ICH uality
`
`An Implementation Guide
`
`Edited by Andrew Teasdale,
`David Elder, Raymond W Nims
`
`Eton Ex. 1112
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`-
`
`1CH Quality Guidelines
`
`An Implementation Guide
`
`Edited by
`
`Andrew Teasdale
`AstraZeneca, London, UK
`
`David Elder
`Consultant (Former GSK), Hertford, Hertfordshire, UK
`
`Raymond W. Nims
`RMC Pharmaceutical Solutions, Inc., Longmont, CO, USA
`
`WILEY
`
`Eton Ex. 1112
`2 of 31
`
`

`

`•
`
`ill on UHi)' be r •produced, lot' •d In o r ' lrlcvol y~1,1.l
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`Rt/is"t m i ,jfi
`J hn Wil
`, & on , Inc., 111 River !reel, Holioken, NJ 070 0, U A
`
`Edit uritJI iffic
`Ill Rh, r ' Lrcet, Hobok 11,
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`I 07030, USA
`For detuil of our globnl editor! I offic
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`.wH )•,com,
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`lso nubU he it book In O ~ rl ty or el ctronic format nnd by pr. lnl•on•demand. Some co 1
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`tl
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`appears In
`t ndard print ver Ion ofthl book mny nol be aval
`e In o ,er ,ormn.ts.
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`pro Ucts \lls11
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`Limit of Unbilit /Dlsdaimer of \'(farrm1ty
`In view of ongoing re earch, equipment modllk Uon , changes In governmental regulations, and U,e
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`
`Ubrary of Congress Catalogi11g•l11·Pttblicati011 Data
`Names: Teasdale, Andrew, editor. I Elder, David (David P.), editor. I ims, Raymond \XI.
`Title: lCH quality guideli nes : an implem ntation guide / edlted by Andrew Teasdale,
`Astr;iZeneca, London, United Kingdom, David Elder, Consultant (fGSK), Hertford,
`Hertfordshire, SG14 2DE, United Kingdom, Raymond\"</, Nim , RMC Pharmaceutical
`Solution , Inc., Longmont, CO, USA.
`Other ti tles: LnternatJonal Conference on Harmonization quality guldellnes
`Description: Fl.rst edlti.on, I Hoboken, J: Wiley, 2018. I Include blbllographicol
`references and Index . I
`Identifiers: LCCN 2017013162 (print) I LCCN 2017014318 (ebook) I ISB 9781118971123 (pdf) I
`JS.B 9781118971130 (cpub) I ISBN 9781118971116 (hordboc:k)
`Subjects:LCSH: Drugclcvelopmcnt. I Drugs- Tc ting. I Drug -QuolitycontroL I
`BISAC: M£D1:CAL / Pharmacology. I TECHNOLOGY & ENGINEERING / Quality Control. I
`SCI.ENCE I Chern! try / lndustrlal & Technical.
`Classification: LCC RM30l.25 (cbook) I LCC RM301.25 .124 2018 (print) I DOC 615.l /9- dc23
`LC record available al hltps://lccn.loc.gov/2017013162
`
`Cover image: <I:> Yagl Studio/Gettyimagc
`Cover design by Wiley
`
`Set in 10/12pt Warnock by SPi Global, Pondlc:herry, India
`
`Printed in tlle United State of America
`
`JO 9 8 7 6 5 4 3 2
`
`l
`
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`

`

`Contents
`
`List of Contributors
`
`ix
`
`An Introduction to ICH Quality Guidelines: Opportunities
`and Challenges 1
`
`1
`
`ICHQl A(R2) Stability Testing of New Drug Substance and Product
`and ICHQ1C Stability Testing of New Dosage Forms 3
`Andy Rignall
`
`2 Stability Testing: PhotostabilityTesting of New Drug Substances
`and Products ICH Q1 B 45
`David Clapham
`
`3
`
`ICH Ql D: Bracketing and Matrixing Designs for Stability Testing of New
`Drug Substances and Products 73
`Raymond Peter Munden
`
`4
`
`ICH Ql E Evaluation for Stability Data 89
`Garry Scrivens
`
`s Q2(R1) Validation of Analytical Procedures: Text and Methodology 127
`Phillip Borman and David Elder
`
`6
`
`Impurities in New Drug Substances and New Drug Products: ICH Q3A/B:
`Key Guidelines in the General Impurity Management Process 167
`Andrew Teasdale, David Elder, James Harvey, and Steven Spanhaak
`
`7
`
`ICH Q3C Impurities: Guideline for Residual Solvents 199
`John Connelly
`
`Eton Ex. 1112
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`

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`vi I onterH
`
`8
`
`9
`
`ICH Q30 Elemental Impurities 233
`Andrew Teasdale and Sarah Thompson
`ICH a4: Pharmacopeial Harmonizatlo~ and Evaluation
`and Recommendation of Pharmacopetal Texts for Use
`In the ICH Regions 281
`David Elder
`
`1 o ICH QSA: Viral Safety of Biotechnology Products 311
`Daniel Galbraith
`
`11
`
`ICH QSB Analysis of the Expression Construct In Cell Lines Used
`for Production of Recombinant ONA-Derived Protein Products 337
`Jlanxln Ye, Zhong Liu, and David Pollard
`
`12
`
`ICH QSC Stability Testing of Biotechnological/Biological Products 345
`John G. Davies, DI Gao, Yoen Joo Kim, Richard Harris~ Patricia W. Cash,
`Timothy L. Schofield, Roujlan Zhang, and Qiang Qin
`
`13 QSO Derivation and Characterization of Cell Substrates Used
`for Production of Biotechnological/Biological Products 37S
`Mark Plavsfc
`
`14 Conduct of Risk. Assessments: .An Integral Part of Compliance with ICH
`QSA and ICH QSD 395
`Raymond W. Nims
`
`15
`
`16
`
`17
`
`ICH QSE Comparability of Biotechnologlcal/Blological Products Subject
`to Changes in Their Manufacturing Processes: Summary and Analysis
`of ICH QSE Guideline 409
`Raman/ R. Raghavan and Robert Mccombie
`
`ICH Q6A Specifications: Test Procedures and Acceptance Criteria for
`New Drug Substances and New Drug Products: Chemical Substances 433
`David Elder
`
`ICH Q6B Specifications: Te.st Procedures and Acceptance Criteria
`for Biotechnological/Biological Products 467
`Scott R. Rudge and Raymond W. Nims
`
`18 Process-Related Impurities in Biopharmaceutlca1s: A Deeper Dive Into
`ICH Q68 487
`Anil Raghani, Kim U, Jeanine L. Bussiere, Joel P. Bercu, and Jinshu Qiu
`
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`

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`Contents I vii
`
`19
`
`ICH 07 Good Manufacturing Practice Guide for Active
`Pharmaceutical Ingredients {APls) 509
`Gordon Munro
`
`20 Q8(R2): Pharmaceutical Development 535
`Per Holm, Morten Alles0, Mette C. Bryder, and Rene Holm
`
`21
`
`ICH 09 Quality Risk Management 579
`David Elder and Andrew Teasdale
`
`22
`
`ICH 010 Quality Systems: ICH 01 O Implementation
`at Genentech/Roche 611
`Larry Wigman and Danny Ooi
`
`23
`
`ICH 011: Development and Manufacture of Drug Substance 639
`Ronald Ogilvie
`
`24
`
`ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities
`In Pharmaceuticals to Limit Potential Carcinogenic Risk 667
`Andrew Teasdale
`
`Index 701
`
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`

`

`List of Contributors
`
`Morten AllesfiJ
`Chemical and Pharmaceutical
`Research
`H. Lundbeck A/S
`Valby
`Denmark
`
`Joel P. Bercu
`Gilead Sciences, Inc.
`Foster City, CA
`USA
`
`Phillip Borman
`GSK
`Ware
`UK
`
`Mette C. Bryder
`Chemical and Pharmaceutical
`Research
`H. Lundbeck A/S
`Valby
`Denmark
`
`Jeanine L. Bussiere
`Amgenlnc.
`Thousand Oaks, CA
`USA
`
`Patricia W. Cash
`Medlmmune
`Gaithersburg, MD
`USA
`
`David Clapham
`David Clapham, Independent
`Pharmaceutical Consultant
`Hertfordshire
`UK
`
`John Connelly
`ApoPharma Incorporated
`Toronto, Ontario
`Canada
`
`John G. Davies
`Medlmmune
`Gaithersburg, MD
`USA
`
`David Elder
`David P Elder Consultancy
`Hertford
`UK
`
`Daniel Galbraith
`BioOursource Ltd.
`Glasgow
`UK
`
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`

`

`L r of ontrlbutors
`
`D/Gao
`traZen ca
`Fr d rl k, MD
`UA
`
`Richard Harris
`A traZ neca
`Frederick, MD
`USA
`
`James Harvey
`GSK
`Ware
`UK
`
`Per Holm
`Chemical and Pharmaceutical
`Research
`H. Lundbeck A/S
`Valby
`Denmark
`
`Rene Holm
`Chemical and Pharmaceutical
`Research
`H. Lundbeck A/S
`Valby
`Denmark
`
`YoenJooK/m
`Medlmmune
`Gaithersburg, MD
`USA
`
`Kimll
`Amgen Inc.
`Thousand Oaks, CA
`USA
`
`Robert Mccombie
`Genentech Inc.
`San Francisco, CA
`USA
`
`Raymond Peter Munden
`Munden Consultancy
`Royston
`UK
`
`Gordon Munro
`Munro-Elbrook Associates
`Welwyn
`UK
`
`Raymond W. Nims
`RMC Pharmaceutical Solution 1
`s, nc
`Longmont, CO
`·
`USA
`
`Ronald Ogilvie
`Pfizer
`Sandwich
`UK
`
`DannyOoi
`Genentech, a Member of the Roche
`Group
`South San Francisco, CA
`USA
`
`Mark Plavsic
`Lysogene
`Cambridge, MA
`USA
`
`Zhong Liu
`Merck & Co. Inc.
`Kenilworth, NJ
`USA
`and
`Currently at: Adella Biologics
`Piscataway, NJ
`USA
`
`David Pollard
`Merck & Co. Inc.
`Kenilworth, NJ
`USA
`and
`Currently at: Amicus Therapeutics
`Cranbury, NJ
`USA
`
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`

`

`List of Contributors I xi
`
`Qlang Qin
`AstraZeneca
`Frederick, MD
`USA
`and
`Current Affiliation: GlaxoSmithKline
`Rockville, MD
`USA
`
`Garry Scrivens
`Pfizer
`Sandwich
`UK
`
`Steven Spanhaak
`Janssen Pharmaceutica NV
`Beerse
`Belgium
`
`JinshuQiu
`Amgen Inc.
`Thousand Oaks, CA
`USA
`
`Anil Raghanl
`Coherus BioSciences, Inc.
`Camarillo, CA
`USA
`
`RamaniR.Raghavan
`Merck & Co., Inc.
`Rahway, NJ
`USA
`
`Andy Rigna/1
`AstraZeneca
`London
`UK
`
`Scott R. Rudge
`RMC Pharmaceutical Solutions, Inc.
`Longmont, CO
`USA
`
`Timothy L. Schofield
`Current Affiliation: GlaxoSmithKline
`Rockville, MD
`USA
`and
`Medlmmune
`Gaithersburg, MD
`USA
`
`Andrew Teasdale
`AstraZeneca
`Macclesfield
`UK
`
`Sarah Thompson
`AstraZeneca
`Macclesfield
`UK
`
`Larry Wigman
`Genentech, a Member of the Roche
`Group
`South San Francisco, CA
`USA
`
`Jianxln Ye
`Currently at: Amicus Therapeutics
`Cranbury, NJ
`USA
`and
`Merck & Co. Inc.
`Kenilworth, NJ
`USA
`
`Roujlan Zhang
`AstraZeneca
`Frederick, MD
`USA
`
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`

`

`An Introduction to ICH Quality Guidelines
`
`Opportunities and Challenges
`
`The International Conference on Harmonisation (ICH) of technical require(cid:173)
`ments for registration of pharmaceuticals for human use was initiated in April
`1990. ICH had the initial objective of coordinating the regulatory activities of
`the European, Japanese, and the United States bodies (along with the pharma(cid:173)
`ceutical trade associations from these three regions), to discuss and agree the
`scientific and technical aspects arising from product registration. This was
`recently supplemented by the addition of Health Canada and Swissmedic, to
`the core ICH Steering Committee (SC) [1].
`At the initial ICH SC meeting the terms of reference were agreed and it was
`decided that harmonisation initiatives would be divided into Safety (S), Quality
`(Q), and Efficacy (E), reflecting the main criteria which underpin the approval
`and authorization of new medicinal products. It was subsequently realised that
`several topics were multi-disciplinary (M) in nature.
`Thus, ICH's mission was to realize greater harmonization in both the inter(cid:173)
`pretation and application of requirements for new product registration, with
`the objective of minimizing repetition/duplication of both testing and report(cid:173)
`ing, which is routinely performed as part of the development of new medicinal
`products. Harmonizing these differences via the ICH guidelines would help
`industry reduce development times, save resources and benefit the patient.
`It is difficult not to underestimate the benefits of the ICH initiative in general
`and the ICH Quality guidelines in particular (and those related Multi(cid:173)
`Disciplinary guidelines), to the CMC community. Although it is fair to state
`that not all of the guidelines have been equally successful; it is very clear that
`the majority have been very successful and there is an ongoing recognition of
`the need to update and maintain the guidance in line with new developments
`and technological advances. Furthermore, the desire to extend the benefits of
`harmonisation beyond the ICH regions through collaborative efforts is to be
`welcomed and brings us a step closer to global harmonisation of these impor(cid:173)
`tant principles of medicinal product evaluation. As part of the objective to
`extend its global outreach, ICH recently welcomed new regulatory members
`
`ICH Quality Guidelines: An Implementation Guide, First Edition. Edited by Andrew Teasdale,
`David Elder, and Raymond W. Nims.
`© 2018 John Wi.ley & Sons, Lnc. Published 2018 by John Wiley & Sons, Inc.
`
`-
`
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`.. - -
`
`l I /CH Quality Gufdelines
`
`;---• • . •1• • • • • I •
`- --"'-:-~ .... ~ .. ~. ·:._·/ .. _· ...
`
`•
`
`fr m Brazil and South Korea. In addition regulatory authorit'
`ICH O
`d
`ies fro
`I
`_ bservers [2 lll. Cll.b
`E azakh tan, and outh Afri~a ~ere ~ so agree as
`h ucc s ofth ICH guidelines, m many ways has been duet
`].
`a.,
`f over rching principles and a guidance framework describ~ the acfopt·
`1~11
`r quirements for compliance without being overly prescrip/ng the 111
`1ve. 'ti
`.
`.
`.
`_
`.
`b
`a1n
`. 1
`et wnu
`varying levels of detailed information has een me uded in the dirt
`Hn s to facilitate understanding, it ha_s left many seeking further ~~:;t_gllic!e~
`on the _practical application of the guidance. The purpose and b
`_if1cation
`fdrelo:1 ;d through de; this
`book is that it allows the reader a feeper 1r;;.1g
`'d
`.
`. ht
`enefit
`f
`d
`chapters into the practical aspects o a spec 1c gm mes applicatio
`Each of the chapters seeks to examine the key requirements of th n.
`guidelines and then considers the chal_lenges b?th in i?terpretation a:dsPec~c
`cal implementation. It is this perspective, lookmg behmd the basic fr
`PractJ_
`and then examining both the intent and practical guidance that I b;ework;
`make this text an essential aid to those involved in CMC matters, both 1;ve Will
`ro.rn an
`industry and regulators' perspective.
`To achieve the intended goal the Editors have pulled together an un . all
`riv ed
`collation of subject matter experts aligned to each chapter, many invol
`directly in the derivation of the ICH guidelines themselves.
`Ved
`
`cated
`
`Dr David Tainsh, Chief Product Quality Officer, GSK
`
`References
`
`1 SwissMedic. ICH Meeting in Minneapolis, USA: SwissMedic and Health
`Canada Included as New Members, July 9, 2014. https:/ /www.swissmedk.ch/
`aktuell/00673/02270/index.html?lang=en. Accessed on February 27, 2017.
`2 ICH. Press Release Osaka Meeting, ovember 17, 2016. http://www.ich.org/
`ichnews/press-releases/view/artide/ich-assembly-osaka-japan-november-2016.
`html. Accessed on April 12, 2017.
`
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`1
`
`ICH01 A(R2) Stability Testing of New Drug
`Substance and Product and ICHQ1 C Stability
`Testing of New Dosage Forms
`Andy Rignall
`
`AstraZeneca, London, UK
`
`1.1
`
`Introduction
`
`A core part of the medicines development process is an understanding of the
`chemical and physical behavior of the active ingredient and the medicinal
`product into which it is incorporated under the storage and usage conditions
`they are likely to encounter. The International Conference on Harmonisation
`of Technical Requirements for the Registration of Pharmaceuticals for Human
`Use (ICH) stability guidance provides a foundation and framework for this
`endeavor.
`Stability testing was one of the first quality, safety, and efficacy topics harmo(cid:173)
`nized across the ICH territories (Europe, USA, Japan, Canada, and Switzerland)
`in tripartite guidance. The latest revision of ICHQlA Stability Testing of New
`Drug Substances and Products was adopted in 2003 [l]. It forms the parent
`guideline to a suite of associated guidelines providing more details on
`recommended stability practice. The guideline provides information on stor(cid:173)
`age conditions and duration and testing requirements that should be used to
`generate the core stability data package in support of product registration in
`the ICH regions. To encompass the behavior of different drug delivery plat(cid:173)
`forms and their input drug substances, the guideline contains some flexibility
`in the requirements. Importantly, the guideline also includes an introductory
`statement recognizing that alternative stability approaches can be used if
`scientifically justified. A short annex to the parent stability guideline is embod(cid:173)
`ied in ICHQlC, which addresses the stability requirements for a new dosage
`form when an applicant develops a new product variant following an original
`drug substance and drug product application [2].
`
`ICH Quality Guidelines: An Implementation Guide, First Edition. Edited by Andrew Teasdale,
`David Elder, and Raymond W Nims.
`© 2018 John Wtley & Sons, Inc. Published 2018 by John Wtley & Sons, Inc.
`
`Eton Ex. 1112
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`

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`41 ICH Quality Guidelines
`
`As worldwide registration is the goal for many medicinal pr d
`standardization and simplification of the global supply chain°£ Ucts, the
`medicine, via harmonized stability and labeling practice, is desirable.~~ new
`intent of the guideline is to recommend the data sets required to r
`.
`ile the
`drug substance and products in the three main ICH regions, its con;g1st_er new
`and used much more widely. The ICH guidelines are also referencede~tis cited
`rial guidance beyond the ICH regions either on a stand-alone 6in_territo-
`as1s or .
`l h
`support oflocal stability guidance. For examp e, t e World Health Org
`.
`in
`an1zati
`(WHO) is a long-standing observer of the ICH process, leading to the.
`0n
`incorpo
`.
`. .
`.
`.
`ration of much of the content of the ICH mto its own stability guidance [3] -
`The ICH stability guidance not only is intended for registration purpose ·
`also informs stability practice during development, for example, the st:r but
`conditions described in the guidance can ~rovide a fr~mework for the devel~g~
`ment stability protocols used to underwnte the quality, safety, and efficac pf
`Y 0
`drug product used in clinical studies.
`While the guidance embodies a traditional approach to stability protocols
`the principles described in terms of the stability performance requirements fo;
`pharmaceutical products have also been translated into targets for predictive
`stability screening tools. These tools can provide assurance that when formal
`stability studies to support product registration are performed in accordance
`with ICH guidance, the likelihood of obtaining unexpected results is reduced.
`Some stability testing requirements are linked with specific product
`platforms and are detailed in other guidance. Examples include instructions
`relating to studies that justify in-use storage, strategies to demonstrate the suit(cid:173)
`ability of protective secondary packaging, and specific studies to underwrite
`temperature excursions during storage and transportation.
`In the "quality by design" era, where pharmaceutical development practice is
`guided by science- and risk-based approaches, highlighted in three more recent
`ICH guidelines on pharmaceutical development [4], risk management [5]. and
`pharmaceutical quality system [6], the focus for stability studies has evolved
`further to emphasize the importance of generating detailed stability knowl(cid:173)
`edge and understanding. This may include establishing the attributes of the
`input materials (drug substance and excipient) and any processing parameters
`that are critical to stability performance. Following identification of the attrib(cid:173)
`utes critical to stability, an integrated control strategy should be established to
`ensure the attributes remain within acceptable limits, thereby assuring that the
`required stability performance is demonstrated. The use of risk management
`tools to ensure development activities are focused on the areas that will have
`the most influence on the control of stability (and therefore quality safety aotl
`efficacy) is also a feature.
`
`From a practical perspective, the goal of performing stability testing r
`
`products intended for global registration remains challenging, requirin~ t~
`development of a protocol that will result in a high probability of approval 10
`
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`
`

`

`ICHQ 1 A(R2) Stability Testing of New Drug Substance and Product I s
`
`major markets. Regions with their own specific stability requirements can
`make the development of a truly "global" registration protocol more challeng(cid:173)
`ing. For example, the guidance on stability study requirements for the registra(cid:173)
`tion of drug products in countries forming the ASEAN region of Southeast
`Asia recommends a different long-term storage condition compared with the
`1CH regions [7).
`This chapter aims to provide an understanding of the fundamental principles
`behind stability testing and then demonstrate how the guidance is typically
`applied during pharmaceutical development.
`
`1.2 The Fundamental Science That Underpins
`Stability Testing
`
`1.2.1 The Stability Process
`
`Quality, safety, and efficacy must be maintained throughout the shelf life of a
`medicine, from manufacture to the end of shelf life and when being used by the
`patient. This can be achieved by developing an understanding of the chemical
`and physical properties of the product so that it is possible to establish meth(cid:173)
`ods to control and monitor the critical parameters and establish the long-term
`behavior of the drug substance and medicine.
`The regulations require an expiry date on drug products or a retest date on
`active pharmaceutical ingredient [8]. For drug product, the expiry date defines
`the period within which the drug product is expected to comply with its
`approved control specification limits when stored under the recommended
`conditions. Similarly, a retest date is assigned to drug substance. If a drug sub(cid:173)
`stance batch is required for drug product manufacture beyond its labeled retest
`date, it should be retested to confirm continued compliance with specification
`prior to use. Stability testing provides the means to investigate how a medicine
`behaves under different environmental conditions and demonstrate that a
`pharmaceutical product maintains its fitness for use throughout this labeled
`shelf life. The stability testing of drug products involves evaluating them on
`storage over time in the container/closure system intended for use in the clinic
`or the commercial market.
`The stability of a pharmaceutical product is the result of a complex interplay
`between environmental factors (temperature, humidity, availability of oxygen,
`and exposure to light), and the intrinsic chemical and physical stability of active
`ingredients and formulation excipients. The conditions under which these
`ingredients are processed to form the medicine, and the degree of protection
`provided by any primary and secondary packaging are also influencing factors.
`The stability process involves finding out what degradation pathways are
`available to a new chemical entity, what steps can be taken to assess the extent
`
`Eton Ex. 1112
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`61 ICH Quality Guidelines
`
`of degradation most likely to be encountered under normal storag
`.
`b
`d d
`1.
`e, and h
`~gradation. Che w_ at
`strategies are available to prevent or 1~t any O serve
`breakdown constitutes a major factor m drug or formulation failure
`rn1caJ
`on st0r
`b' l
`·
`·
`l h
`i
`but physical, biological, and micro 10 og ca c anges can also be a so
`age,
`instability.
`Urce of
`Chemistry driven changes include changes in product quality or
`performance characteristics caused by
`
`Product
`
`• Increase in levels of degradation products with potential impact on sa£
`• Potency loss associated with chemical breakdown/reaction of active in etl .
`'th
`ff'
`· l ·
`g ed1-
`ent w1
`potentta impact on e 1cacy
`• Change in visual, taste, or odor caused by increased levels of degradar
`with potential impact on overall product acceptability
`ion,
`
`The extent of chemical breakdown does not need to be significant for potential
`problems to occur, for example, formation oflow levels of a breakdown product
`that gives rise to specific safety concerns or small amounts of a highly colored
`degradation product affecting visual appearance.
`
`1.2.2 Factors Affecting Stability
`
`Demonstrating stability knowledge and appropriate control involves develop(cid:173)
`ing an understanding of the factors that can affect the stability of a medicine
`and confirming that appropriate controls are in place to assure quality, safety,
`and efficacy throughout the labeled shelf life. These factors include
`
`• The intrinsic stability of the active pharmaceutical ingredient(s)
`• Input excipient properties and how they affect the stability of the API
`• The unit operations associated with the manufacturing process
`• Environmental factors (external, internal, and microenvironment)
`• The materials and functionality associated with any packaging system
`
`Further factors affecting product stability are outlined in Figure 1.1
`
`Intrinsic Stability of the Active Pharmaceutical Ingredient
`1.2.2.1
`Pharmaceuticals are often developed as salts of organic acids or bases in order
`to achieve the desired physicochemical properties. Ironically often the
`functionality that imparts the desired efficacy in a medicine may also make tbe
`molecule less stable. Pharmaceuticals are generally composed of carbon
`skeletons with additional functional groups. Electron distribution, bond P~~r(cid:173)
`
`ity, and steric factors associated with the carbon skeleton can all affect stab~ i
`
`Factors affecting the electron distribution or electron density, in a dru
`l
`ou·
`molecule, can greatly affect its susceptibility to degradation. For examp ~• via
`ble bonds alternated across a structure can impart stabilizing conjugation·gid
`delocalized electron density. The conjugation can make a molecule more rl
`
`Eton Ex. 1112
`15 of 31
`
`

`

`ICHQ1A(R2) Stability Testing of New Drug Substance and Product 17
`
`Input material
`properties
`
`Manufacturing
`process
`
`Mixing/agitation
`Size reduction
`Compaction
`Drug/exciplent ratio
`
`Pharmaceutical
`product
`stability
`
`Impact of unit operations
`
`Intrinsic stability
`surtace properties
`Physical state/form
`Impurities
`Contaminants
`Hygroscoplcity ----1""
`
`Degree of protection
`Moisture permeability
`Leaching of additives
`
`Temperature
`Humidity
`Transportation
`Patient usage
`
`Packaging
`
`Environment
`
`Figure 1.1 Factors potentially affecting product stability.
`
`and also enhance the absorption of UV light. The delocalized electrons can act
`as a conduit for the transmission of electron density or full negative or positive
`charge, and this resonance can stabilize charged species making them more
`likely to form. Inductive effects can result in bond polarization, a movement of
`electron density across the bond depending on the electronegative or
`electropositive nature of substituents. Substituent groups can profoundly
`affect the reactivity, and therefore stability, of pharmaceuticals. Neighboring
`substituents may interrupt conjugation inhibiting electron delocalization and
`the potential for resonance stabilization. More often neighboring substituents,
`especially the bulky ones, prevent a reagent getting to the reaction site,
`particularly true for nucleophilic substitution (SN2) reactions. Similarly, the
`presence of a bulky counterion such as chloride can protect the salt-forming
`center of the drug substance from oxidative attack. These are all examples of
`steric hindrance.
`Knowledge of the shape and molecular arrangement in tandem with the
`knowledge of how functional groups react enables theoretical prediction on
`how a new chemical entity might behave under given physical and chemical
`conditions [9].
`Knowledge of the environment within the formulation allows prediction of
`those conditions that may initiate or catalyze the reactions causing
`breakdown.
`Therefore, developmental stability programs should be designed to dem(cid:173)
`onstrate how robust a product is to environmental conditions of heat,
`humidity, and light. These programs are often more extreme than the default
`ICH storage conditions as there is a desire to accelerate the degradation to
`
`Eton Ex. 1112
`16 of 31
`
`

`

`a I ICH Quality Guidelines
`
`allow meaningful decisions to be made in shorter time period
`s. Ser
`·
`l
`.
`·th
`ee1uh
`studies to investigate chem1ca reactions w1
`extraneous spe .
`.
`.
`k
`,,g
`. cies s
`dd" .
`l
`Uch a
`process impurities or formu ation or pac agmg a 1tives should al
`sidered as well as studies to assess the potential for physical chan so be cor/
`.
`ges to
`.
`0cc\J.t
`on storage.
`
`1.2.2.1. 7 Degradation Reaction Pathways
`Chemical Breakdown There are four main reaction mechanisms all
`of Whi k
`.
`b t·
`d
`'
`.
`d
`may occur as part of a degra atlve process: su s 1tut1on, a dition, elirninar clt
`10n,
`and rearrangement. Degradation reactions can be broadly catego .
`.
`d .
`.
`nzed a
`t.
`hydrolysis, oxidation, photolysis, an 1somenza ion or rearrangement. In
`.s
`tion, specific interactions between the active molecule and functional addi.
`xt
`d .
`·t·
`groups
`l
`on excipients, process-re ate 1mpun 1es, or e raneous contaminants
`also result in additional degradation reaction pathways.
`
`rnay
`
`Hydrolysis Due to the ubiquity of water as a potential reactant, the most
`prevalent reaction mechanism associated with degradation reactions is hydrol(cid:173)
`ysis. Derivatives of carboxylic acids such as esters, amides, imides, lactones,
`lactams, and acid chlorides are particularly susceptible [10]. It is difficult to
`completely eliminate water from solid drug products, and it is also the most
`commonly used solvent for parenteral products. The general reaction for car(cid:173)
`boxylic acid derivatives is shown:
`
`RCOOR' + H 2O (cid:157) RCOOH + R'OH
`
`Water acts as a nucleophile attacking electron-deficient or electropositive sites
`within drug molecules. The acyl derivatives ester, amide, and imide are most
`prone to attack, and acid or base can catalyze the reaction.
`Alkaline hydrolysis involves the initial nucleophilic attack of a hydroxide ion
`on the electropositive center and then, for example, in the case of an ester,
`elimination of the alkoxy substituent to form an acid and alcohol.
`In acid-catalyzed hydrolysis of esters, the carbonyl oxygen is protonated and
`then water nucleophilically attacks the electron-deficient carbon center.
`Aromatic esters are more reactive compared with aliphatic.
`The products are the same via either mechanism. Heat/light and local pH
`can also catalyze hydrolysis.
`Although this is a second-order reaction, if water is present in a large excess,
`thi
`it will exhibit pseudo-first-order kinetics.
`5
`A similar situation occurs with solvents that can act as nucleophiles an~
`is termed solvolysis. The polarity (or dipole moment) of the solvent 15 an
`important factor in such reactions.
`tu·
`Pr~tecting a~ ~c~ive ingredient that is prone to hydrolytic degradationa~:ble
`rally mv~lves Iin:11ting th_e presenc~ of unbound water, which would be av ility in
`for react10n. Usmg a suitable moisture barrier with low water permeab
`
`Eton Ex. 1112
`17 of 31
`
`

`

`fCHQ1A(R2) Stability Testing of New Drug Substance and Product 19
`
`Prinla!Y and/or secondary pack will reduce the amount of moisture being
`the
`f
`th
`al
`.
`.
`.
`t
`Ported rom e ex ern environment ms1de the pack. Employing a desiccant
`rrans
`1
`.
`. .
`.th 1
`.
`has silica ge, usmg exciptents w1
`ow moisture content or excipients that can
`sudc rb unbound water such as colloidal silicon dioxide, will also help to maintain
`el .
`a so
`1
`'d th
`·
`1 w humidity lev s ms1 e e protecttve pac (. As extremes of pH can cause hydro-
`0 . breakdown, the use of buffers (more often in solution dosage forms but there
`uf£
`.
`lytIC
`are solid state b er systems muse as well) can stabilize a system.
`
`oxidation Due to its presence in the atmosphere, oxygen represents another
`readily available reactant for potential degradation mechanisms. Where the
`reaction occurs with aerial oxygen, this is often called "autoxidation:• The oxi(cid:173)
`dation me