequate to
support any conclusions drawn from the synthesis of the literature. Given the size of the
pharmaceutical industry and the journals and magazines devoted to the various aspects of
pharmaceutical development and manufacturing, any literature review must, of necessity, attempt
to be representative rather than comprehensive. It is also assumed that individuals responding to
the survey will have adequate knowledge to provide informed opinions and will answer honestly.
Limitations
This study has several real and potential limitations. First, it has a relatively narrow
focus. It addresses a science that is extensive and understood differently by individuals in
industry with different backgrounds and areas of expertise. For example, what a chemist
interested in polymer extraction might view as adequate guidance and appropriate industry
activity could be different from the view of a mechanical engineer interested in the durability of a
container. Thus, our sampled population, which was drawn from experts belonging to the
Parenteral Drug Association (PDA) Packaging Science Interest Group (PSIG) may not be
sufficiently broad or comprehensive to give a balanced view. The response rate was relatively
low as is typical for electronic surveys of this type, presumably because many individuals who
were qualified to share their views may have declined the opportunity because of their busy
schedules or lack of sufficient knowledge in this area. As is typical of the industry,
pharmaceutical companies engage in substantial research and development. Some of the
information derived from these activities is proprietary and seldom shared with individuals
outside the FDA, where rules exist to limit disclosure. Therefore, the questions in the survey
must be phrased in such a way as to avoid undue disclosure of what may be proprietary

9
information, and there may sometimes have been a failure to understand where the boundaries are
drawn. It is a further limitation of this study that the answers provided to the questionnaire can
for the moment be validated only from information available in published literature. If for any
reason, the information provided is not honest or well-informed, it will be difficult to validate the
responses without further repetition of the survey on other populations of individuals in the same
job sector, or by using a different method, such as a more in depth analysis using interviews. In
addition, there might be challenges with regard to the relatively small, highly targeted sample
population consisting of the PSIG of the PDA, whose number is less than 400, and the use of a
web-based survey mechanism for this study (Foote 2011).
1.6 Definitions, from ICH Q1A(R2) (ICH 2003)
Container closure system: The sum of packaging components that together contain and protect
the dosage form. This includes primary packaging components and secondary packaging
components if the latter are intended to provide additional protection to the drug product. A
packaging system is equivalent to a container closure system.
Dosage form: A pharmaceutical product type (e.g., tablet, capsule, solution, cream) that contains
a drug substance generally, but not necessarily, in association with excipients.
Drug product: The dosage form in the final immediate packaging intended for marketing.
Drug substance: The unformulated drug substance that may subsequently be formulated with
excipients to produce the dosage form.
Excipient: Anything other than the drug substance in the dosage form.

10
Extractables: Compounds that can be extracted from elastomeric, plastic components, or
coatings of the container and closure system when in the presence of an appropriate solvent(s)
(ICH 1996).
Leachables: Compounds that leach from the elastomeric, plastic components, or coatings of the
container and closure system as a result of direct contact with the formulation (ICH 1996).
Primary container closure: See container closure system.
Secondary container closure: See container closure system

11
Chapter 2: Literature Review
2.1 Introduction
A drug product is the sum of its parts. One part of the product that is often given rather
little attention is the package that encloses and protects the dosage form. Yet, for as long as there
have been pharmaceutical products there has been a need to protect those products in some sort of
container. A century ago, when most drugs were compounded in a storefront pharmacy close to
the homes of the users, drug products were typically placed in the few types of bottles and vials
that were readily available to the pharmacist from a relatively small set of suppliers. Today the
attention to packaging has increased dramatically, driven by at least three forces. First, drugs are
now typically produced not by compounding pharmacists but by manufacturers that can be
located thousands of miles or even continents away. The need to protect drug products for longer
periods of time so that they can withstand the rigors of transportation, temperature shifts and
extended periods on retail shelves has made the packaging a critical component of the drug
product as a whole. Second, advances in materials and packaging technologies have permitted
the development of a broad array of innovative designs that improve the convenience and stability
of products. Third, an increasing ability to detect contaminants and breakdown products has
brought scientific scrutiny to the packaging as a potential source of contaminants as well as a
shield for contamination. All of these factors have created an environment where packaging
technologies have become both sophisticated and financially valuable. Thus, the development of
pharmaceutical packaging – its formulation, manufacturing, microbiology, and controls
development – has taken its place as a key component in the design and development of a
pharmaceutical product (Bauer 2009).

12
The attention to packaging as a potential source of concern during the manufacture and
storage of drug product is underlined by a number of unfortunate events in the last two decades
that have made the evaluation and regulation of packaging a much more important part of the
drug development process than was typical previously. A few examples may illustrate
specifically how serious problems can result if packaging is problematic. One well-publicized
incident occurred when Ortho Biotech, a subsidiary of Johnson and Johnson, reformulated its
synthetic erythropoietin-replacing biologic, Eprex
®
(epoetin alfa) in 1998 by replacing human
serum albumin with polysorbate 80 as a stabilizer, in order to alleviate fears of possible
contamination of the human albumin with infectious agents such as prions. This substitution
resulted in a cascade of events that appeared from leaching studies to have been initiated because
the new polysorbate excipient facilitated the extraction of low levels of vulcanizing agents from
the uncoated rubber components of the pre-filled Eprex syringe (Boven, Knight et al. 2005; Pang,
Blanc et al. 2007; Jenke 2010). The vulcanizing agents were thought to interact with and change
the tertiary structure of the Eprex. As a result of this change, the incidence of antibody-mediated
pure red-cell aplasia (PRCA) increased significantly to a rate of 4.6/10,000 patient years from a
previous level of only 0.26/10,000 patient years, about a 17- fold change (Boven, Knight et al.
2005). This observation was important because red cell aplasia is a serious adverse event, in
which the precursors to red blood cell formation are lost and the patient receiving the drug is no
longer able to produce red blood cells. The condition was primarily developed by recipients
given the drug by the subcutaneous route employing pre-filled syringes as the drug delivery
device. It was thought to originate from the development of neutralizing antibodies to the
artificial erythropoietin. The neutralizing antibodies then attacked native erythropoeitin as well,
essentially making the recipient allergic not only to the newly introduced drug but also to their
own native hormone. The problem was not seen in Japan, where components in the prefilled

13
syringe were coated with a fluororesin. The problem was eventually corrected by isolating the
uncoated rubber components in the US with a fluoropolymer overcoat, so that leaching of the
vulcanizing reagents was no longer possible. Since conversion from the uncoated to coated
components, the incidence of PRCA was observed to return to baseline for this and similar
products (Boven, Knight et al. 2005).
A second example was that experienced in 2006 by Schwartz Pharmaceuticals, and
forced a recall of the cardiac stimulant drug, Isoket
®
(isosorbate dinitrate). The recall was limited
to product sold in 50 mL vials but not in individual ampoules, after contaminants were detected in
the vials. Investigation by the company suggested that the problem arose from an impurity
extracted from the rubber stopper used on the vial. The impurity in this case was a preservative
common to many polymers, called butylated hydroxytoluene (BHT). The impurity arose when
the company changed from a latex to a chlorobutyl rubber stopper on the vial (Markovic 2009).
Not only can the quality of the drug product be altered by organic molecules leaching
from container closure components; it can also be affected by inorganic constituents in the
container closure as well. Examples include situations in which:
• a divalent metal cation leaching from a rubber stopper activated a metalloprotease and
caused N-terminal degradation of a protein (Markovic 2009).
• a change in the primary closure vendor resulted in barium leaching from the new
container component and subsequently causing the precipitation of barium sulfate into
the solution (Markovic 2009).
• the presence of aluminum and zinc metal ions altered the physical stability and
secondary structure of a derived peptide, from mostly α-helix to a higher β-sheet level
(Christensen, Moeller et al. 2007).

14
• a biological product contained within a pre-filled syringe became oxidized and then
aggregated due to the metal ion tungsten which had leached from the syringe
components (Osterberg 2005).
All of these examples underline the importance of assuring the safety of container closure
systems, especially for situations in which interactions between drug product and container are
relatively intimate such as that where product is suspended or dissolved in a liquid vehicle.
2.2 Evolution of Packaging Regulations
Drug products have been considered to be inherently risky for almost as long as they
have been commercialized. Most countries therefore have laws and regulations to control the
manufacture and sale of drugs and to ensure that marketed drugs have an appropriate balance
between benefit and risk. As a result, basic regulations to manage problems with pharmaceutical
products have been in place well before specific concerns about packaging became a subject of
concern to most pharmacists and regulators. The origin of modern United States (US)
pharmaceutical law dates to the Federal Food, Drug, and Cosmetic Act of 1938 (FDCA) (U.S.C
1938), which, like many laws in the health care sector, was introduced as a reaction to a specific
tragic circumstance. In this case, the tragedy occurred the year before, in 1937, when over 100
people, most of them children, died from the ingestion of diethylene glycol that was used as a
solvent in a newly marketed elixir containing sulfanilamide (Swann (n.d.)). The public was
outraged by the deaths, and also by the failure of the government to ensure the safety of the
product in the first place. The Pure Food and Drug Act of 1906, the legislation in force at the
time, was a relatively weak piece of legislation. It had no provisions to require drug
manufacturers to establish the safety of drugs intended for human consumption; it permitted the
marketing of an unsafe drug as long as the product was honestly labeled and the contents were

15
not adulterated with unlabelled ingredients or filth (Swann (n.d.)). Thus, the FDA could only
order a recall of the drug. Its enforcement capabilities were limited to charging the company with
failure to follow the rules for elixirs, whose official definition required the use of alcohol
(ethanol) as the solvent. In this case, the use of diethylene glycol as a solvent was violative
(Swann (n.d.)). However, the case built awareness that more stringent rules were needed to
prevent similar situations. Thus, when the FDCA was enacted, the FDA acquired broad new
powers to require proof of product safety before marketing, through an explicit submission called
a New Drug Application.
The FDCA was signed into law by President F. D. Roosevelt on June 25, 1938. The Act
both empowered and directed the FDA to establish regulations governing the quality and safety of
drug products marketed in the United States. The FDCA has been amended a number of times
since it original enactment; each amendment has typically increased the authority and the scope
of regulatory oversight applied to drugs by the FDA (Swann (n.d.)).
The FDCA is a fairly high-level document that must be expanded through the enunciation
of specific regulations, which establish the boundaries of required activities and documentation to
prove safety. All of these regulations are found in Title 21 of the Code of Regulations (CFR).
The subset of regulations of particular importance in reference to drug container and closure
systems is found in Part 211 of Title 21 (CFR 2010). This section governs current good
manufacturing practices (cGMP) for finished drugs. The specific regulations dealing with
container closure components of drug products give those components the same status and
requirements for conformance as all other drug product components (see 21 CFR 211.80). More
specifically, as stated in subpart E titled “Control of Drug Product Containers and Closures”:

16
(a) There shall be written procedures describing in sufficient detail the receipt,
identification, storage, handling, sampling, testing, and approval or rejection of
components and drug product containers and closures; such written procedures shall be
followed.
(b) Components and drug product containers and closures shall at all times be handled
and stored in a manner to prevent contamination.
The essence of 21 CFR 211.80 is that the primary container closure, including all of its
components, is an integral part of the drug product and is subject to the same cGMP criteria and
controls as the drug formulation itself.
The regulations further describe basic requirements for the receipt, storage, testing and
approval of drug product containers and closures, and the use of those containers and closures.
However, these regulations tend to be brief; they do not provide specific guidance as to how to
meet the requirements of the specific regulation. As an example, 21 CFR 211.80 General
Requirements, quoted above, identifies the need to have “written procedures describing in
sufficient detail the receipt, identification, storage, handling, sampling, testing and approval or
rejection of components and drug product containers and closures.” Left undefined is the phrase,
“sufficient detail.” The regulatory authorities typically expect that manufacturers will use best
practices but the threshold for best practices is often unclear.
As an aid to pharmaceutical manufacturers, the FDA from time to time issues guidance
documents in an attempt to provide more detail regarding their expectations in a particular area of
concern. The recommendations in these guidance documents typically set the bar for minimal
compliance with the relevant regulations. The guidance documents themselves are not
regulations. They should be considered as non-binding recommendations and thus are not
enforceable. However, it is wise to follow the recommendations or be prepared to justify why
deviation from them is acceptable. As stated on the FDA website
(http://www.fda.gov/RegulatoryInformation? Guidances/default.htm),

17
Guidance documents represent FDA's current thinking on a topic. They do not create or
confer any rights for or on any person and do not operate to bind FDA or the public.
One can use an alternative approach if the approach satisfies the requirements of the
applicable statutes and regulations.
2.3 The Current State of Guidance Documents
It is in the guidance documents that we find the origins of the central problem that is at
the heart of this dissertation. There is, in fact, no single comprehensive guidance document for
the development of container closure systems. Instead, multiple guidance documents exist that
span a time frame of over a decade, and are spread over multiple centers at the FDA. In addition,
there are official compendia as well as regional and international guidance documents that impact
container closure development, particularly those that have been published in order to guide
manufacturers marketing in other countries, as described in more detail below. In addition, the
International Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH), a consortium between the US, the European Union (EU),
and Japan, has been particularly active in the promulgation of guidance documents that have
some elements useful for container closure development.
Principal Guidance Documents
The manufacturer who is initiating a program to assure the quality of its container closure
systems has an array of governmental and quasi-governmental literature to consult. Table 1 lists
the most significant regulatory guidance documents from the ICH, FDA, European Medicines
Agency (EMA), and Health Care Canada. These regulatory guidance documents in fact govern
pharmaceutical development for container closures across most of the world, because many
countries harmonize their expectations with either FDA or EMA guidelines.

18
Table 1: Comparison of FDA, EMA, and ICH Guidances for Container Closures
FDA/ICH Guidances
1
EMA/ICH Guidances
2

Q8(R2) Pharmaceutical Development (2009) Q8(R2) Pharmaceutical Development (2009)
Guidance for Industry Bioavailability and
Bioequivalence for Nasal Aerosols and Nasal
Sprays for Local Action (Draft
3
, 2003)

Metered Dose Inhaler (MDI) and Dry Powder
Inhaler (DPI) Drug Products (Draft
3
, 1998)
EMEA/CHMP/QWP/49313/20005 Guideline on
the Pharmaceutical Quality of Inhalation and
Nasal Products (2006)

(Also, Pharmaceutical Quality of Inhalation and
Nasal Products (2006) HC Canada 06-106624-
547, harmonized with EMA)
Appendices A and C of
Guidance for Industry Container Closure
Systems for Packaging Human Drugs and
Biologics (1999)
CPMP/QWP/4359/03/EMEA/CVMP/205/04
Guideline on Plastic Immediate Packaging
Materials (2005)
Q1A(R2) Guidance for Industry Q1A(R2)
Stability Testing: New Drug Substances and
Products (2003)
Q1A(R2) Guidance for Industry Q1A(R2)
Stability Testing: New Drug Substances and
Products (2003)
Q6A Guidance on Q6A: Specifications, Test
Procedures and Acceptance Criteria for New
Drug Substances and New Drug Products:
Chemical Substances (2000)
Q6A Guidance on Q6A: Specifications, Test
Procedures and Acceptance Criteria for New
Drug Substances and New Drug Products:
Chemical Substances (2000)
Guidance for Industry Container Closure
Systems for Packaging Human Drugs and
Biologics (1999)

Q1B Guidance for Industry: Photostability
Testing of New Drug Substances and Products
(1996)
Q1B Guidance for Industry: Photostability
Testing of New Drug Substances and Products
(1996)
1 http://www.fda.gov/RegulatoryInformation?Guidances/default.htm
2 http://www.ema.europa.eu.ema/index.jsp
3 Draft guidances are not final and official; however, they are often used as references for
compliance purposes.

19
The international consensus documents developed by the ICH are also important because they
have a significant impact beyond just the US, EU, and Japan, the countries primarily responsible
for creating the documents. However, merely listing these guidance documents is not enough to
become knowledgeable about their impact on container closure development for two reasons.
First, the documents can be surprisingly redundant, yet still contain elements or recommendations
that diverge and are not immediately apparent without close reading. Second, the format and
flow of different documents may vary in ways that reflect regional differences in style, so that
comparisons are further challenging. For example, the EMA guidance “Guideline on the
Pharmaceutical Quality of Inhalation and Nasal Products” in Table 1 has been harmonized with
the HealthCare Canada guidance, “Pharmaceutical Quality of Inhalation and Nasal Products,” so
that the technical content of these two guidance documents is almost completely the same.
However, the two documents differ in format, so that the similarities in the content can only be
recognized after both documents have been read carefully.
To assist the reader in appreciating which guidance documents contain equivalent or
overlapping information, Table 1 is organized to align related guidance documents from different
sources on opposing sides of the table. The harmonized ICH guidance documents [Q1A(R2),
Q6A, and Q8(R2)] are of course the same for both the FDA and the EMA, who were both parties
to their creation. However, non-harmonized, non-ICH guidance documents can differ in some
respects, and this often can be attributed, at least in part, to a difference in the timing of the
documents. The EMA has typically lagged the FDA in its publication of a comparable guidance
document by three to eight years. Thus one might expect the later document to reflect some
maturation in thinking. Also, regional differences exist related to the specifics of content in US
versus EU documents; some topics that are covered by the FDA are not covered by the EMA,
while others are covered by EMA but not the FDA. However, any drug product intended to be

20
marketed globally must be compliant with both FDA and EMA regulations. Thus, the sponsor of
a globally marketed drug must pursue a container closure development paradigm that respects the
recommendations of both the FDA and EMA, as well as ICH documents on which the
governments rely heavily.
Table 2 lists guidance and compendial information from the Japanese Ministry of Health,
Labor and Welfare (MHLW), and its administrative agency, the Pharmaceuticals and Medical
Device Agency (PMDA), as well as the English version of the fifteenth edition of the Japanese
Pharmacopeia (JPXV) (JPXV 2006).
Table 2: Japanese Container Closure Regulatory Information
Source Title
Pharmaceutical and Medical Device
Agency, 2006
Points to be Considered by the Review Staff Involved in
the evaluation of New Drug (FINAL), April 17, 2008
Japanese Pharmacopeia, 2006 7. Tests for Containers and Packing Materials
Japanese Pharmacopeia, 2006 17. Plastics Containers for Pharmaceutical Products

The amount of guidance related to container closure information from these sources is
sparse in comparison to that available from comparable US and EMA sources. As an example,
the information in “Points to be Considered by the Review Staff Involved in the Evaluation of
New Drug (FINAL), April 17, 2008” (PMDA 2008) outlines very general recommendations for
the content of a new drug marketing application. The emphasis of this document is on the clinical
information to be included in the application. No specific reference is made to requirements for
the primary container closure system. The corresponding US documents are the FDA guidances
where the details of FDA expectations are listed and described. The volume of information from

21
the US FDA compared to the PMDA is advantageous to the drug product sponsor where the less
coherent organization of this information makes it difficult to use the references with confidence.
Content of Key Guidance Documents
In the US, the principal guidance document describing expectations for container and
closure systems is that written in 1999, titled “Container Closure Systems for Packaging Human
Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation” (FDA 1999).
This 56 page document has several purposes. It provides working definitions of different aspects
of container closure systems. It identifies the relevant laws that impact container closure systems,
and it explains how container closure systems are to be documented in submissions to the FDA as
part of investigational and drug marketing applications. However, its most important role is
perhaps to describe in detail what the agency considers to be an appropriate approach to the
evaluation, testing and acceptance of container closure systems. An important concept introduced
in this document is that of “degree of concern.” It identifies that inhalation aerosols and
solutions, injections and injectable suspensions have the highest degree of concern because of the
intimate relationship between the formulation and the container, and because any contaminants
that might be present in the products are introduced directly into the body without the filter of a
dermal or mucosal skin layer to moderate the exposure of the body to the potentially injurious
contaminants. The document then describes general considerations that underlie testing. Key is
the suitability of the packaging for its intended use, including considerations of protection,
compatibility, safety and performance capabilities. In general, the guidance is kept flexible as
reflected in an early introductory statement and later, more specific statements related to
container closure safety, perhaps the most detailed section of the guidance document (FDA
1999):

22
In general, this guidance does not suggest specific test methods and acceptance criteria
(except for references to The United States Pharmacopia methods), nor does it suggest
comprehensive lists of tests. These details should be determined based on good scientific
principles for each specific container closure system for particular drug product
formulations, dosage forms, and routes of administration. …Making the determination
that a material of construction used in the manufacture of a packaging component is safe
for its intended use is not a simple process, and a standardized approach has not been
established.
As mentioned earlier, the guidance document is intended to provide a roadmap to explain
key elements of testing and thought that must accompany certain key submissions, particularly
new drug submissions (NDA) or biologic licensing applications (BLA) that are sent to the
regulatory agency as a pre-condition for marketing approval. However, it also highlights
situations in which changes in container closure systems may trigger a problem and specifies
when changes must be reported to the FDA in subsequent stages of the product life cycle. Thus
some of the most useful information comes as a result of specific instructions on what
information should be provided to FDA, because in that information are the core elements
considered as basic requirements for container closure description and testing. Testing
requirements appear to rely principally on USP testing methods that will be described in more
detail below. The document indicates that where it seems useful or necessary to use tests other
than those identified by the USP, such other tests do not normally stand in for standard USP tests.
For example, in reference to testing to demonstrate the barrier properties of the packaging, the
document states:
Testing for properties other than those described in USP (e.g., gas transmission, solvent
leakage container integrity) may also be necessary…. For non-USP tests, an applicant
should provide justification for the use of the test, a complete and detailed description of
how the test was performed, and an explanation of what the test is intended to establish.
If a related USP test is available, comparative data should be provided using both
methods. (FDA 1999)

23
Two areas that also provide a useful degree of specificity are 1) descriptions of required
information and testing to be provided from vendors of packaging materials and 2) the role of
stability studies in detecting any sign of packaging issues. The document then directs the
attention of the reader to a more specific guidance titled “Stability Testing of Drug Substance and
Drug Products” (ICH 2003) that was still in draft form at the time when the guidance document
was published. In addition, for nasal sprays and oral inhalation products, the reader is also
referred to guidance documents that were at the time of publication only under development.
These were the Guidance for Industry “Metered Dose Inhaler (MDI) and Dry Powder Inhaler
(DPI) Drug Products; Chemistry, Manufacturing and Controls Documentation” (FDA 1998) and
the Guidance for Industry “Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
Products; Chemistry, Manufacturing and Controls Documentation” (FDA 1998). Thus, this
master guidance document in part relies on further guidance documents to provide specificity.
Perhaps the most useful part of this guidance are the tables provided to illustrate for particular
dosage forms how the manufacturer should proceed with regard to a testing strategy. Two of
those tables are replicated in Figure 1 and Figure 2 because these particular tables describe
requirements as of 1999 in the areas in which this dissertation research is most focused, that of
injectable and other liquid drug products. Codes to understanding Figure 2 are listed in Figure 3.

24
Figure 1: Explanation of “degree of concern” concept enunciated by FDA with respect to
packaging materials. Reproduced from Guidance for Industry: Container
Closure Systems for Packing Human Drugs and Biologics (FDA 1999).

25
Figure 2: Table from FDA guidance to show the level of detail suggested for package
testing. Reproduced from Guidance for Industry: Container Closure Systems
for Packing Human Drugs and Biologics (FDA 1999).

26
Figure 3: Explanation of short-forms in Table 2. From Guidance for Industry: Container
Closure Systems for Packing Human Drugs and Biologics (FDA 1999).

27
A small number of later guidance documents published subsequently by FDA deal with
more specific issues related to container closure development, and are often quite focused in their
subject matter. As an example, the “Guidance for Industry: Bioavailability and Bioequivalence
for Nasal Aerosols and Nasal Sprays for Local Action” (FDA 2003) deals only with aspects of the
requirements for the drug products and container closure systems associated with the subject
matter of the title.
The EMA has similar guidance documents that parallel FDA guidance documents in
terms of subject matter. There are differences in the format of the documents from the two
regions, and there are some differences in content, but the thrust of the EMA documents, like the
FDA documents, is the importance of establishing “suitability for the purpose” when considering
the container closure systems.
Content of ICH guidelines
The ICH guidance documents are quite different from those of regulatory agencies, in
that they contain supplementary information. This additional information is sometimes
incorporated into the FDA and EMA regulatory guidance documents by reference, when the
regulatory guidance postdates the ICH guidance. However, in circumstances where the ICH
guidance postdates the earlier regulatory guidance, as it typically had done in the US, it is up to
the drug product sponsor to assure that the requirements of both regulatory and ICH guidance
documents are met. Therefore, the situation that exists is one in which the FDA and the EMA
each have its own set of guidance documents, and both typically refer to the ICH guidance
documents when possible. As a consequence, there is considerable alignment between the FDA
and the EMA. This alignment suggests that a common container closure developmental paradigm
can be established that would satisfy all global regulatory bodies. If the most stringent

28
requirements from all sources were to be delineated, the final compilation would likely meet or
exceed regulatory requirements of all of the regulatory agencies independent of regional
variations.
Role of the Pharmacopeia
In addition to governmental bodies and international standard-setting organizations, many
industrially developed countries have a Pharmacopeia, which can be either a non-governmental or
governmental document. Whatever its association the Pharmacopeia is nevertheless an officially
authorized compendium drawn from volunteer experts that set standards for testing and other
forms of standardized evaluation. Their standards are generally accepted to set the bar for certain
types of product testing in the country in which the Pharmacopeia is developed. This can lead to
some challenges, because different national organizations can have different standards that are
not harmonized. Thus testing of products to be sold multi-nationally may have to be repeated
using different methodologies if different testing standards are called out by different
constituencies, and this can lead to substantial added expense and time. However, all of these
organizations, the best known of which are the United States Pharmacopeia (USP), the Japanese
Pharmacopeia (JP) and the European Pharmacopeia (Ph Eur or EP), have been unusually
important players in the development of test methods required for some container closure
evaluations. This is reflected in comments made in the FDA container closure guidance
document (FDA 1999) that extensively references the USP (USP 2011) (see also Tables above):
In general, this guidance does not suggest specific test methods and acceptance criteria
(except for references to The United States Pharmacopia methods), nor does it suggest
comprehensive lists of tests:…The United States Pharmacopeial Convention has
established requirements for containers which are described in many of the drug product
monographs in The United States Pharmacopeia/National Formulary (USP/NF). For
capsules and tablets, these requirements generally relate to the design characteristics of
the container (e.g., tight, well-closed or light-resistant). For injectable products,
materials of construction are also addressed (e.g., "Preserve in single-dose or in

29
multiple-dose containers, preferably of Type I glass, protected from light"). These
requirements are defined in the "General Notices and Requirements" (Preservation,
Packaging, Storage, and Labeling) section of the USP. The requirements for materials of
construction are defined in the "General Chapters" of the USP (see Attachment A).
Some of the compendial standards considered to be central for the testing of container
closure systems in the US are shown in Table 3. Table 3 lists as well as compares compendial
information related to container closures from both the USP (USP 2011) and the Ph Eur (EP
2010). An attempt has been made to match the corresponding USP chapter to the appropriate Ph
Eur chapter of the same topic. In doing so, it is quite apparent that Table 3 illustrates the
substantial lack of harmonization between the USP and the Ph Eur. However, it should not be
assumed that corresponding chapters of the USP and Ph Eur as listed in Table 3 are the same in
content or requirements, as USP and Ph Eur requirements on the same topic are often different to
some degree. Also, only chapters that concern pharmaceutical containers have been included.
Chapters that do not deal directly with pharmaceutical containers, such as those on
microbiological testing and transfusion and infusion sets, have not been specifically excluded
from Table 3. The lack of harmonization between the USP and Ph Eur requirements for container
closure system qualification substantially increases the burden on the pharmaceutical industry
when developing a pharmaceutical product intended for global distribution.
The JPXV (JP Fifteenth Edition) Chapters 7 and 17 (JPXV 2006) are largely the same as
the corresponding chapters in the USP (USP 2011) and Ph Eur (EP 2010). Table 4 lists a
comparison between the Japanese documents described in Table 3 with the corresponding
regulatory and compendia documents from Tables 1 and 2. As can be seen from Table 4, the
Japanese requirements are a subset of FDA/USP and EMA/Ph Eur requirements. Since the
FDA/USP and EMA/Ph Eur requirements are both more extensive and more detailed, the

30
synthesis of information for the purposes of this dissertation will concentrate on the FDA/USP
and EMEA/Ph Eur source documents to be found in Tables 1 and 3.
Table 3: Summary of Compendial Sources of Container Closure Information
USP
1
USP Title
3
Ph Eur
2
Ph Eur Title
3

General
Notices
10.
PRESERVATION,
PACKAGING, STORAGE,
AND LABELING

<1> Injections
<87> Biological Reactivity Tests,
In Vitro

<88> Biological Reactivity Tests,
In Vivo

<381> Elastomeric Closures for
Injection
3.1.9
3.2.9
Silicone elastomer for closures and tubing
Rubber closures for containers for aqueous
parenteral preparations for powders and for
freeze dried powders
<601> Aerosols
<660> Containers - Glass 3.2.1 Glass containers for pharmaceutical use
<661> Containers – Plastics 3.1.3
3.1.4

3.1.5

3.1.6

3.1.7

3.1.15

3.2.2

3.2.2.1

3.2.8
Polyolefins
Polyethylene without additives for containers
for parenteral preparations and for ophthalmic
preparations
Polyethylene with additives for containers for
parenteral preparations and for ophthalmic
preparations
Polypropylene for containers for parenteral
preparations and for ophthalmic preparations
Polyethylene –vinyl acetate for containers and
tubing for total parenteral nutrition
preparations
Polyethylene terephthalate for containers for
preparations not for parenteral use
Plastic containers and closures for
pharmaceutical use
Plastic containers for aqueous solutions for
infusion
Sterile single-use plastic syringes

31
Table 3: Summary of Compendial Sources of Container Closure Information (continued)
USP
1
USP Title
3
Ph Eur
2
Ph Eur Title
3

<671> Containers – Performance
Testing

<771> Ophthalmic Ointments
<1031> The Biocompatibility of
Materials Used in Drug
Containers, Medical Devices,
and Implants

<1136> Packaging – Unit-of-Use
<1041> Biologics
<1079> Good Storage and Shipping
Practices

<1151> Pharmaceutical Dosage
Forms

<1207> Sterile Product Packaging –
Integrity Evaluation

3.1.8 Silicon oil used as a lubricant
3.1.10 Materials based on non-plasticised polyvinyl
chloride for containers for non-injectable
aqueous solutions
3.1.11 Materials based on non-plasticised polyvinyl
chloride for containers for dry dosage forms
for oral administration
3.1.13 Plastics additives
1 United States Pharmacopeia, 2011.
2 European Pharmacopeia, 2010.
3. Note that non pharmaceutical container closure chapters have been omitted.

32
Table 4: JPXV Chapters and their Corresponding USP and Ph Eur Chapters
JPXV
1
USP
2
Ph Eur
3

7.01 Test for Glass Containers
and Packing Materials
<660> Containers - Glass 3.2.1 Glass containers for
pharmaceutical use
7.02 Test Methods for Plastic
Containers
<661> Containers - Plastics 3.2.2 Plastic containers and
closures for pharmaceutical use
7.03 Test for Rubber Closure for
Aqueous Infusions
<381> Elastomeric Closures for
Injections
3.2.2.1 Plastic containers for
aqueous solutions for infusion
17. Plastics Containers for
Pharmaceutical Products
<661> Containers - Plastics 3.2.2 Plastic containers and
closures for pharmaceutical use
1 Japanese Pharmacopeia XV, 2006 (JPXV 2006)
2 United States Pharmacopeia, 2009 (USP 2011)
3 European Pharmacopeia, 2010 (EP 2010)

Concerns about Regulatory Guidance
From the attention that had been given to packaging quality and safety by the regulatory
and standards-setting bodies, one might be led to believe that sufficient information should be
available to permit manufacturers to formulate a testing plan appropriate for regulatory approval
from just this information. However, as early as 2000, a level of dissatisfaction appeared to be
detectable with the amount and specificity of guidance provided by these sources in certain areas
of concern. Further, many of these concerns were not addressed in the later ICH guidance
materials published in 2003. A survey of all of the diverse areas in which concern has been
expressed, e.g., standards for testing cotton and rayon fillers found in USP <691> or the adequacy
of testing procedures for testing moisture vapor transmission rates found in USP <671> (USP
2011), is beyond the scope of this dissertation. However, the area that is arguably of greatest and
most serious concern is that which has been associated with the most serious safety problems,

33
outlined earlier in this literature review. It is the concern about contamination by extractables and
leachables of drug products that are introduced rapidly and without hope of retrieval into
vulnerable body areas such as the lungs or vascular system (products at Level of Concern III).
The management of extractables and leachables is commonly identified as one of the
most problematic issues facing those who must validate the quality and safety of packaging. As
defined by Yu and colleagues (Yu, DeCou et al. 2010),
Extractables are compounds that can be extracted from source materials using
appropriate solvents under vigorous laboratory conditions. Leachables are compounds
present in drug products caused by leaching from container, closure, or processing
components. Therefore, leachables can be considered a subset of extractables.
A strong understanding of the extractable and leachable profile of the pharmaceutical
container closure systems is central to assuring the safety of injectable and inhaled drugs. The
FDA guidance documents in 1999 (FDA 1999) were seen to be a major step forward to organize
thinking about this important issue, but the guidance document was regarded as lacking in detail.
Further, inspection of the guidance document, with its emphasis on USP methods to satisfy
certain testing requirements, might lead the reader to expect that regulatory requirements could be
satisfied by standard compendial analyses, but this has proven not to be the case. The listed
compendial methods have been criticized as being outdated and insufficient for current needs
(DeGrazio 2009). Further they do not cover all of the areas in which testing is considered to be
useful. The introduction of ICH guidance, “Impurities in New Drug Products” (ICH 2006)
further elaborated on useful ways to think about contaminants in drug products, but this guidance
was focused primarily on drug substance degradation products rather than testing of extractables
and leachables. This could potentially be a serious problem because “characterization and control
of leachables and extractables represents possibly the most significant challenge facing a

34
pharmaceutical development team…detecting, identifying, and qualifying organic leachables is a
formidable task” (Northup 2008).
2.4 Recent Initiatives to Improve Extractables/Leachables Testing
In an attempt to assist regulators and manufacturers, two groups of experts, the
International Pharmaceutical Aerosol Consortium (IPAC) and the AAPS Inhalation Technology
Review Group (ITFG), decided to work together to identify and clarify approaches to certain
central concerns regarding the testing and risk prioritization of extractables and leachables. In
2001, they submitted a “Points to Consider” document to FDA (DeGrazio 2003). This document
identified two important goals. First, it highlighted the need to expand and consolidate testing
requirements for extractables and leachables. Second, it called for the development of
“reporting” and “qualification” thresholds for contaminants that would divide such materials into
actionable and non-actionable categories. This second recommendation was seen to be critical
because some types of packaging materials can leach many compounds - elements such as
plasticizers, antioxidants and accelerators - in very tiny amounts, and rules were needed to focus
experimental efforts on those compounds that were present in significant amounts or had
bioreactive profiles known or suggested to pose a safety concern.
The report of this committee was advanced to the FDA. From this interaction came a
new initiative to develop data and recommendations to improve the characterization of
extractables and leachables using a more science-based paradigm. A new group was formed
within the Product Quality Research Institute (PQRI) that had as its aim the development of
scientifically-based thresholds that would signal the need to report and further test particular
types of leachables and extractables. The group focused particularly on the safety of extractables
and leachables in inhaled drug products. It conducted an extensive series of bench tests and

35
studied the precedent experience in other agencies such as the Center for Food Safety and
Nutrition and the Environmental Protection Agency to produce its recommendations. The work
culminated in a 2006 document titled: “Safety Thresholds and Best Practices for Extractables and
Leachables in Orally Inhaled and Nasal Drug Products” (PQRI 2006). In the document the
working group recommended that a “Safety Concern Threshold” (SCT) be established for organic
leachable compounds, and its value be set at 0.15 micrograms/day based on toxicological
assessments of leachable chemical classes. This level is a threshold below which leachable
contaminants would present essentially no threat for the development of cancer or other safety
issues. They also proposed an actionable level of contamination called the Qualification
Threshold (QT) set at 5 micrograms/day. A detailed discussion of this 271-page document is
beyond the scope of this literature review. For good summaries of this position paper, the reader
is referred to Ball and colleagues (2007) and Norwood and colleagues (2007). What is important
for here is that this extensive analysis provided a clear set of rules by which manufacturers could
triage the data coming from analytic studies of extractables and leachables.
The document produced by PQRI was limited in its scope to nasal and orally-inhaled
products, but its impact was great. First, it provided the first attempt to frame a systematic
quantitative approach to extractables and leachables testing based on scientific principles.
Second, it set the stage for what is anticipated to be other public-private partnerships to conduct
similar analyses into related areas. In 2008, a second Working Group in PQRI was formed to
extend this work into the study of safety and analytical thresholds and best practices for injectable
and parenteral drugs, as well as ophthalmic drugs. The schedule published by PQRI for this
project called for results to be released in the second quarter of 2010
(http://www.pqri.org/commworking/minutes/pdfs/dptc/podpwg/Addl/podp_work_plan_schedule.
pdf). The PQRI has now issued a draft report of the results of its study. The draft report and

36
supporting information were made public at a conference held by the PQRI in February of 2011
in Bethesda, Maryland (PQRI 2011).
The documents produced by the PQRI have far-reaching implications for the oversight
and management of extractable and leachable testing, some of which are only now becoming
apparent. Most individuals who deal with this type of packaging validation are scientists whose
peer-reviewed papers are usually focused on the particulars of analytic methods or case studies of
particular scenarios. Normally such papers would not be expected (or encouraged by journal
editors) to deal with policy implications or personal opinions regarding the state of the art.
However, in this instance, several indications of confusion and even dissatisfaction can be
detected in the peer-reviewed and trade literature regarding the current best practices that should
be adopted with regard to extractables and leachables. Some of the confusion seems to center on
unanticipated regulatory requests for new data after the submission of a new drug application
using methods not identified in compendial references (Gurley 2008). Some questions also exist
about the “changing goalposts” for testing, particularly outside of the scope of the types of
products subjected to study in the available reports. As stated by Norwood (Norwood, Paskiet et
al. 2008), “the PQRI thresholds and qualification process were developed with FDA regulatory
support and are expected to be used in pharmaceutical development programs and by regulators
assessing drug applications.”
What is not clear is when and how these requirements will be introduced as regulatory
expectations, whether new regulations will fully embrace the recommendations of the PQRI
report, and to what extent the recommendations will be applied as “soft law” in other areas of
drug CMC validation beyond that for nasal and orally inhaled products. Uncertainty is to some
degree fueled because the FDA has already begun to extend its use of the PQRI report as part of
its review process and recommendations to sponsors for products outside of the scope of the

37
original intended area of inhalation and nasal spray drug products (Norwood, 2010). This leaves
several questions about the current approaches and concerns of companies trying to design
strategies to source, approve and validate packaging for other types of products such as
injectables, ophthalmic products and disposable materials used in bioprocessing (Gurley 2008;
Northup 2008; Yu, Wood et al. 2008; DeGrazio 2009).
Thus the central question can be stated: “What are the current requirements and
standards for extractable and leachable testing, in the absence of regulatory guidance since
1999?” Those original regulatory guidances instructed the sponsor to conduct extractable and
leachable studies, and they make reference to the relevant compendial chapters for details on
methods for such work as it relates to extractables, but not leachables. The compendial chapters
that consider methods to extract compounds from containers and closures discuss how to do these
studies, but do not reference regulatory requirements. More information on extractable studies
and detailed information on leachable studies can only be found in the literature outside
regulatory guidances and compendial references. To understand the full requirements for testing
extractables and leachables, the sponsor must have detailed knowledge of the regulatory guidance
documents, all relevant compendial information, and both the peer reviewed and non-peer
reviewed literature including the PQRI recommendations. Only then is it possible to understand
all of the requirements for extractables and leachables. In addition, at this point, meetings with
FDA may be needed to ensure that the testing strategy will be acceptable at the future time when
the drug marketing application is submitted.
2.5 Synthesis of the Literature
It is clear from a review of the relevant literature that there are two major sources of
information for container closure development. These two sources are:

38
• regulatory guidances and associated compendial requirements,
• peer and non-peer reviewed literature and industry generated recommendations.
It is also clear that these two major sources of information have significant differences in
perspective. Regulatory guidances and compendial requirements emphasize what to do, but not
how to do it in any systematic way. Where there is compendial information on how to do a
particular task, detail is often lacking. This leaves the sponsor with some level of insecurity
regarding whether the procedures or approaches that they have chosen might satisfy regulatory
requirements. These concerns are to some degree justified. For example, DeGrazio (2010)
identified a case in which a company changed its delivery system from a glass vial with a
bromobutyl stopper to a prefilled syringe with the same bromobutyl material used for the syringe
plunger. As stated by DeGrazio in an earlier paper (DeGrazio 2009), “the drug company had
assumed that since the elastomeric formulation was the same for both….the limited leachables
work they had completed would be acceptable.” As they found out, this was not the case.”
Part of the reason why this was thought to occur was the fact that CMC reviewers with
experience in nasal and inhalation products (where, as stated above, the PQRI recommendations
have become to some extent accepted), began to have the same level of expectation for injectable
drugs, even though similar standards for injectable drugs have not been promulgated. A situation
with this kind of fluid expectation is unsettling for a manufacturer, for whom transparent
regulatory expectations are helpful in clarifying the developmental path forward.
On the other hand, the related literature and particularly the industry-stimulated reports of
the PQRI are more focused on providing clear and workable tools by which regulatory clarity can
be increased. The working groups participating in the effort are at this point still at relatively
early stages of defining what they regard as best practices. Thus it is not clear whether the

39
information that is available to the manufacturers in general, and to the scientists responsible for
container closure validation in particular, is adequate for their needs. It is not know on balance
whether companies are satisfied with the information that is now available, and with the way that
it is being integrated into regulatory expectations. We also do not know whether scientists have
particular needs that are not currently being addressed by the initiatives that are emanating from
both regulatory agencies and industry. The survey research outlined in this dissertation is
intended to provide more insight into current thinking about the regulations and expectations for
extractables and leachables testing in the context of drug development and commercialization.
Such insight may help to clarify where additional information is needed and how such
information should be integrated into the research framework.

40
Chapter 3: Methodology
3.1 Introduction
Overview
The present exploratory study was directed at probing the views of packaging scientists,
particularly in the parenteral and ophthalmic sectors of industry, with regard to current
approaches for container closure development. A survey instrument was developed to gather
information on industry practices and views (see Appendix 1). It was then improved through the
review of two groups. One group was comprised by the members of the Packaging Science
Interest Group (PSIG) of the Parenteral Drug Association (PDA), who attended the Spring 2010
PDA annual meeting. The second group was comprised by the Scientific Advisory Board (SAB)
of the PDA. The survey was then distributed to the packaging scientists who comprise the full
membership of the PSIG. To facilitate this process, the PDA formally agreed to sponsor and send
the instrument to its membership. A summary of its results was promised to participants who
took the survey.
Development of the Survey Instrument
The purpose of the survey developed in this research was to determine current practices
in container closure validation, especially in the area of extractables and leachables testing. It
further probed the level of satisfaction expressed by packaging scientists with the current
regulatory guidance available for extractables and leachables. The survey was developed and
deployed using the web-based survey tool, SurveyMonkey, which is the preferred web-based
survey tool of the PDA. Questions initially developed by the investigator were discussed with a

41
small cadre of academic and industry associates and then circulated to the Packaging Science
Interest Group for its comments, as described above.
3.2 Preliminary Survey Reviews
PDA Packaging Science Interest Group (PSIG)
The survey was described in a ten minute, PowerPoint presentation to the members of the
PDA who attended the PSIG meeting at the PDA annual meeting in March of 2010. The
discussion that followed was recorded by long-hand capture and the participants were invited to
provide follow-up input regarding the survey after the survey in draft form was distributed to
them at the conference.
PDA Scientific Advisory Board (SAB)
Because the survey was sponsored by the PDA, it was not only desirable to obtain their
feedback but was necessary to submit the survey to the SAB for review. Thus, the revised survey
was discussed at a second, more systematically constructed forum that considered the initial
revisions suggested by the initial review of the Packaging Science Interest Group. The PDA’s
SAB is composed of scientists who direct the scientific and regulatory activities of the PDA.
From the PDA website (http://www.pda.org/Science-and-Regulatory-Affairs/SAB.aspx).
The SAB establishes the strategic direction and provides oversight for PDA's scientific
and technical activities through the development of guidelines, technical reports, and
technical bulletins and recommendations of other activities such as conferences or
training courses.
The survey featured a range of question types as shown in Appendix 1, and included
questions that identify the experience of the survey participant. The SAB recommended several
changes to these questions in order to improve the clarity or the survey, and thus acted as a “de

42
facto” review group for the survey (Foote 2011). The outcome of the review was captured in
notes by the investigator, and then the survey was revised to address the suggestions of the SAB.
3.3 Sample and Population
The PSIG of the PDA was selected as the sample population for this survey. The choice
was made after the author investigated subgroups within the major pharmaceutical professional
associations such as the PDA, the American Association of Pharmaceutical Scientists, the Drug
Information Association, and the Regulatory Affairs Professionals Society. At the time that
research began on this dissertation, the author found the only group devoted to pharmaceutical
packaging to be the PSIG within the PDA. The PSIG is composed of scientists and engineers
who devote their time to packaging science, and more specifically, to the selection and
qualification of materials for pharmaceutical packing uses. Thus the concept of the survey was
presented to a meeting of the PSIG held at the annual meeting of the PDA in Orlando, Florida on
March 15, 2010. The concept of the survey was well received at the meeting, and it was decided
to prepare such a survey for the membership of the PSIG.
3.4 Data Collection and Analysis
A web-based survey link was sent by email to the participants in the PSIG of the PDA.
Initiation of the survey via email through the PDA was made with the generous help of Iris Rice,
Manager, S&RA Department at PDA. Responses were logged and printed for storage and
security purposes. Questions of yes/no or multiple choice formats were graphed and analyzed to
determine the major trends in the topic areas covered by the survey. Questions that solicited
open-ended responses were examined for information content and were used to supplement or
clarify responses in the multiple choice answers. Information regarding the number of

43
individuals to whom the email was sent was compared to the number of returned surveys to
estimate the response rate. After data were analyzed, they were presented to the meeting of the
PSIG held in conjunction with the 2011 PDA/FDA Joint Regulatory Conference meeting
September 19 to 23, Washington, D.C. The report will be redrafted in a manuscript for potential
publication in the PDA Journal of Pharmaceutical Science and Technology after the dissertation
process is complete.

44
Chapter 4: Results
4.1 Survey Review, Validation and Distribution
An initial draft of the survey was reviewed by Edward Smith, Ph.D., chairman of the
PSIG. Through Dr. Smith’s efforts, the PDA agreed to sponsor the survey, and distribute it using
a web-based survey tool. The two opportunities to revise the survey through the review groups
configured through the PDA resulted in several suggestions for changes to questions. Most
changes were editorial in nature to improve the wording of a few of the questions in order to
improve their clarity. However, the review groups also suggested the deletion of a few questions
that were unrelated to the topic of extractables and leachables, because of concerns that the
survey might become overly long and might lack sufficient review on key questions. However,
neither review group identified substantive changes to the survey direction or to its principal areas
of inquiry.
The survey was distributed twice by the PDA using SurveyMonkey. The first survey
was sent on March 25, 2011 and closed on April 7, 2011. The responses numbered only 16. A
presentation of preliminary data was made to the PSIG at the annual PDA meeting in San
Antonio, Texas, on April 11, 2011. At the meeting, the help of the PSIG was solicited to improve
the response numbers. The same survey was again sent out on June 8
th
, with a closing date of
July 15
th
, 2011. Members of the PSIG were instructed to refrain from completing the second
round of the survey if they had participated in the first round. The second round of surveys
resulted in an additional 30 responses, for a total of 46 responses to the survey (see Appendix 2
for the consolidated results of the two rounds of the survey).

45
4.2 Analysis of Survey Results
The PSIG distribution list for the surveys totaled 361 individuals. In addition, the author
distributed the survey link to an additional 20 individuals known to the author to be involved in
packaging science but not present on the PSIG distribution list. The author was blinded to the
identity of the respondents. Of 381 survey links distributed, 46 responses were received,
representing a 12.1% response rate. Results from the surveys are described below, grouped by
subject area. Note that a few respondents did not answer all questions. The numbers of
responses to individual questions ranged from 35 to 46 out of a total of 46 responses.
Background of Survey Respondents
As shown in Figure 4, 39/46 (85%) of respondents indicated a career review in
pharmaceutical products, 34/46 (74%) in biological products, 16/46 (35%) in medical devices,
and 3 each of 46 (6.5%) in food and cosmetics. The number of identified career foci (85)
exceeded the total number of responses (46) because some respondents identified more than one
career review.

46
Figure 4: Question 1: Do you consult for/manufacture/market products in a field that the
FDA regulates? Check all that apply.

Forty-three of 46 respondents answered Question 2 (Figure 5). Of the responses, 21/43
(49%) did not work with devices, while 10/43 (23%) worked with Class I devices, 19/43 (44%)
worked with Class II devices, and 8/43 (19%) worked with Class III devices.
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
Pharmaceuticals
Biologicals
Devices
Cosmetics
Food
I do not work in
any of these
fields

47
Figure 5: Question 2: If you deal with devices, please indicate which class(es) of devices
that you market. Check all that apply.

Forty-six of 46 (100%) respondents indicated that they worked with some form of
pharmaceutical product (Question 3, see Figure 6). Almost all, 45/46 (97%) of respondents, had
experience with parenteral and injectable product packaging, as expected given the association of
the respondents with the PDA. In addition, 11/46 (23%) worked with ophthalmic product
packaging, 11/46 (23%) worked with packaging for solid dosage-form drugs, 9/46 (20%) worked
with packaging for topical drugs, and 6/46 (13%) worked with packaging for inhalation/nasal
sprays. Eighty-two self-identifications were made across the 46 respondents, indicating that the
respondents worked with more than one product line.

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Class I Class II Class III I do not deal with
devices

48
Figure 6: Question 3: If you deal with pharmaceutical products, please identify which
types of primary container closure systems that you use. The primary container
closure is that part of the container closure and any associated packaging that
has direct physical contact with the drug product. Check all that apply.

Primary Container Closure Qualification
In this survey, questions 4 through 8 attempted to identify basic practices of respondents
with regard to container closure qualification, including stability studies, integrity versus sterility
testing, moisture barrier studies, studies of the adsorption of the drug product to the primary
container closure, and studies on the justification of use of materials for the primary container
closure.
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
120.0%

49
Stability Studies
ICH Q1A(R2) (ICH 2003) recommends that all primary and commercial stability studies
be conducted in the primary container closure intended for the marketed product. When queried
about their current practices with respect to such studies (Question 4, Figure 7), all
46 respondents provided a response, but 9/46 (20%) of those respondents indicated that they
could not answer the question. Of the remaining respondents, 31/46 (67%) indicated that they
always conduct stability studies in the proposed container closure for the marketed product, 4/46
(9%) indicated that they usually conduct such studies, 0/46 (0%) responded that they sometimes
did such studies, and 2/46 (4%) indicated that they never conduct such stability studies.
Figure 7: Question 4: Does your company perform primary stability studies of your drug
product in the proposed marketing configuration for the primary container
closure system?

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
Never Sometimes Usually Always Cannot answer

50
Integrity testing
Respondents were asked whether their company conducted primary container closure
integrity testing in lieu of sterility testing as described in FDA Guidance (FDA 2008). Of
46 responses (Question 5, Figure 8), 5/46 (11%) indicated that they could not answer the
question. Of the remaining respondents, about half, 25/46 (54%), indicated that they perform
both integrity and sterility testing. The other respondents had mixed answers; 3/46 (6.5%)
indicated that they never conducted such integrity testing in lieu of sterility testing, 6/46 (13%)
indicated that they sometimes did, 3/46 (6.5%) indicated that they usually did, and 4/46 (8.7%)
indicated that they always substituted integrity testing in lieu of sterility testing.
Figure 8: Question 5: Does your company conduct studies to establish the integrity of the
primary container closure system in lieu of sterility testing?

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Never Sometimes Usually Always Do both tests Can't answer

51
Moisture barrier studies
Moisture barrier studies are conducted for drug products that are subject to adulteration
by moisture absorption, or have a permeable container. When asked about whether they conduct
moisture barrier studies, 4/46 (8.7%) of respondents indicated that they could not answer the
question. A further 3/46 (6.5%) indicated that they never conducted moisture barrier studies,
15/46 (33%) indicated that they sometimes did these studies, 11/46 (24%) indicated that they
usually did such studies and 13/46 (28%) indicated that they always do these studies (Question 6,
Figure 9).
Figure 9: Question 6: Does your company conduct studies to establish the level of
protection from moisture for the drug product in the primary container closure
system?

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
Never Sometimes Usually Always Cannot answer

52
Adsorption studies
Question 7 asked respondents whether they conduct studies to establish the potential for
adsorption of the drug product to the primary container closure system container. Of the 44/46
respondents replying to this question, 4/44 (9%) indicated that they could not answer the question
(Figure 10). Of the remaining responses, 2/44 (4.5%) indicated that they never conducted
adsorption studies, 17/44 (39%) indicated they sometimes do, 9/44 (21%) indicated they usually
do, and 12/44 (27%) indicated that they always conduct such studies.
Figure 10: Question 7: Does your company conduct studies to establish the potential for
adsorption of the drug product to the primary container closure system
container?

Studies to justify use of secondary packaging materials
Question 8 asked respondents whether they conducted studies to establish the
justification for use of materials for the secondary packaging system with the primary container
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
Never Sometimes Usually Always Cannot answer

53
closure system. Of the 46 respondents, 7/46 (15%) could not answer the question, 3/46 (6.5%)
indicated that they never conduct studies to justify the use of secondary packaging materials,
27/46 (59%) said they sometimes did, 4/46 (8.7%) indicated they usually did, and 5/46 (11%)
indicated that they always conduct such studies (Figure 11).
Figure 11: Question 8: Does your company conduct studies to establish the justification
for use of materials for the secondary packaging system with the primary
container closure system?

Extractables and Leachables in Shipping Materials
A major review of the survey was on questions relating to the evaluation of extractables
and leachables of different components and at different times in the life cycle of the product.
Results suggested that most respondents were quite rigorous about conducting studies of
extractables and leachables from the primary container closure system but not necessarily from
other aspects of the system.
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Never Sometimes Usually Always Cannot answer

54
Question 9 (Figure 12) asked if leachables studies are conducted with shipping materials
other than the primary and secondary container closure. One respondent skipped the question; of
the remaining 45 who responded, 21/45 (47%) said never they never conducted such studies,
10/45 (22%) said they sometimes do, 0/45 (0%) said they usually do, 2/45 (4.4%) said they
always do, and 12/45 (27%) said that they could not answer the question.
Figure 12: Question 9: Do you conduct studies on container leachables for drug product
interaction with shipping materials other than the primary and secondary
container closure system?

Drug Delivery Devices and Drug Master Files
Question 10 (Figure 13) asked whether studies on the accuracy and reproducibility of
drug product delivery devices are conducted when they are part of the primary container closure
per ICH Q1A(R2) (ICH 2003). Of 46 responses, 1/46 (2.2%) said they never did such studies,
12/46 (26%) said sometimes, 8/46 (17%) said usually, 14/46 (30%) said always, 2/46 (4.3%)
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
50.0%
Never Sometimes Usually Always Cannot answer

55
could not answer the question, and 9/46 (20%) said the question was not applicable for their
company.
Figure 13: Question 10: Does your company conduct studies to establish the accuracy and
reproducibility of drug product delivery devices that are part of the primary
container closure system?

Question 11 (Figure 14) asked if the respondent used packaging drug master files
(Type III DMF) for their regulatory submission dossiers. The Type III DMF contains detailed
information on the characteristics and suitablity of pharmaceutical packaging materials for use in
primary and secondary container closures. Of 46 respondents, 9/46 (20%) said they never used
DMF files for the container closure components, 7/46 (15%) sometimes did, 4/46 (8.7%) usually
did, 15/46 (33%) always used DMFs. The remaining 11/46 (24%) could not answer the question.

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
Never Sometimes Usually Always Can't answer Not
applicable

56
Figure 14: Question 11: Does your company use packaging drug master files (Type III
DMF) to support your submission dossier for your drug product?

Extractables and Leachables General Studies
Question 12 (Figure 15) explored whether studies are performed on extractables from the
container closure only, or any of its subcomponents. Two respondents skipped the question.
Only two of 44 respondents (4.5%) responded that they never perform extractables studies on the
primary container closure and the drug product, 6/44 (14%) sometimes do these studies, 4/44
(9%) usually do them, and the majority, 34/44 (77%), always do these types of studies. When
dealing with primary container closure subcomponents, the proportions of respondents were
different for each subcomponent. For the container closure label only, 21/44 (48%) never
perform studies of extractables and the drug product, 18/44 (41%) sometimes did perform these
studies, none of the respondents usually perform these studies, and 5/44 (11%) always perform
these studies. For studies of extractables from the label adhesive only, 19/44 (43%) responses
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
Never Sometimes Usually Always Cannot answer

57
never did these studies, 18/44 (41%) sometimes did these studies, none (0%) usually did these
studies, and 9/44 (20%) always performed these studies. Extractable and drug product interaction
studies were always performed with label inks by 5/44 respondents (11%), whereas 21/44
respondents (48%) reported never conducting these studies; 18/44 (41%) sometimes did these
studies, none (0%) usually did, and 5/44 (11%) always performed these studies.
Figure 15: Question 12: Do you conduct studies on container extractables for drug
product interaction with the primary container closure system?

Question 13 (Figure 16) asks if the respondent performs leachable studies with the drug
product during, or as part of, primary stability testing protocols. Primary stability studies
generally involve Phase 3 clinical supplies and are performed prior to commercial manufacture of
the drug product. Of 46 responses, 44 answered the question; 8/44 (18%) never do these types of
studies, 15/44 (34%) sometimes do them, 3/44 (6.8%) sometimes do them, and 18/44 (41%)
always perform leachable studies during primary stability studies.
0
5
10
15
20
25
30
35
40
45
50
With the container
itself
With the container
label
With the label
adhesive
With the label inks
Never
Sometimes
Usually
Always

58
Figure 16: Question 13: Do you include the primary container closure leachables as part
of primary stability testing protocols?

Question 14 (Figure 17) asks a follow-on question, to explore whether the respondent
performs leachable studies as a part of on-going commercial stability. The responses to
question 14 were quite different from question 13. Of the 44 who answered the question, 18/44
(41%) never did such studies, 15/44 (36%) sometimes did these type of studies, 2/44 (4.5%)
usually did these studies, and 8/44 (18%) always did leachable studies as a part of commercial
stability testing.

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
Never Sometimes Usually Always

59
Figure 17: Question 14: Do you monitor leachables as part of ongoing commercial
stability?

Product Recalls and Marketing Approval Delays
Question 15 (Figure 18) asks the respondent if their company has experienced a product
recall due to container leachables. The largest response indicated that 32/42 (76%) of the
42 respondents who answered the question had never experienced a recall due to container
leachables. Of the 42 responses, 6/42 (14%) indicated that a leachable related product recall was
a rare occurrence, and 4/42 (9.5%) indicated that this was an occasional occurrence. Question 16
(Figure 19) asked if the respondent had ever experienced a delayed marketing application due to a
packaging issue involving extractables and leachables. Of 42 responses, 32/42 (55%) indicated
that a delay in their application had never happened due to a packaging issue such as extractables
and leachables, 15/42 (36%) indicated that this was a rare occurrence, and 4/42 (9.5%) indicated
that this event happened occasionally.
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
Never Sometimes Usually Always

60
Figure 18: Question 15: Have you ever had a drug product recall due to container
leachables?

Figure 19: Question 16: Have you ever had a marketing application delayed due to a
packaging issue such as extractables and/or leachables?

Question 17 (Figure 20) queried whether studies are conducted to establish the safety of
materials of construction for the primary container closure system. Of 44 responses to the
question, 7/44 (16%) indicated that they never conduct such studies, 11/44 (25%) indicated that
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
Never Rarely Occasionally
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Never Rarely Occasionally

61
such studies are conducted sometimes, 12/44 (27%) indicated that such studies are conducted
usually, and 14/44 (32%) indicated that such studies are always conducted.
Figure 20: Question 17: Do you conduct studies to establish the safety of materials of
construction of the primary container closure system?

Adequacy of Guidance and Compendial Documents for Testing
Questions 18 through 22 explore the adequacy and useage of guidance documents and
compendial references used for compliance with regulations and testing requirements for
extractables and leachables in particular, and container closure development in general.
Question 18 (Figure 21) asks about the perceived adequacy of the most common guidance
documents with regard to extractables and leachables testing. Responses generally indicated that
guidance documents are helpful but outdated. For the statement, “The guidances from FDA meet
my needs for extractables/leachables testing,” 2/43 (4.7%) respondents strongly agreed, 14/43
(33%) agreed, 5/43 (12%) were neutral, none (0%) strongly disagreed, and 7/43 (16%) were
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
Never Sometimes Usually Always

62
unable to state an answer. For the statement, “The guidance documents are broadly adequate but
require more information about certain topics,” 7/45 (16%) respondents strongly agreed, 20/45
(44%) agreed, 10/45 (22%) were neutral, 2/45 (4.4%) disagreed, none of 45 (0%) strongly
disagreed, and 6/45 (13%) were unable to state an answer. For the statement, “The guidance
documents are relatively old and no longer provide adequate guidance for extractable/leachable
testing,” 3/46 (6.5%) respondents strongly agreed, 24/46 (52%) agreed, 9/46 (20%) were neutral,
7/46 (15%) disagreed, and none (0%) strongly disagreed, while 3/46 (6.5%) were unable to state
an answer.
Figure 21: Question 18: Which of the following statements best describes your feelings
about the adequacy of the guidance documents from FDA for
extractable/leachable testing?

Question 19 (Figure 22) asks about the adequacy of chapters of the USP (USP 2011) for
the purposes of extractables and leachables testing. The question was broken down into three
0
5
10
15
20
25
30
35
40
45
50
The guidances from
FDA meets my needs
for
extractable/leachable
testing.
The guidance
documents are broadly
adequate but require
more information about
certain topics.
The guidance
documents are
relatively old and no
longer provide
adequate guidance for
extractable/leachable
testing.
Strongly Agree
Agree
Neutral
Disagree
Strongly
Disagree

63
parts. Part one asked if the compendial chapters met the respondents needs for testing. Only 1/45
(2.2%) respondents strongly agreed, 13/45 (29%) agreed, 6/45 (13%) were neutral, 12/45 (27%)
disagreed, 3/45 (6.6%) strongly disagreed, and 10/45 (22%) were unable to state an answer. In
part two of this question, the respondent was asked if the compendial chapters are broadly
adequate but that certain topics require more information. Of 45 respondents, 3/45 (6.6%)
strongly agreed with the statement, 16/45 (36%) agreed, 11/45 (24%) were neutral, 2/45 (4.4%)
disagreed, and 3/45 6.6%) strongly disagreed with the statement. Again, 10/45 (22%) were
unable to answer this question. Lastly, respondents were asked if the compendial chapters were
relatively old and no longer provided adequate guidance for extractable/leachable testing. Of
46 respondents, 5/46 (11%) strongly agreed with the statement, 17/46 (40%) agreed, 7/46 (15%)
were neutral, 7/46 (15%) disagreed with the statement, and none (0%) strongly disagreed. Again,
10/46 (22%) were unable to state an answer.

64
Figure 22: Question 19: How do you feel about the adequacy of the USP and/or Ph Eur
compendial chapters for extractable/leachables testing?

Question 20 (Figure 23) asked the respondent to identify the documents that are in
routine use in his/her work. Of 46 respondents, 44 answered this question. The majority (39/44,
87%) chose the FDA 1999 guidance on container closures, 21/44 (48%) chose the ICH Q6A
guidance on specifications, 31/44 (71%) chose the ICH Q1A(R2) guidance on stability testing,
28/44 (64%) chose the FDA 2008 guidance on container closure integrity testing, and 24/44
(55%) chose the ICH Q8 guidance on pharmaceutical development. Responses for the other
documents individually accounted for under 10% of the responses.
0
5
10
15
20
25
30
35
40
45
50
The compendial
chapters meet my
needs for
extractable/leachable
testing.
The compendial
chapters are broadly
adequate but require
more information about
certain topics.
The compendial
chapters are relatively
old and no longer
provide adequate
guidance for
extractable/leachable
testing.
Strongly Agree
Agree
Neutral
Disagree
Strongly
Disagree

65
Figure 23: Question 20: Which of the following documents do you use routinely?

Question 21 (Figure 24) asked the respondent which of several key documents was the
one most useful document in his/her opinion. Despite its relative age, the FDA guidance of 1999
(FDA 1999) was the document of choice for slightly more than half of packaging scientists, with
24/44 (55%) choosing this document. None chose the ICH Q6A Specifications guidance or the
FDA 2003 guidance on bioavailability and bioequivalence. The remainder of the responses were
almost evenly divided between the four remaining guidance documents (see Figure 21).
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
FDA 1999
Container Closure
Systems
ICH Q1A (R2)
Stability Testing
FDA 2008
Container Closure
Integrity Testing
PQRI Document
Nasal/Inhalation
Products
ICH
Q8
Pharm
Dev
ICH
6A
Specs
FDA
2003
BA/BE
Nasal
Spray

66
Figure 24: Question 21: If you lost access to one document, which document would be the
one that would have the greatest impact on your extractable/leachable
program? The choices are:

Answer Options
Response
Percent
FDA 1999 Container Closure Systems for Packaging
Human Drugs and Biologics
54.5%
ICH Q6A Specifications 0.0%
ICH Q1A(R2)Stability Testing 13.6%
FDA 2003 BA & BE Nasal Aerosols and Sprays for
Local Action
0.0%
FDA 2008 Container Closure Integrity Testing in lieu
of Sterility Testing in Stability
11.4%
ICH Q8 Pharmaceutical Development 9.1%
PQRI Document on Nasal/Inhalation Products 11.4%

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%

67
Question 22 (Figure 25) asked about the adequacy of specific guidance documents for the
purposes of container closure development. Of 44 responses, 7/44 (16%) indicated the FDA 1999
guidance on container closures was adequate, 16/44 (36%) indicated that this guidance was
adequate but needed revision soon, 12/44 (27%) indicated that this guidance was out of date and
needed revision, and 9/44 (20%) could not judge the adequacy of the FDA 1999 guidance.
For the question on the adequacy of the ICH Q6A guidance on specifications, 12/41
(29%) indicated that this guidance was adequate, 7/41 (17%) indicated that it was adequate but
needed revision soon, 1/41 (2.4%) indicated that this guidance was out of date and should be
revised, while 21/41 (51%) could not answer the question.
For the ICH A1(R2) guidance on stability testing, 20/42 (48%) indicated that this
guidance was adequate, 6/42 (14%) indicated that this guidance was adequate but needed revision
soon, 1/42 (2.4%) indicated that this guidance out of date and should be revised, while 15/42
(36%) could not answer the question.
For the FDA 2003 guidance on bioavailability and bioequivalence in nasal aerosols and
sprays for local action, 5/40 (13%) indicated that this guidance was adequate, none (0%)
indicated that this guidance was adequate but needed revision soon, none (0%) indicated that this
guidance was out of date and should be revised, while 35/40 (88%) could not judge the question.
For the FDA 2008 guidance on container closure integrity testing in lieu of sterility
testing in stability, 19/43 (44%) indicated that this guidance was adequate, 5/43 (13%) indicated
that this guidance was adequate but needed revision soon, 3/43 (7.0%) indicated that this
guidance was out of date and needed revision, and 16/43 (37%) could not judge the question.
For the ICH Q8 guidance on pharmaceutical development, 24/42 (57%) indicated that
this guidance was adequate, 5/42 (12%) indicated that this guidance was adequate but needed

68
revision soon, 1/42 (2.4%) indicated that this guidance was out of date and needed revision, and
12/42 (29%) could not answer the question.
Figure 25: Question 22: Please choose the best answer to describe your feelings about
each of these documents.

Comments on the Survey Instrument
The last question (Question 23) gave respondents an opportunity to make comments
relevant to the survey on topics not included in the body of the survey. Of 46 responses, only
seven respondents made comments and these are presented in unedited form in Table 5.
Responses 2 and 4 had no attached comments. Responses 1, 5 and 6 suggested that information
and guidance for container closure development needs to be updated, increased, and made more
specific. Response 3 stated that the survey did not include oral liquid products. The most
interesting response was number 7, which commented on the state of development of new
0
5
10
15
20
25
30
35
40
45
50
FDA 1999
Container Closure
Systems
ICH A1 (R2)
Stability Testing
FDA 2008
Container Closure
Integrity Testing
Sufficiently current for my
needs
Adequate but needs
revision soon
Out-of-date and should
be revised
Cannot judge
ICH
Q6A
Specs
FSA
2003
BA/BE
Nasal
ICH Q8
Pharm
Dev

69
guidance and compendial documents for extractables and leachables, and will be more fully
discussed in Chapter 5 of this dissertation.
Table 5: Comments from the Survey Instrument, Question 23
# Response Text
1 Needs to be more concise and more current with new technology
2 No
3 Your survey never asked about oral liquid products.
4 No comments
5 More specificity regarding limits and threshold values for identification of extractables and
leachables.
6 Needs more guidance
7 The PQRI recommendations document for Parenteral & Ophthalmic drug products will be
drafted in 2012. The methodology used to generate data to demonstrate Best Practices for
L/E will be posted at PQRI by May 2011. The FDA and Health Canada are participating in
creating the Thresholds and Best Practices Recommendation Document PODP and MHRA
is providing feedback. A USP chapter on Extractables will be published in the USP NF in
2012. This will be consistent with PQRI methodology.

Comment 7 in Table 5 refers to the PQRI working group on extractables and leachables
in parenteral and ophthalmic drug products (PODP) (PQRI 2011). This working group within the
PQRI is drafting a recommendation for the FDA to consider for extractables and leachables in
parenteral and ophthalmic drug products as was done previously for inhalation and nasal spray
drug products (PQRI 2006).

70
Chapter 5: Discussion
Regulatory and compendial documents are very demanding and costly to develop and
maintain. Governmental organizations and standards-setting bodies must decide when to invest
significant time and resources to revise such documents at the expense of other important and
competing demands, and then must decide the extent to which these needs can be met through
regulatory means or vehicles such as privately developed standards, voluntary self-regulation or
education through private sector stakeholders (Shapiro 2003). The present study was undertaken
to provide information on the views of industry practitioners with regard to current practices in
extractables and leachables testing, and further to obtain information on the perceived adequacy
of regulatory guidance documents and other regulatory support materials that deal with the testing
of extractables and leachables. Such information is useful in deciding whether these materials
need to be revised or whether they are still useful and appropriate for current industry needs.
A first stage in the assessment of such views can be derived from already available
documentary sources, and this was summarized in chapter 2. The review in chapter 2 identified
two major sources of information for container closure development, 1) regulatory authority
guidance documents and associated official compendial documents, and 2) peer and non-peer
reviewed literature and industry generated recommendations. These two major sources of
information were found to have significant differences in perspective. Regulatory guidance
documents emphasize minimum requirements for compliance. Typically, they emphasize what to
do in a high-level or general way, but lack detail as to how to perform specific tasks.
Beierschmitt (Beierschmitt 2009), for example, identified this orientation by saying,
There are currently limited regulatory guidelines available to aid the toxicologist in risk
assessing extractables and leachables (e.g. FDA Container Closure Guidance, 1999).

71
Compendial information such as USP standards attempt to deal with this deficiency by providing
methods for specific procedures or tasks but these materials also may lack detail. More troubling,
their instructions may lag well behind current practice, conflict with the standards of other
countries or use outmoded technology, deficiencies that are recognized by the USP itself (USP
2009). In contrast, the available literature attempts to build a more practical perspective of best
practices, but it is often presented in a fragmented or narrow way that reflects the particular
experiences of the authors rather than views of industry experts more generally. Nevertheless, the
relatively sparse literature that could be found regarding the state of the current regulations also
painted a picture of a less than perfect system. To understand and address needs and issues
related to extractables and leachables testing, the pharmaceutical industry, through the Product
Quality Research Institute (PQRI), participated in several efforts to bring more science to bear on
the problem of container closure extractables and leachables by focusing first on inhalation and
nasal spray products (PQRI 2006), and more recently on parenteral and ophthalmic products
(PQRI 2011), the latter still in a draft document for review by both industry and regulatory
authorities in the US, Canada, and the UK. These documents were not designed to cover the
needs of all product classes, yet CMC reviewers with experience in nasal and inhalation products
(where the PQRI recommendations have become to some extent accepted) began to apply the
same level of expectation for parenteral and ophthalmic drug products (even though similar
standards for these drugs have not been approved or promulgated widely). A situation with this
type of fluid expectation is unsettling for manufacturers for whom transparent regulatory
expectations are helpful in clarifying a developmental path forward.

72
5.1 Consideration of Methods
The survey developed here and sponsored by the PDA and its Packaging Science Interest
Group represents a second, exploratory stage of research to assess the adequacy of regulatory
guidance with respect to extractables and leachables testing. To put these results in context, it is
important to consider elements of the experimental design that may affect the results obtained by
this particular methodological approach.
Delimitations
This research was delimited to the pharmaceutical industry, and more specifically, to
companies that operate primarily in the parenteral and/or ophthalmic drug product sectors who
dominate the membership of the Packaging Science Interest Group. Within these companies, the
survey instrument explored current practices seen through the eyes of a subset of individuals who
have an expertise and professional role in packaging science. Thus the survey conducted in this
study may not sample uniformly from pharmaceutical professionals in general. This delimitation
was felt to be necessary because expertise in container closures is typically confined to
individuals with a specialized knowledge in fields of chemistry, manufacturing and controls, and
is further highly specific to a subfield known as packaging science.
Although respondents all belonged to the PDA, it seemed clear from the self-
identifications of the respondents that they did have some degree of breadth with regard to their
backgrounds. For example, the fact that 82 affiliations with different product types were
identified by the 46 respondents suggests that many respondents worked with more than one
product type and that at least one-third (16/46) were involved in devices as well as or instead of
pharmaceutical products (Question 1, see Figure 4). However, the numbers of respondents
working with devices were hard to assess definitively, because inconsistencies were identified in

73
responses to later questions that also queried the experience of the respondents. In Question 2
(see Figure 5), one-half rather than one-third of respondents indicated that they work with
devices; in Question 10 (see Figure 13) about three-quarters of the respondents indicated that they
work with drug delivery devices, a substantially higher number than suggested by the responses
to earlier questions.
The reason for the discrepancy between responses is not clear. The discrepancy might be
the result of the manner in which the questions were phrased, and a different phrasing might lead
to better agreement between the answers to these questions. It may be that respondents
considered drug delivery devices as merely packaging for the pharmaceutical formulations, and
therefore did not see themselves as working in the device field. The respondents may have
interpreted the notion of “working with devices” as a description of work carried out as a
primary, stand-alone effort. Typically, when a pharmaceutical scientist “works with devices”, the
device component is usually the subordinate member of a combination product and the drug has
the primary mode of action. In this case, the combination product is regulated primarily under
drug rather than device rules (Robinson 2005) and the respondent may self-identify with the drug
first and the device second, or the device not at all. A primary focus on the drug as the principal
element of interest is typical for both inhalation and nasal spray drug products, as well as for
many parenteral drugs such as intravenous solutions and injectables such as pre-filled syringes.
Since 45/46 (97%) of respondents work in the parenteral and injectable drug product area
(Question 3), where drugs may be administered in prefilled syringes or specialized delivery
systems, a likely bias towards devices as ancillary to the drug product is likely to prevail. The
structure of this survey did not allow the respondent to go back to previous answers, so it is
unclear if the respondent would have reconsidered his or her answers to questions about device
experience once were prompted to think about their involvement with drug delivery devices.

74
More carefully worded questions might have been able to remove at least some of this
discrepancy.
The fact that most of the respondents had a broad and detailed knowledge of the
packaging industry was suggested by the infrequent failure to answer the question entirely or the
infrequent selection of the “Cannot Answer” response. Across all of the multiple choice
questions, response rates ranged from 92% to 100%. However, for questions 4 through 11 that
focused on general practices in the company, the response “Cannot Answer” was somewhat more
common than for other questions, ranging between 4% for question 10 to 27% for question 9, and
on average accounting for 15% of answers to these eight questions. This trend may suggest that
the respondents were unable to answer certain questions because the questions fell outside of their
immediate area of expertise in packaging and materials testing.
The study was further delimited by geography and time. It focused primarily on US and
European requirements. The study was further delimited to the years of 2010 and 2011, and so
represents a snapshot of views. It is likely that standards will change as guidance documents and
other materials evolve in the future. Thus the results reported here must be interpreted in the
context of best practices and regulatory requirements as of 2010. These might be expected to
change in the future.
Limitations
This study has several real and potential limitations. The sampled population, which was
drawn from experts belonging to the Parenteral Drug Association Packaging Science Interest
Group, may not be sufficiently broad or comprehensive to give a balanced view. The response
rate (12.1%) was relatively low as is typical for electronic surveys of this type (Fincham 2008),
presumably because many individuals who were qualified to share their views declined the

75
opportunity because of their busy schedules or insufficient knowledge in this area. As is typical
of the industry, pharmaceutical companies engage in substantial research and development.
Some information derived from these activities is proprietary and seldom shared with individuals
outside of the FDA, where rules exist to limit disclosure. As an example, a survey sent to 27
companies by the PDA in 2011 received only 19 responses (PDA 2011). Therefore, the questions
in the survey must be phrased to avoid undue disclosure of proprietary information. If we were in
fact failing to understand where the boundaries exist, we might have expected more respondents
to skip questions, and this did not seem to be a large problem in this study.
It is a further limitation of this study that the answers provided to the survey can be
validated only from information available in published literature that is sparse and often
anecdotal. The relatively small, highly targeted nature of the interests typical for the sample
population may also pose a challenge to external validity. Validity would be challenged further if
the information provided by the respondents was not honest or well-informed, and it would be
difficult to validate the responses without repeating the survey by polling other samples of
individuals in the same type of job but outside of the PDA, or by triangulating the data by using
different methods, such as an interview methods (Hess-Biber and Leavey 2011). However, it
would be difficult to identify and reach individuals with sufficient knowledge of the area who do
not belong to the Packaging Science Interest Group. All of these limitations must be borne in
mind when interpreting the findings in Chapter Four (Litman 1995).
5.2 Consideration of Results
Extractables and Leachables Testing
The primary goal of the survey was to understand the extent and nature of extractables
and leachables testing across the industry. This specialized subject typically does not attract

76
much attention of individuals outside of testing laboratories, but its importance became more
visible unexpectedly during the period in which this research was conducted when a number of
drug products made by McNeil Consumer Healthcare, a subsidiary of Johnson and Johnson, were
removed from store shelves because of unanticipated leachables. In this case, a breakdown
product of a fungicide called 2,4,6-tribromoanisole (TBA) contaminated a number of drug
shipments of Tylenol
®
and several other products (FDA 2010). TBA is volatile and develops
over time as the breakdown product is produced. This breakdown product has a musty odor that
can be detected by the human nose in minute quantities below the level of detection of commonly
used assays (Bleiler 2011). The origin of the contaminant was traced to chemicals in wooden
pallets used to ship drug products. This issue seems to have blindsided the industry (PDA 2011).
Even though this problem was recognized as early as 2009, and cost the company an estimated
$900 Million in sales (2011), responses in the present survey suggested that the this problem has
not yet had much impact on the way that shipping and storage materials are managed. It is
interesting and potentially problematic that most respondents either did not know if their
companies conducted studies on leachables from shipping materials (Question 9, see Figure 12),
or identified that they never conducted studies on container leachables to detect interactions with
shipping materials other than those associated with the primary and secondary container closure
system.
It will be interesting to see whether more studies of shipping materials will be required in
the future, given the common use of fungicides and preservatives in storage areas, especially in
countries from which active pharmaceutical ingredients and even finished products are
outsourced. To underscore the importance of this new area of concern with respect to
extractables and leachables (see definitions in Chapter 1), the Parenteral Drug Association formed
a task force to consider the question of leachables from drug product shipping materials. The task

77
force conducted a survey of 27 pharmaceutical industry companies (PDA 2011). As stated by the
PDA,
The results from this survey were used to benchmark the current situation in our industry
and to assess areas in which more guidance could be provided to industry in handling
issues with TBA/TCA odors and taints through a PDA Technical Report on this topic. To
date, the primary focus in industry has been on the use of Heat Treated (HT) pallets
(TBA/TCA-free) to prevent risks of TBA/TCA odors and taints from entering into the
supply chain.
In contrast, the testing of extractables from the container closure itself appeared to be
almost standard practice. It was surprising to find that only two respondents never performed
extractables studies on the drug product in its primary container closure, whereas the majority
(74%) always did these types of studies (Question 12, Figure 15). Most previous literature
suggested that studies of extractables were not as common as studies of leachables (Jenke,
Swanson et al. 2005; Beierschmitt 2009; DeGrazio 2009).
The stage in development at which leachable testing is conducted is also interesting to
identify. Typically, studies of container closure leachables as part of primary stability studies
serve to establish the presence or absence of container closure leachables in the package proposed
for marketing, in order to set preliminary specifications should leachables be found during the
course of the stability study (Paskiet 2008). The data from the primary stability studies can then
be used along with data from commercial batches of the drug product to set specifications for the
acceptable levels of leachables from the container closure. Thus it might at first glance seem
prudent to conduct such testing for most products. However, when respondents were asked
whether they conduct such studies as part of primary stability (Question 13,see Figure 16) it
appeared that early stage testing is not carried out for many products. Only about 40% of
respondents identified that they always conducted studies of leachables as part of primary
stability studies, although another 40% conducted such studies either sometimes or usually at this

78
stage. It is noteable that a sizeable percentage (18%) reported that they never performed such
studies. There may be two reasons for this result. Respondents who do not perform such studies
may be working with specific types of drug products, such as tablets and capsules, that do not
typically require studies of leachables. Per the Guidance for Industry: Container Closure Systems
for Packaging Human Drugs and Biologicals (FDA 1999), such studies are only required for
parenteral/injection drugs, ophthalmic drugs, and oral/nasal inhalation/spray drugs. Topical and
solid dosage form drugs are outside of the scope of the requirement. However, this explanation
may be weakened by the fact that most respondents (98%) self-identifed that they worked with
parenteral products. Alternatively, respondents could be working with container closures made of
materials such as glass that typically do not introduce worrisome levels of extractables and
leachables (Northup 2008), and could be using a closure for the glass container that is already
well characterized. However, even seemingly well-characterized materials can yield surprises
that greatly impact the risk profile of a container closure once thought stable. For example,
recent observations of delamination of glass microparticulates from the interior surface of glass
vials have led packaging scientists to query the safety of glass vials that are almost ubiquitous as
containers for parenteral solutions (Iacocco 2011). Not only can the particles themselves have
undesirable direct consequences to the patient, but they can also destabilize suspensions of drug
products through adsorption of the drug substances to the microparticles (Hoehne, Samuel et al.
2011). The capability to detect microparticles from glass vials has led to several highly visible
recalls of parenterals with glass microparticles in the drug product over the last few years
(Reyolds and Paskiet 2011).
Leachable studies appear to be performed less commonly at later stages of the product
lifecycle when commercial stability is assessed. Nearly half of the respondents (41%) indicated
that they never perform studies of leachables during their assessments of commercial stability,

79
compared to only 18% who always did. A conclusion that might explain these results is that
many respondents consider assessments of extractables and leachables during primary stability
testing to be sufficient. If this were to be the case, further studies might be seen to be
unwarranted when commercial stability is tested. Also, once qualified, pharmaceutical
companies tend to use the same container closure materials for all new drug products. In fact,
Stegemann (Stegemann 2012) has observed that,
When developing a new pharmaceutical product, pharmaceutical scientists typically
focus on the Quality Target Product Profile (QTPP) and primary and secondary
packaging is selected as an afterthought from a few off-the-shelf standards.

Other Elements of Pharmaceutical Container Closure Development
Extractables and leachables are not the only features that must be considered when
assessing the suitability of the primary container closure. A number of possible parameters could
influence the suitability/safety of the container closure for the drug product with which it comes
in contact. The opportunity was taken in this survey to understand the extent to which
manufacturers carried out certain other practices important to maintaining the quality of packaged
products. One aspect of this protection is assuring that products are protected from moisture.
This particular question may seem surprising in a survey of extractables and leachables testing,
because water is not typically considered a leachable, but in fact water contamination over time
can be a significant source of concern for certain product classes. For example, some drugs
degrade or decompose in the presence of moisture (Yokiosha and Stella 2000). In these
instances, the container closure must also act as a moisture barrier to prevent water from leaching
into the product and degrading the potency and purity of the drug product (FDA 1999).
Responses in this survey showed that moisture barrier or protection studies are carried out
consistently by about half of the respondents. Most of the remaining respondents either

80
sometimes performed these studies, or never performed them. These results may not be
surprising. Moisture barrier studies are not needed for all types of primary container closures.
For drug products that are not subject to adulteration by moisture absorption, or have an
impermeable container such as glass or a metal tube, these studies may not be necessary (FDA
1999). The results therefore provide an interesting insight into the extent of such testing but do
not necessarily reflect poor practice.
A second aspect of this protection is assuring that the drugs in solution do not adsorb to
the walls of their container or closure, and thereby reduce the potency of the drug product (FDA
1999). Testing for such adsorption seems much more common than moisture barrier testing as
indicated by the fact that most respondents carried out such studies at least occasionally, and
more than half reported that such tests were done usually or always (Question 7, see Figure 10).
However, such results may in fact simply reflect the nature of the containers with which the
survey respondents work in their laboratories. The possibility that drug ingredients might adsorb
to container walls is a particular concern for parenteral products (FDA 1999; Wang and Roberts
2010).
In addition to considerations of interactions between the drug substance and the container
closure, and the influence of the primary container closure on overall drug product quality, a third
aspect of protection is assuring that materials for use in secondary packaging cannot contaminate
products. As an example, the small box or carton that contains the primary container filled with
drug product can also produce leachables that can contaminate the drug product if not adequately
controlled (DeGrazio 2009). Most respondents reported that they carried out investigations of
secondary container leachables at least sometimes, but only a small minority (about 10%) always
carried out such studies. These results may be explained by a common practice in industry of
qualifying a few primary and secondary packaging components, and then using these components

81
across the lifecycle of the product (Jenke, Swanson et al. 2005). For example, extractable studies
performed on a plastic container for a particular product may not need to be repeated for each
subsequent drug product that uses that same plastic container. Such a packaging strategy ensures
well qualified packaging components while reducing the number of both primary and secondary
container closure qualification studies that need to be performed for any particular drug product.
The final question in this series dealt with the use of Type III Drug Master Files (DMF)
for packaging components as a source of packaging component information for regulatory
purposes (Question 11, see Figure 14). A DMF is a submission made to a regulatory agency by
the vendor company. This file is a way in which the vendor company can communicate material
or component features and manufacturing methods without sharing proprietary information with
the client drug manufacturer (FDA 1989). The client company does not have access to the
information submitted as part of the DMF but has a right of reference so that the regulatory
agency can inspect the DMF to complement the client company’s regulatory submission. The
DMF also allows a vendor company to conduct certain types of validation testing once and then
supplying the results in the DMF for the use of several client companies (FDA 1989). Such
studies then can be referenced by the client company to reduce testing time and duplication. The
use a DMF typically comes at the point where submissions are developed for regulatory
activities, and testing scientists in the laboratory may not be involved in this regulatory aspect of
product management. Thus it may not be surprising that nearly a quarter of respondents did not
appear to know if their company used such packaging master files. It is also not surprising that a
modest number of respondents did not use DMFs. A DMF can only be used for regulatory filing
purposes if one actually exists, that is, the vendor of a packaging component has written a DMF
for its packaging and then has filed that DMF with the FDA. At the same time, more than half of
respondents stated that they use DMFs at least some of the time, suggesting that the use of DMFs

82
for packaging components is a common practice (Gurley 2008). It presumably reflects the fact
that at least some packaging is outsourced from vendors well-familiar with the needs of the
regulated industry (DeGrazio 2003). In fact a vendor that can offer a DMF with some types of
testing can facilitate the drug development process for the manufacturer, and this provides
competitive advantage for the vendor.
Recalls and Marketing Approval Delays
When drugs have problems with extractables and leachables or fail qualification testing,
recalls or marketing delays commonly follow. The contamination issues discussed earlier from
pallets treated with fungicide provide a cautionary lesson. Nevertheless, this survey suggests that
such recalls or delays are relatively uncommon. About three-quarters of respondents had never
experienced a recall due to container closure leachables. Further, more than half (55%) had never
encountered a delay in marketing approval delay because levels of container leachables were
unacceptable. Such problems are not however insignificant because a quarter of the respondents
reported having a recall for these reasons, and nearly half had experienced marketing delays.
Since delays and recalls are very expensive, the ability to recognize container closure leachables
before reaching a point where a recall or delay would be necessary would appear to be an
important concern for the pharmaceutical industry. These concerns might be reduced by clearer
regulatory requirements and guidances for appropriate testing.
Guidance Documents and Compendial Information
It is clear that extractables and leachables testing is an important part of product
development and that practices vary, presumably because products differ and the importance
placed on various types of testing can vary as well. It is also clear that concerns exist about the
adequacy of guidelines for such testing, but in the past such reports were largely anecdotal. In

83
this survey, a larger number of respondents could be questioned regarding their perceptions of the
adequacy of regulatory guidance (Question 18, see Figure 21). The mixed responses of the
respondents were surprising given the often negative slant of anecdotal literature; approximately
equal numbers agreed or disagreed that the currently available guidance documents are adequate
for their needs. A nearly even split of opinion was also seen when respondents were queried
about the perceived adequacy of compendial information (USP and Ph Eur) for the testing of
extractables and leachables. The fact that about one-third believed that current compendial
information is adequate, whereas another third disagree or strongly disagree that current
compendial information is adequate, may relate to the type of product that they produce, or the
level of concern based on past regulatory or compliance experience. However, further insight
into this question was handicapped because the survey tool used for this study did not have the
option of cross tabulating the expertise or areas of activity of the respondents with their answers
on this question. In the future, this survey might provide more insightful information if the
answers could be stratified according to the type of product and level of experience of the
respondent.
What are the regulatory guidance documents that respondents use most frequently to
guide their testing? According to respondents surveyed here, the single most important guidance
document that was selected from the list of guidance documents found in Table 1 of Chapter 2
was the FDA guidance of 1999 (FDA 1999) on container closure systems for human drugs.
However, only 16 % of respondents felt that the guidance is fully adequate for their needs. Most
instead felt that the guidance was either adequate but in need of revision soon or was out of date
altogether. This question alone is important because it provides input to the regulatory
community that the FDA guidance needs serious attention. Perhaps the reason that this guidance

84
is still the document of choice relates to its legal status as a benchmark to which accompany must
comply in order to be reasonably confident that it will not fail an FDA audit.
Interestingly, the document that is most current and detailed, the PQRI document for
nasal and inhalation products, was not selected as a key reference by most of the respondents.
This may reflect its rather narrow focus on a class of products that represents a relatively small
fraction of the pharmaceutical market and an interest of very few respondents in this study. It
may also be because the contents of the document, that in many respects can be generalized to
other product classes, have not been brought to the attention of those responsible for extractables
and leachables testing for other product classes. It might be important to promote this guidance
more actively so that a broader range of individuals can indentify its strengths and weaknesses. If
the content of the document were more widely appreciated, it might provide a beginning template
or benchmark for discussion to inform the improvement of other documents.
Answers to survey questions that dealt with the adequacy of guidance documents
suggested that the major regulatory and compendial guidance documents are out of date and need
to be revised and updated. This view was reinforced in a final question that solicited text
comments regarding the adequacy of the standards and guidance documents. Most of these
responses suggested that the documents should be more specific and current form a scientific
perspective. However, one comment was different and deserves special discussion because it
attempted to provide useful insight into the future of activities in this area. As this respondent
stated,
The PQRI recommendations document for Parenteral & Ophthalmic drug products will
be drafted in 2012. The methodology used to generate data to demonstrate Best
Practices for L/E will be posted at PQRI by May 2011. The FDA and Health Canada are
participating in creating the Thresholds and Best Practices Recommendation Document
PODP and MHRA is providing feedback. A USP chapter on Extractables will be
published in the USP NF in 2012. This will be consistent with PQRI methodology.

85
This comment reflects the important ongoing role of the PQRI, with the involvement of the PDA,
the USP Convention, and the FDA (PQRI 2011) in spearheading change in guidance documents
(Norwood, Ball et al. 2006; Norwood, Paskiet et al. 2008; Norwood 2010) . It would appear that
discussions over the last decade regarding the inadequacy of guidance on extractables and
leachables have begun to have a positive effect on the field. However, it is still unclear how long
it will take for this process to deliver a more general document to be used across different drug
forms. Further it is not clear whether new regulations will fully embrace the recommendations of
the PQRI report, and to what extent the recommendations will be applied as “soft law” in other
areas of drug CMC validation beyond that for nasal and orally inhaled products. Such an
approach can reduce the transactional costs associated with revision of the law itself or delegated
legislation in the form of regulations (Shapiro, 2003). Uncertainty is to some degree fueled
because the FDA has already begun to extend its use of the PQRI report as part of its review
process and recommendations to sponsors for products outside of the scope of the original
intended area of inhalation and nasal spray drug products (Norwood 2010). Further, regulatory
practice may be impacted by newer initiatives, such as the new PQRI draft report on extractables
and leachables in parenteral and ophthalmic products (PQRI 2011) and the new development of
an industry-based database called ELSIE, to document specific to extractables and leachables
(Nagao, Beierschmitt et al. 2011). The survey results reported here seem to indicate that such
efforts should be accelerated to ensure that manufacturers have better information about best
practices in this field.

86
5.3 Future Directions and Recommendations
A review of the literature and the results of the survey conducted here suggest that the
paradigm underlying the development of pharmaceutical container closures is undergoing change.
This change is being driven by multiple stakeholders including:
• regulatory authorities such as the FDA in the US and the EMA in Europe
• the ICH as a global organization representing multiple stakeholders
• the organizations behind the various pharmacopeias, particularly the USP and Ph
Eur
• the pharmaceutical industry itself
• industry associations and other support organizations such as the PDA and PQRI
Over the last decade, much of the impetus to change the paradigm of container closure
development has come from considerations of container closure extractables and leachables. It
will therefore be interesting to observe the progress of the recent draft of the PQRI
recommendation for extractables and leachables testing for parenteral and ophthalmic drug
products that is now being finalized for submission to the FDA and other regulatory authorities.
(PQRI 2011). It remains to be seen whether this latest product of the PQRI will receive the same
treatment as the earlier PQRI report on extractables and leachables in oral inhalation and nasal
spray products ((PQRI 2006) - that is, as an unofficial suggestion for use - or if it will achieve
more formal status as an official guidance. The results of this survey suggest that the FDA and
other regulatory authorities would be justified in investing time and resources to revise guidance
documents and other forms of recommendations on how to manage extractables and leachables as
part of pharmaceutical container closure development (DeGrazio 2003; Norwood, Ball et al.
2006; Norwood, Paskiet et al. 2008).

87
The introduction of the latest PQRI draft for parenterals and ophthalmics as a final
document will change the framework for extractables and leachables for both regulatory
authorities and industry. Since the FDA is involved in the review of the latest PQRI draft report,
it is likely that the PQRI recommendations will receive at least unofficial recognition. However,
if the recommendations result in updates to the USP, as suggested in comment 7 under question
23, the recommendations will have even greater impact. Because FDA regulations generally
refer to the USP as a “related statutory instrument” (U.S.C 1938), any changes to it are binding on
industry and enforceable by the FDA.
This survey represents the views of industry at a single point in time, between March and
July of 2011. It would be useful to repeat this survey in the future, either after about 5 years or
after the PQRI report on extractables and leachables in parenterals and ophthalmics and the new,
proposed USP chapter on extractables have been introduced formally. One can anticipate
changes to the paradigm for container closure development given these forthcoming initiatives. If
the new documents accomplish their objectives, a higher level of satisfaction would be
anticipated and this could be captured by a later survey. However, since the primary document
for the respondents was the FDA Guidance document (FDA 1999), it would seem prudent to
update this guidance document as well. No doubt there will be additional contributions to the
extractables and leachables literature that will follow the final PQRI report and the USP new
chapter. Measuring this new literature against repeated survey results would serve to benchmark
the effectiveness of changes in industry practice after packaging scientists have had the chance to
gain experience with new ideas and recommendations. The pharmaceutical industry might find
itself then at a point much closer to consensus on the appropriate way to test and control
extractables and leachables during container closure development.

88
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93
Appendix A: The Survey Instrument
Do you work in a field that the FDA regulates? Check all that apply.
Pharmaceuticals
Biologicals
Devices
Cosmetics
Food
I do not work in any of these fields

If you deal with devices, please indicate which class(es) of devices that you market. Check all
that apply.
Class I
Class II
Class III
I do not deal with devices

94
If you deal with pharmaceutical products, please identify which types of container closure
systems that you use. Check all that apply
Parenteral/injectable
Ophthalmic
Solid dosage form
Topical
Inhalation/nasal spray
None of the above

Does your company perform primary stability studies of your drug product in the proposed
marketing configuration for the primary container closure system?
Never
Sometimes
Usually
Always
Cannot answer

95
Does your company conduct studies to establish the integrity of the primary container closure
system in lieu of sterility testing?
Never
Sometimes
Usually
Always
Cannot answer

Does your company conduct studies to establish the level of protection from moisture for the drug
product in the primary container closure system?
Never
Sometimes
Usually
Always
cannot answer

96
Does your company conduct studies to establish the potential for sorption of the drug product to
the primary container closure system container?
Never
Sometimes
Usually
Always
cannot answer

Does your company conduct studies to establish the justification for use of materials for the
secondary container closure with the primary container closure system?
Never
Sometimes
Usually
Always
cannot answer

97
Do you conduct studies on container leachables for drug product interaction with shipping
materials other than the primary and secondary container closure system?
Never
Sometimes
Usually
Always
cannot answer

Does your company conduct studies to establish the accuracy and reproducibility of drug product
delivery devices that are part of the primary container closure system?
Never
Sometimes
Usually
Always
cannot answer

98
Does your company use packaging drug master files (Type III DMF) to support your submission
dossier for your drug product?
Never
Sometimes
Usually
Always
cannot answer

Do you conduct studies on container extractables for drug product interaction with the primary
container closure system?
Do you conduct studies on container extractables for drug product interaction with the primary
container closure system?
Never Sometimes Usually Always
With the container itself

With the container label

With the label adhesive

With the label inks

99
Do you include the primary container closure leachables as part of primary stability testing
protocols?
Never
Sometimes
Usually
Always

Do you monitor leachables as part on ongoing commercial stability?
Never
Sometimes
Usually
Always

100
Have you ever had a drug product recall due to container leachables?
Never
Rarely
Occasionally

Have you ever had a marketing application delayed due to a packaging issue such as extractables
and/or leachables?
Never
Rarely
Occasionally

101
Which of the following statements best describes your feelings about the adequacy of the
guidance documents from FDA for extractable/leachable testing?

Strongly
Agree
Agree Neutral Disagree
Strongly
Disagree
Unable to
State
The guidances from
FDA meet my needs for
extractable/leachable
testing.

The guidance
documents are broadly
adequate but require
more information about
certain topics.

The guidance
documents are
relatively old and no
longer provide adequate
guidance for
extractable/ leachable
testing.

102
How do you feel about the adequacy of the (USP and/or Ph Eur) compendial chapters for
extractable/leachables testing?

Strongly
Agree
Agree Neutral Disagree
Strongly
Disagree
Unable to state
The compendial
chapters meet my
needs for
extractable/leachable
testing.

The compendial
chapters are broadly
adequate but require
more information about
certain topics.

The compendial
chapters are relatively
old and no longer
provide adequate
guidance for
extractable/ leachable
testing.

103
Which of the following documents do you use routinely?
FDA 1999 Container Closure Systems for Packaging Human Drugs & Biologics
ICH Q6A Specifications
ICH Q1A(R2) Stability Testing
FDA 2003 BA & BE Nasal Aerosols and Sprays for Local Action
FDA 2008 Container Closure Integrity Testing in lieu of Sterility Testing in Stability
ICH Q8 Pharmaceutical Development
PQRI Document on Nasal/Inhalation Products

If you lost access to one document, which document would be the one that would have the
greatest impact on your extractable/leachable program?
FDA 1999 Container Closure Systems for Packaging Human Drugs & Biologics
ICH Q6A Specifications
ICH Q1A(R2) Stability Testing
FDA 2003 BA & BE Nasal Aerosols and Sprays for Local Action
FDA 2008 Container Closure Integrity Testing in lieu of Sterility Testing in Stability

104
ICH Q8 Pharmaceutical Development
PQRI Document on Nasal/Inhalation Products

Please choose the best answer to describe your feelings about each of these documents
Please choose the best answer to describe your feelings about each of these documents

Sufficiently
current for my
needs
Adequate but
needs revision
soon
Out-of-date and
should be revised
Cannot judge
FDA 1999 Container
Closure Systems for
Packaging Human
Drugs & Biologics

ICH Q6A
Specifications

ICH Q1A(R2) Stability
Testing

FDA 2003 BA & BE
Nasal Aerosols and
Sprays for Local Action

FDA 2008 Container

105
Please choose the best answer to describe your feelings about each of these documents

Sufficiently
current for my
needs
Adequate but
needs revision
soon
Out-of-date and
should be revised
Cannot judge
Closure Integrity
Testing in lieu of
Sterility Testing in
Stability
ICH Q8 Pharmaceutical
Development

Do you have any comments about the current state of regulatory guidance for
extractables/leachables validation or regulatory submission?

106
Appendix B: The Survey Results

1. Pharmaceutical Container Closure Development Survey
Do you consult for/manufacture/market products in a field that the FDA
regulates? Check all that apply.
Answer Options
Response
Percent
Response
Count
Pharmaceuticals 84.8% 39
Biologicals 73.9% 34
Devices 34.8% 16
Cosmetics 6.5% 3
Food 6.5% 3
I do not work in any of these fields 0.0% 0
answered question 46
skipped question 0

Note: The total number of surveys sent out was 385, 361 from PDA and 20
from Allergan.
The total number of responses is 46, a response rate of 12.1%

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
Pharmaceuticals
Biologicals
Devices
Cosmetics
Food
I do not work in any
of these fields

107
2. Pharmaceutical Container Closure Development Survey
If you deal with devices, please indicate which class(es) of
devices that you market. Check all that apply.
Answer Options
Response
Percent
Response Count
Class I 23.3% 10
Class II 44.2% 19
Class III 18.6% 8
I do not deal with devices 48.8% 21
answered question 43
skipped question 3

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Class I Class II Class III I do not deal with
devices

108
3. Pharmaceutical Container Closure Development Survey
If you deal with pharmaceutical products, please identify which types of
primary container closure systems that you use. The primary container
closure is that part of the container closure and any associated packaging
that has direct physical contact with the drug product. Check all that
apply.
Answer Options
Response
Percent
Response Count
Parenteral/injectable 96.7% 45
Ophthalmic 23.3% 11
Solid dosage form 23.3% 11
Topical 20.0% 9
Inhalation/nasal spray 13.3% 6
None of the above 0.0% 0
answered question 46
skipped question 0

0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
120.0%

109
4. Pharmaceutical Container Closure Development Survey
Does your company perform primary stability studies of your drug
product in the proposed marketing configuration for the primary container
closure system?
Answer Options
Response
Percent
Response Count
Never 4.3% 2
Sometimes 0.0% 0
Usually 8.7% 4
Always 67.4% 31
Cannot answer 19.6% 9
answered question 46
skipped question 0

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
Never Sometimes Usually Always Cannot answer

110
5. Pharmaceutical Container Closure Development
Survey
Does your company conduct studies to establish the integrity of the
primary container closure system in lieu of sterility testing?
Answer Options
Response
Percent
Response Count
Never 6.5% 3
Sometimes 13.0% 6
Usually 6.5% 3
Always 8.7% 4
Do both tests 54.3% 25
Can't answer 10.9% 5
answered question 46
skipped question 0

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Never Sometimes Usually Always Do both tests Can't answer

111
6. Pharmaceutical Container Closure Development
Survey
Does your company conduct studies to establish the level of
protection from moisture for the drug product in the primary
container closure system?
Answer Options
Response
Percent
Response Count
Never 6.5% 3
Sometimes 32.6% 15
Usually 23.9% 11
Always 28.3% 13
Cannot answer 8.7% 4
answered question 46
skipped question 0

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
Never Sometimes Usually Always Cannot answer

112
7. Pharmaceutical Container Closure Development
Survey
Does your company conduct studies to establish the potential for
adsorption of the drug product to the primary container closure
system container?
Answer Options Response Percent
Respons
e Count
Never 4.5% 2
Sometimes 38.6% 17
Usually 20.5% 9
Always 27.3% 12
Cannot answer 9.1% 4
answered question 44
skipped question 2

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
Never Sometimes Usually Always Cannot answer

113
8. Pharmaceutical Container Closure Development Survey
Does your company conduct studies to establish the justification for use of
materials for the secondary packaging system with the primary container
closure system?
Answer Options Response Percent Response Count
Never 6.5% 3
Sometimes 58.7% 27
Usually 8.7% 4
Always 10.9% 5
Cannot answer 15.2% 7
answered question 46
skipped question 0

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Never Sometimes Usually Always Cannot answer

114
9. Pharmaceutical Container Closure Development Survey
Do you conduct studies on container leachables for drug product
interaction with shipping materials other than the primary and
secondary container closure system?
Answer Options Response Percent Response Count
Never 46.7% 21
Sometimes 22.2% 10
Usually 0.0% 0
Always 4.4% 2
Cannot answer 26.7% 12
answered question 45
skipped question 1

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
50.0%
Never Sometimes Usually Always Cannot answer

115
10. Pharmaceutical Container Closure Development
Survey
Does your company conduct studies to establish the accuracy and
reproducibility of drug product delivery devices that are part of the
primary container closure system?
Answer Options Response Percent Response Count
Never 2.2% 1
Sometimes 26.1% 12
Usually 17.4% 8
Always 30.4% 14
Can't answer 4.3% 2
Not applicable 19.6% 9
answered question 46
skipped question 0

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
Never Sometimes Usually Always Can't answer Not
applicable

116
11. Pharmaceutical Container Closure Development
Survey
Does your company use packaging drug master files (Type III
DMF) to support your submission dossier for your drug product?
Answer Options Response Percent Response Count
Never 19.6% 9
Sometimes 15.2% 7
Usually 8.7% 4
Always 32.6% 15
Cannot answer 23.9% 11
answered question 46
skipped question 0

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
Never Sometimes Usually Always Cannot answer

117
12. Pharmaceutical Container Closure Development Survey
Do you conduct studies on container extractables for drug product interaction with the primary container closure system?
Answer Options Never Sometimes Usually Always Response Count
With the
container itself
2 6 4 34 46
With the
container label
21 18 0 5 44
With the label
adhesive
19 18 0 9 46
With the label
inks
21 18 0 5 44
answered question 44
skipped question 2

0
5
10
15
20
25
30
35
40
45
50
With the container
itself
With the container
label
With the label
adhesive
With the label inks
Never
Sometimes
Usually
Always

118
13. Pharmaceutical Container Closure Development Survey
Do you include the primary container closure leachables as part of primary
stability testing protocols?

Answer Options
Response
Percent
Response Count

Never 18.2% 8

Sometimes 34.1% 15

Usually 6.8% 3

Always 40.9% 18

answered question 44

skipped question 2

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
Never Sometimes Usually Always

119
14. Pharmaceutical Container Closure Development Survey
Do you monitor leachables as part of ongoing commercial stability?
Answer Options
Response
Percent
Response Count
Never 40.9% 18
Sometimes 36.4% 16
Usually 4.5% 2
Always 18.2% 8
answered question 44
skipped question 2

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
Never Sometimes Usually Always

120
15. Pharmaceutical Container Closure Development Survey

Have you ever had a drug product recall due to container leachables?

Answer Options
Response
Percent
Response Count

Never 76.2% 32

Rarely 14.3% 6

Occasionally 9.5% 4

answered question 42

skipped question 4

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
Never Rarely Occasionally

121
16. Pharmaceutical Container Closure Development
Survey
Have you ever had a marketing application delayed due to a
packaging issue such as extractables and/or leachables?

Answer Options
Response
Percent
Response Count

Never 54.8% 23

Rarely 35.7% 15

Occasionally 9.5% 4

answered question 42

skipped question 4

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Never Rarely Occasionally

122
17. Pharmaceutical Container Closure Development Survey
Do you conduct studies to establish the safety of materials of construction of the
primary container closure system?

Answer Options
Response
Percent
Response Count

Never 15.9% 7

Sometimes 25.0% 11

Usually 27.3% 12

Always 31.8% 14

answered question 44

skipped question 2

0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
Never Sometimes Usually Always

123
18. Pharmaceutical Container Closure Development Survey
Which of the following statements best describes your feelings about the adequacy of the
guidance documents from FDA for extractable/leachable testing?
Answer Options
Strongly
Agree
Agree Neutral Disagree
Strongly
Disagree
Unable
to State
To
tal
The guidances from
FDA meets my needs
for
extractable/leachable
testing.
2 14 5 15 0 7 43
The guidance
documents are
broadly adequate but
require more
information about
certain topics.
7 20 10 2 0 6 45
The guidance
documents are
relatively old and no
longer provide
adequate guidance
for
extractable/leachable
testing.
3 24 9 7 0 3 46
answered question 46
skipped question 0

0
5
10
15
20
25
30
35
40
45
50
The guidances from
FDA meets my needs
for
extractable/leachable
testing.
The guidance
documents are
broadly adequate but
require more
information about
certain topics.
The guidance
documents are
relatively old and no
longer provide
adequate guidance for
extractable/leachable
testing.
Strongly Agree
Agree
Neutral
Disagree
Strongly
Disagree

124
19. Pharmaceutical Container Closure Development Survey
How do you feel about the adequacy of the USP and/or Ph Eur) compendial chapters for
extractable/leachables testing?
Answer Options
Strongly
Agree
Agree Neutral
Dis-
agree
Strongly
Disagree
Unable to
State
To
tal
The compendial
chapters meet my
needs for
extractable/leachable
testing.
1 13 6 12 3 10 45
The compendial
chapters are broadly
adequate but require
more information
about certain topics.
3 16 11 2 3 10 45
The compendial
chapters are
relatively old and no
longer provide
adequate guidance
for
extractable/leachable
testing.
5 17 7 7 0 10 46
answered question 46
skipped question 0

0
5
10
15
20
25
30
35
40
45
50
The compendial
chapters meet my
needs for
extractable/leachable
testing.
The compendial
chapters are broadly
adequate but require
more information about
certain topics.
The compendial
chapters are relatively
old and no longer
provide adequate
guidance for
extractable/leachable
testing.
Strongly Agree
Agree
Neutral
Disagree
Strongly
Disagree

125
20. Pharmaceutical Container Closure Development Survey

Which of the following documents do you use routinely?

Answer Options Response Percent
Response
Count
FDA 1999 Container Closure
Systems
86.6% 39
ICH Q6A Specifications 47.7% 21
ICH Q1A (R2) Stability Testing 70.5% 31
FDA 2003 BA & BE Nasal Aerosols
and Sprays
4.5% 2
FDA 2008 Container Closure Integrity
Testing
63.6% 28
ICH Q8 Pharmaceutical Development 54.5% 24
PQRI Document Nasal/Inhalation
Products
9.1% 4
answered question 44
skipped question 2

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
FDA 1999
Container Closure
Systems
ICH Q1A (R2)
Stability Testing
FDA 2008
Container Closure
Integrity Testing
PQRI Document
Nasal/Inhalation
Products
ICH
Q8
Pharm
Dev
ICH
6A
Specs
FDA
2003
BA/BE
Nasal
Spray

126
21. Pharmaceutical Container Closure Development Survey
If you lost access to one document, which document would be
the one that would have the greatest impact on your
extractable/leachable program?

Answer Options Response Percent
Response
Count
FDA 1999 Container
Closure Systems for
Packaging Human
Drugs and Biologics
54.5% 24
ICH Q6A
Specifications
0.0% 0
ICH
Q1A(R2)Stability
Testing
13.6% 6
FDA 2003 BA & BE
Nasal Aerosols and
Sprays for Local
Action
0.0% 0
FDA 2008 Container
Closure Integrity
Testing in lieu of
Sterility Testing in
Stability
11.4% 5
ICH Q8
Pharmaceutical
Development
9.1% 4
PQRI Document on
Nasal/Inhalation
Products
11.4% 5
answered question 44
skipped question 2

0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%

127
Sufficie ntly
current for
my needs
Adequate
but needs
re visio n
Out-of-date
and should
be revised
Cannot judge
Response
Co unt
7 16 12 9 44
12 7 1 21 41
20 6 1 15 42
5 0 0 35 40
19 5 3 16 43
24 5 1 12 42
44
2
Please choose the best answer to describe your feelings about each of these documents.
FDA 2003 BA & BE Nasal Aerosols and Sprays
FDA 1999 Container Closure Systems
IC Q8 Pharmaceutical Development
22. Pharmaceutical Container Closure Development Survey
ICH A1 (R2) Stability Testing
skipped question
Answer Options
FDA 2008 Container Closure Integrity Testing
ICH Q6A Specifications
answered question
0
5
10
15
20
25
30
35
40
45
50
FDA 1999
Container
Closure Systems
ICH A1 (R2)
Stability Testing
FDA 2008
Container
Closure Integrity
Testing
Sufficiently current for my needs
Adequate but needs revision soon
Out-of-date and should be revised
Cannot judge
ICH
Q6A
FSA 2003
BA/BE
Nasal
Spray
ICH Q8
Pharm
Dev

23. Pharmaceutical Container Closure
Development Survey
D you have any comments about the current state of regulatory
guidance for extractables/leachables, validation or regulatory
submission?
Answer Options
Response
Count
7
answered question 7
skipped question 39

Number Response Date
Response
Text
Categories

1 Jun 23, 2011 3:18 PM Needs to be more concise and more current with new technology

2 Jun 16, 2011 5:14 PM no

3 Jun 15, 2011 1:31 PM Your survey never asked about oral liquid products.

4 Jun 8, 2011 2:29 PM
No
comments

5 Mar 28, 2011 12:41 PM More specificity regarding limits and threshold values for identification of
extractables and leachables.

6 Mar 26, 2011 3:28 PM Needs more guidance

7 Mar 25, 2011 9:24 PM
The PQRI recommendations document for Parenteral & Ophthalmic drug
products

will be drafted in 2012. The methodology used to generate data to demonstrate

Best Practices for L/E will be posted at PQRI by May 2011. The FDA and Health

Canada are participating in creating the Thresholds and Best Practices

Recommendation Document PODP and MHRA is providing feedback.

A USP chapter on Extractables will be published in the USP NF in 2012.

This will be consistent with PQRI methodology.

128

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Asset Metadata

Creator Mauzey, Duane L. (author)

Core Title Current practices in pharmaceutical container closure development

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 05/04/2012

Defense Date 03/23/2012

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

Tag container closure,current practice survey,Development,extractables,leachables,OAI-PMH Harvest,pharmaceutical

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Alkana, Ronald L. (committee chair), Clemens, Roger (committee member), Fleitman, Jeffrey (committee member), Loeb, Gerald E. (committee member), Richmond, Frances J. (committee member)

Creator Email DLMauzey@AOL.com,mauzey_duane@allergan.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-28701

Unique identifier UC11290339

Identifier usctheses-c3-28701 (legacy record id)

Legacy Identifier etd-MauzeyDuan-753.pdf

Dmrecord 28701

Document Type Dissertation

Rights Mauzey, Duane L.

Type texts

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

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

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA