ICH uality
`
`An Implementation Guide
`
`Edited by Andrew Teasdale,
`David Elder, Raymond W Nims
`
`Eton Ex. 1034
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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. 1034
`2 of 43
`
`

`

`•
`
`This edllion first pnbllshrd :.!018
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`
`library ofCongre,ss Cataloging-i11-P11blicatio11 Data
`Names: Teasdale, Andrew, editor. I Elder, David (David P.), editor. I Nims, Raymond W.
`TI tie: !CH quality guidelines : an implementation guide/ edited by Andrew Teasdale,
`AstraZeneca, London, United Kingdom, David Elder, Consultant (fGSK), Hertford,
`Hertfordshire, SG14 2DE, United Kingdom, Raymond \YI, Nims, RMC Pharmaceutical
`Solutions, Inc., Longmont, CO, USA.
`Other titles: lnternational Conference on Humonization quality guidelines
`Description: First edition, I Hoboken, NJ : Wiley, 2018, I Includes bibliographic.al
`references and index. I
`Identifiers: LCCN 2017013162 (print) I LCCN 2017014318 (ebook) I ISBN 9781118971123 (pdf) 1
`ISBN 9781118971130 (epub) I ISBN 9781118971 116 (hardback)
`Subjects: LCSH: Drug development. I Drugs-Testing. I Drugs-Quality control. I
`BISAC: MEDICAL I Pharmacology. I TECHNOLOGY & ENGINEERING / Quality Control. 1
`SCIENCE I Chemistry / Industrial & Technical.
`Classification: LCC RM301.25 (ebook) I LCC RM30l.25 .124 2018 (print) I DOC 615.l /9-dc23
`LC record available at htlps:f/lccn.loc.gov/2017013l62
`
`Cover image: 10 Yagi Studio/Gettyimagcs
`Cover design by Wdey
`
`Set in 10/ 12pt Warnock by SPi Global, Pondicherry, Lndia
`
`Printed in the United States of America
`
`10 9 8 7 6 5 4 3 2 1
`
`Eton Ex. 1034
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`

`

`Contents
`
`List of Contributors
`
`ix
`
`An Introduction to ICH Quality Guidelines: Opportunities
`and Challenges 1
`
`1
`
`ICHQ1 A(R2) Stability Testing of New Drug Substance and Product
`and ICHQ1 C Stability Testing of New Dosage Forms 3
`Andy Rigna/1
`
`2 Stability Testing: Photo stability Testing of New Drug Substances
`and Products ICH Q1 B 45
`David Clapham
`
`3
`
`ICH Q1 D: Bracketing and Matrlxing Designs for Stability Testing of New
`Drug Substances and Products 73
`Raymond Peter Munden
`
`4
`
`ICH Q1 E Evaluation for Stability Data 89
`Garry Scrivens
`
`S Q2(R1) Validation of Analytical Procedures: Text and Methodology 127
`Phi/lip 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
`
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`

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`(cid:127)-
`
`vi I Contents
`ICH Q30 Elemental Impurities 233
`Andrew Teasdale and Sarah Thompson
`
`8
`
`9
`
`tcH Q4: Pharmacopeial Harmonizatio~ and Evaluation
`and Recommendation of Pharmacope1al Texts for Use
`in the ICH Regions 281
`David Elder
`1 o ICH QSA: Viral Safety of Biotechnology Products 311
`Doniel Galbraith
`
`11
`
`tcH QSB Analysis of the Expression Construct in Cell Lines Used
`for Production of Recombinant ONA-Derived Protein Products 337
`Jianxln 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 Horris, Patricio W. Cash,
`Timothy L. Schofield, Roujian Zhong, and Qiang Qin
`13 QSD Derivation and Characterization of Cell Substrates Used
`for Production of Biotechnological/Biological Products 375
`Mark Plavsic
`
`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 Biotechnological/Biological Products Subject
`to Changes in Their Manufacturing Processes: Summary and Analysis
`of ICH QSE Guideline 409
`Romani 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: Test Procedures and Acceptance Criteria
`for Biotechnological/Biological Products 467
`Scott R. Rudge and Raymond W. Nims
`
`18 Process-Related Impurities in Biopharmaceutlcals: A Deeper Dive into
`ICH Q6B 487
`Anil Raghani, Kim Li, Jeanine L. Bussiere, Joel P. Bercu, and J/nshu Qiu
`
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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 010 Implementation
`at Genentech/Roche 611
`Larry Wigman and Danny Ooi
`
`23
`
`ICH Ql 1: 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 Alles'1J
`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
`Amgen Inc.
`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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`

`

`..
`
`x I List of Contributors
`
`DIGao
`AstraZeneca
`Frede rick, MD
`USA
`
`Richard Harris
`AstraZeneca
`Frederick, MD
`USA
`
`James Harvey
`GSK
`Ware
`UK
`
`Per Holm
`Chem ical 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
`
`Kim Li
`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 Ph armaceutical Solution
`s, nc
`1
`Longm ont, CO
`·
`USA
`
`Ronald Ogilvie
`Pfizer
`Sandwich
`UK
`
`DannyOoi
`Genentech, a Member of the Roche
`Group
`South San Francisco, CA
`USA
`
`Mark Plavsic
`Lysogene
`Cambr idge, MA
`USA
`
`Zhong Liu
`Merck & Co. Inc.
`Kenilwor th, NJ
`USA
`and
`C urrently at: Adello 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
`
`Qiang 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 Raghani
`Coherus BioSciences, Inc.
`Camarillo, CA
`USA
`
`Romani R. Raghavan
`Merck & Co., Inc.
`Rahway, NJ
`USA
`
`Andy Rignall
`AstraZeneca
`London
`UK
`
`Scott R. Rudge
`RMC Pharmaceutical Solutions, Inc.
`Longmont, CO
`USA
`
`Timothy L. Schofield
`Current Affiliation: GlaxoSmithKline
`Rockville, MD
`USA
`and
`Medimmune
`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
`
`Jianxin 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
`
`!CH Quality Guidelines: An Implementation Guide, First Edition. Edited by Andrew Teasdale,
`David Elder, and Raymond W. Nims.
`© 2018 John Wiley & Sons, Inc. Published 2018 by John Wiley & Sons, Inc.
`
`-
`
`Eton Ex. 1034
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`

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`~ - -
`
`21 ICH Quality Gulde/Ines
`
`from Brazil and South Korea. ln addition regulatory authorir
`Kazakhstan, and South Africa were also agreed as ICH Observ~:: ~ 0tn C:ttb
`The success of the ICH guidelines, in many ways has been duet
`].
`a,
`f
`'d
`k
`Othe d
`of overarching principles and a gm ance ramewor describ·
`a opr
`requirements for compliance without being overly prescrip/ng the rn1
`~1\
`ive. Yi
`. 1 d
`.
`h b
`.
`a11\
`et Whu
`varying levels of detailed information as een me u ed m the dif£
`lines to facilitate understanding, it has left many seeking further ~~e~t gltide~
`on the practical application of the guidance. The purpose and b
`ar_ificatiol\
`'d
`enefit f
`. ht
`.
`d
`~ this
`book is that it allows the reader a eeper msig provi ed through
`'d 1·
`,
`if.
`ded1
`f
`chapters into the practical aspects o a spec 1c gm e mes applicatio
`<:ated
`Each of the chapters seeks to examine the key 1:'e~uirements of th:
`. •
`6
`guidelines and then considers the cha~lenges b~th m i~terpretation and P:c1f'.c
`cal implementation. It is this perspective, lookmg behmd the basic fr P acti.
`and then examining both the intent and practical guidance that I b;rework;
`make this text an essential aid to those involved in CMC matters, both i;ve Will
`rom an
`· d
`d
`l
`'
`·
`m ustry an regu ators perspective.
`To achieve the intended goal the Editors have pulled together an unrivaIJ
`collation of subject matter experts aligned to each chapter, many invoJ ed
`directly in the derivation of the ICH guidelines themselves.
`Ved
`
`Dr David Tainsh, Chief Product Quality Officer, GSK
`
`References
`
`SwissMedic. ICH Meeting in Minneapolis, USA: SwissMedic and Health
`Canada Included as New Members, July 9, 2014. https://www.swissmedic.ch/
`aktuell/00673/02270/index.html?lang=en. Accessed on February 27, 2017.
`2 ICH. Press Release Osaka Meeting, November 17, 2016. http:/ /www.ich.org/
`ichnews/press-releases/view/article/ich-assembly-osaka-japan-november-2016.
`html. Accessed on April 12, 2017.
`
`Eton Ex. 1034
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`
`

`

`1167
`
`6
`·,ties in New Drug Substances
`1,ripur
`d New Drug Products
`an
`A/B: Key Guidelines in the General Impurity
`!CH 03
`agement Process
`Man
`d W Teasdale 1, David Eide?, James Harvey,
`An re
`4
`and Steven Spanhaak
`
`, AJttoltt>t<0,Mocdt1fltld, UK
`1 (/0',ldPEJdtrCo,ucJtoncy, Htrtford, UK
`, GSK. Watt, UK
`, JotlJUfl PhotmoctUti<o rN, Betrst, B,lgfum
`
`Introduction
`6.1
`Within the ICH framework, guidelines regulating the management of impuri(cid:173)
`ties in the broader sense started more than two decades ago with the concep(cid:173)
`tion of ICH Q3A fl] and ICH Q3B [2]. 1 These two guidelines are considered
`key within the overall ICH quality guidelines framework since they introduced
`the concept of a thresholded approach to determine when to report, identify,
`and qualify an impurity (or degradant). Qualification is arguably an important
`but correspondingly challenging process to define. It encompasses deciding
`whether or not an identified impurity is, from a safety point of view, below a
`safe limit (which may or may not be the ICH Q3A or Q3B qualification limits)
`based on either available or obtained data or generically defined safe limits
`(like the ICH Q3A or Q3B qualification limits).
`Over time safety and quality requirements have evolved and become more
`prescriptive. Starting with ICH Q3C (3], the guidance issued immediately
`
`1 For almost 20 years since the original versions of both guidelines were issued, they remained
`largely unaltered, despi te minor revisions being made to both. ICH Q3A was first revised In 2002
`:!CH Q3A (RI)) and again in 2006 (!CH Q3A (R2)). !CH Q3B was first revised in 2003 ()CH Q3B
`RI )) ,tnd Jgam m 2006 (ICH Q3B (R2)). For the sake of simplicity throughout the remainder of
`t(hc ch.ipti·r th,•, e guidance documents will simply be referred to as ICH Q3A and !CH Q3B
`pee, 1c rc,cn•nce to revision status., although this infers the latest versions).
`W1thou1 s . ·1 •
`~~~;~ity Grudelines: An Implementatio11 Guide, First Edition. Edited by Andrew Teasdale,
`0 2018 J ~r, and Raymond W. Nims.
`0 n Wiley & Sons, Inc. Published 2018 by John Wiley & Sons, Inc.
`
`r
`
`Eton Ex. 1034
`12 of 43
`
`

`

`168 , ICH Quality Guidelines
`
`•
`
`1:
`
`.
`following Q3A and Q3B, limits have been provided for
`.
`spec1fi
`. . Th
`·al .
`.
`le 'lllp
`ese limits
`impurities.
`organic solvents and e ement
`I
`11
`titie8 ll
`called 1,ermilled daily exposure (PDE) approach introd Were basec1
`on
`uced ·
`.
`1~
`. 1n this
`I b
`_the e
`Such an approach can however on Y e applied for thos
`e llnpu .
`b
`d' h
`&t11.i SQ,
`r
`compound-specific sa,ety stu 1es ave een conducted T
`r1ties r
`\lel:.
`· he
`1or "Ile,
`w~c~
`ICH Q
`same
`3D [4).
`was adopted for the far more recent
`Another area where initial guidance within ICH Q3A
`apProijcL
`and Q
`11
`• (
`t
`3B h
`further expanded relates to geno mac mutagenic) irnpu . .
`as b
`r1t1es A.
`ICH Q3A [
`. .
`een
`lth0 ll
`·
`1) and Q3B [2)
`defined in terms of genotoxicity,
`state h &h
`hr
`l
`•
`t at ll
`ally toxic substances may warrant ower t esholds tha h
`no1
`defined in these guidelines. This is further addressed in tnht ose gene ~lls11.
`e I CH
`r1cau
`.
`.
`.
`.
`. M7 g .. · I
`line [5] that deals with (potentially) mutagemc 1mpuritie 1
`•1de
`s. his
`h'
`· 1:
`1·
`guide!· ·
`provides a lower generic sa1ety 1m1t 1or t ts type of impur'
`ity as, .. I 1ne
`·
`'f' 1·
`t
`·t 1:
`approach to define spec1 1c 1m1 s 1or mu agemc carcinoge b .,.e I as
`ns ased
`. .
`.
`ill!
`. d .
`2 b
`on th
`so-called TDso values o tame m carcmogemc1ty studies
`c
`Per,orrn
`e
`ed 1Yith
`these compounds [5].
`Thus over time the concept of qualification has become mor
`e corn I
`P ex and
`has extended beyond the scope of ICH Q3A and B.
`.
`Interestingly reporting and identification thresholds have r
`ema1ned th
`1
`.
`. h h
`e
`t e tmp ementation of ICH
`same as defined decades ago, even wit
`latter indeed specifically states that actual impurities or degradants ;~· The
`those observed in the drug substance (DS) above the ICH QaA r
`cl~de
`thresholds and that ident_ificat!~n ~f actual impurities is expected :i:nrting
`levels exceed the relevant 1dentif1catlon thresholds as outlined by !CH Q3A tbe
`impurities and !CH Q3B for degradants. However, also here a refinement for
`introduced with the finalization of the ICH M7 [5]. A number of poten:
`impurities or degradants have to be investigated regardless whether they have
`been identified as actual impurities above the relevant ICH Q3A/B thresholds
`in the DS. This concerns potential impurities arising from the synthesis of the
`DS including starting materials, reagents, and intermediates in the route of
`synthesis from the starting material to the DS. Potential degradants in the
`DS and drug product (DP) that may be reasonably expected to form during
`long-term storage conditions also need to be assessed. For these potential
`impurities/ degradants, the most important factor in deciding whether or not
`assessments are required (as per ICH M73 and regardless of ICH Q3 ~nd 8
`defined thresholds) is the probability of their presence in DS or DP at signili·
`cant levels. 4
`
`·aJ
`2 TD50 is the dose giving a 50% tumor incidence in carcinogenicity studies.
`3 That is, in silico assessment of its potential mutagenicity and, if considered a potent!
`1 ical concern
`.
`mutagen, of actual levels present in DS or DP.
`4 That is, actual levels that are above acceptable safety limits (threshold of toXICO og
`(TTC) levels) for mutagenic compounds as defined in ICH M7.
`
`Eton Ex. 1034
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`
`

`

`161·
`
`i
`
`for
`
`Impurities In New Drug Substances ond New Drug Producls \ 169
`·al impurities or degradants need be taken into considera-
`otentl
`otall P
`·
`hat subset that 1s expecte
`d
`b
`to e presenl al significanL
`{h115;\lever, 0~:l ~Sor DP. For potential impurities the risk of carry-over
`U·oll• h. to the fi
`essed based on process knowledge and purging factors
`s tn
`be ass
`ie~s pS ca~ d radants knowledge of relevant degradation pathways is
`iJllo tile potential . ~g s on the selection of potential degradation products to
`. dec1s1on
`.
`g1.11de
`l
`f
`tagenic1ty [51, for examp e, rom degradation chemistry
`.
`osed t~11ated for rou tress testing studies, and development stability studies.
`evai
`\evant s
`f h .
`l)e_ ip\eS, r~
`.
`this specific part o t e impurity management process are
`pr1:er details o~er 24 on ICH M7.
`fo ·ded in Chap knowledge is that for any "unknown" impurity (i.e., those not
`Pro'll
`t to ac
`I ,portan
`· ·
`d
`d
`tential impurities or egra ants as described previously) it
`·
`the po
`11,
`. .
`100gingto
`ptable to apply the ongmal ICH Q3A and B identification
`'
`·dered acce
`l)e
`f
`Is coos1
`h
`"
`h' leaves a gap or t ose unl<nown 1mpurit1es at might consti-
`th
`.
`lds T 15
`,1.reshO
`'al
`·
`t
`. ·ing a potentt mu agemc impurity t at 1s a ove the TTC and
`. .
`. h
`. b
`. k of miss
`u•
`lllte a ris . dentification threshold. However, given the already very conserva-
`.
`t,e10W the I h nderlying the TTC levels and the fact that not all mutagenic
`1hie approac w~ actually be human carcinogens (ICH M7 [51), this slightly
`cornP0~dsotential mutagenic risk is considered to be sufficiently low as not to
`increase; effort required to evaluate every impurity and potentially reduce
`\\'arrant b el w TTC levels. It is recognized that this would make drug develop-
`th rn to eo
`e al ost impractical given the scale of effort tt would require.
`.
`m~~;gh very helpful to guide industry to produce safe and high quality
`d t !CH Q3A and Band the other related (and referred to) ICH guide-
`pro uc s,
`.
`. still leave a number of gaps. Examples mclude early development com-
`1:~nds as well as molecules (like biologicals) that are considered out of scope
`ior !CHQ3A and Q3B those where exposure is less than lifetime. These have
`up to now been addressed either o~ ~ _ad hoc ba_sis by additional r~gional
`guidelines in specific areas (e.g., anttb1ot1cs) or by industry best practices or
`internal company procedures.
`In this chapter we will provide an overview of the identified gaps as well as
`proposals for a more general approach.
`Finally, the Q3 series of guidelines, and in particular the Q3A and Q3B, can
`be viewed as the starting point or basis for impurity management. This chapter
`therefore aims to address the general flow of impurity management, tying in all
`aspects that have been covered by other ICH guidelines (ICH Q3C-Residual
`Solvents [31, ICH M7-Mutagenic Impurities [S], and ICH Q3D-Elemental
`:k to examine other aspects not covered by current guidelines (e.g., biologi-
`~mpurities [41, all discussed in further detail elsewhere in this book). It will also
`-5 See Note 4.
`s,early development thresholds, etc.).
`
`" •
`
`• •
`
`Eton Ex. 1034
`14 of 43
`
`

`

`110
`
`,c
`
`G ;defines
`I H ouolitY II
`• 1es
`•
`sasiC prir,CIP
`.
`f impurity management hin
`6.2
`. section 6.1, u,1e ::1:e~holds: the reporting, identific;~~ Ott ll\e
`As indicated ,n t of three define these w ee thresh~lds are core to s Ott,a.rid
`rinclPal conce~eshoJds, As suc6P, defining key qu~1~ aspects of druafeguard
`~unllficalion th unlltY of DS a~d ntification of impurities, and listing ol lllaii~.
`the sofety on~sqclassification, id:spects are mainly cov~red ~y the ident:PUti.
`'ocrure such
`. ns The safety CH Q3A and B, quahficat1on is defi
`tcauoh
`•·
`ifjcat10 .
`d In I
`. h
`th
`.
`ned
`.,
`ties in sp~c
`. on threshol s.
`. data that estabh~ es e biologicals as the
`and qual1ficatJuiring and evaluatl~~r a given impunty/degradant profu afel)-of
`proces~ ?f a~qimpurity/degra~an eans that for impurities (i.e., includin eat the
`an ind1v1du ified In practice it m , urities), it has to be decided Wh g degra.
`Jevel(s) spehc bles. and mutagenicfi°:1 pw below the relevant limit (wh.1'chether or
`Jeac a
`'
`. t o vie '
`.
`.
`.
`Illa
`dants,
`e from a safety poin B ualification lmut dependmg on the I Yor
`not they abr th, e !CH Q3A or Q~ q si'dered to be safe. If this is not th c ¾ift.
`ay not e
`h'ch 1s con
`m . of the impurity), w 1
`e cas .
`. or other process-related activities re ,}t1t
`cation
`. al urification
`.
`.
`' sl.lltin
`trigger addiuon P
`f the impurity m question.
`g
`may
`ble levels o
`ld 1 1
`. lower and accepta
`3A [l ] or B (2) thresho
`eves can vary bas d
`in The actual applied I~~ Q d and whether the impurity/degradant arts ~n
`f DS dmimstere
`.
`.
`d .
`the amount o
`es 111
`a
`d
`t An overview 1s presente m Table 6 1
`th £ rmulated pro uc .
`ifi b
`.
`.
`. .
`the DS or e O
`d .. "what was the scient ic as1s when these !Ctt
`A question oftenldhear e1so. riginally defined?'' Although hard to answer aft
`3A dB thresho s wer
`. db d
`Q an
`er
`d
`·t appears they were def me
`ase on empirical exp
`than two deca es, 1
`.
`. C
`e-
`~ore
`th t'me The value of 0.05% as applied m I H Q3A [l] most likely
`nence at e 1
`'bl
`•
`·
`f
`d th ty •cal limit of quantification possi e usmg o a standard high
`e P1
`reflecte
`r· d
`'th UV
`,
`nee liquid chromatography (HPLC) 1tte wi
`a
`detector. The
`per1orma
`d al'fi
`.
`th h ld . l
`basis of the identification threshold an q u ~ 1cation . res o 1s ess clear.
`ICH Q3A [1] guideline states that for maximum daily doses of DS $2g/day,
`the qualification threshold is 0.15% or 1 mg/day intake (whichever is lower),
`This infers that a 1 mg/day limit is considered safe for lifelong exposures to
`nonqualified impurities. For degradants that could even be higher based on the
`corresponding ICH Q3B [2] qualification threshold. The appropriateness of
`this 1 mg/day safe limit for lifelong exposure to non-mutagenic impurities will
`be discussed in detail in a later section of this chapter.
`Regarding the reporting and identification thresholds, technical capabilities
`certainly have increased to enable reporting and identification at significantly
`lower levels than the current thresholds. However, taking into consideration
`the caveat made by ICH M7 for (potential) mutagenic impurities/degradants,
`f~om a safety and quality perspective, there is no apparent need to modify 1
`! -dese, e~peci~ y since two decades of experience with the current thresholds
`1 not 1dent1fy any issue.
`
`•
`
`Eton Ex. 1034
`15 of 43
`
`

`

`.
`Aeport1 n91
`
`i,le6,1
`fl
`
`Impurities in New Drug Substances and New Drug Products j 111
`identification, and qualification thresholds for DS and DP.
`
`Amount of OS administered per day In milligrams
`
`<1
`
`1- 10
`
`>10- 100 >100- 1000
`
`>1000-2000 >2000
`
`~ 0rtilll
`
`596
`0.0
`0,196
`
`0.05%
`0.1%
`
`0.0596
`0.1%
`
`0.1096
`or
`1.0 mg"
`1.0%
`o r
`5µ(
`
`0.10%
`or
`1.0mg"
`0.5%
`or
`20µg"
`
`0.10%
`or
`l.0mg0
`0.2%
`or
`2mg"
`
`0.0596
`0.196
`
`0.10%
`o r
`1.0mg"
`0.2%
`or
`2mg"
`
`0.0596
`0.05%
`
`0.10%
`or
`1.0 mg"
`0.2%
`o r
`2mg"
`
`0.0396
`0.0596
`
`0.05%
`
`0. 1%
`
`tiold for
`
`Q3A)
`fltP
`ps(ICJ-1
`(JCJ-1 Q3B)
`
`111
`111 DP
`ljicilfiOJI
`fdt1lf
`s((CJ-1 Q3A)
`111D
`
`DP (ICJ-1 Q3l3)
`
`111
`
`QuafificatiOII
`111 OS (JCH Q3A)
`
`In DP (JCH Q3B)
`
`0.15%
`or
`l.0mg"
`0.5%
`or
`200 µg"
`
`0.15%
`or
`1.0 mg"
`0.2%
`or
`3mg"
`
`0.15%
`or
`l.0mg"
`0.2%
`or
`3mg"
`
`0.0596
`
`0.1596
`
`0.15%
`0.15%
`o r
`or
`l.O mg"
`1.0mg"
`1.0%
`1.0%
`or
`or
`50 µ g"
`50 µg"
`Sollrct: !CH Q3A [ll and !CH Q3B [2]. Courtesy of ICH.
`'Whichever is lower, expressed either as a 96 of the DS or as total dally intake (TOI) of the
`impurity/degradant.
`The complex relationship between ICH Q3A and ICH M7 is examined in
`figure 6.1. The scenarios presente d in this figure cover most if not all situations
`that could be encountered. In Figure 6.1 potential impurities relate to materials
`known to be associated with the synthes is of the DS.
`for true unknown impurities, that is, impurities below the ID threshold in
`DS/DP or earlier steps (e.g., impurities in the starting material), identification
`and further assess ment is not required unless the relevant ICH Q3A ide ntifica(cid:173)
`tion threshold is exceeded. Although ICH Q3A/ Q3B clearly predate ICH Q 9
`(Risk Management} [7], this is consistent with the principles of a risk-based
`approach. Indeed section 3.1 of the ICH Q 3A guideline [1] specifies that the
`focus of any assessment should be centered on actual and potential impurities
`emphasizing the need to focus on those that m ight reasonably be expected.
`
`Eton Ex. 1034
`16 of 43
`
`

`

`(/)
`
`C = t ::,
`.s
`i: ::,
`E .,,
`-;;;-
`
`0..
`
`0
`
`.0 .,, -!
`
`Q)
`0)
`
`i5
`c; .,,
`a:
`
`Qualification TH
`
`Identification TH
`
`Reporting TH
`
`Scenario 1: Potential Impurities
`
`•
`
`'I
`
`a+b
`•
`•
`•
`•
`•
`
`•
`•
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`•
`
`Potential Impurities In the OS can Include starting
`materials, reagents and Intermediates. For any of these
`which are:
`
`Within the range well below the TTC:
`If, based on purging arguments, the worst-case anticipated exposure
`dose/day is well below the TTC: no further actions are required
`
`Within the range around the TTC up to the identification TH:
`If, based on purging arguments, the worst-case anticipated exposure
`dose/day can not be excluded to be well below the TTC: assess for
`(potential) mutagenicity
`
`2a
`2b
`
`Outcome: non-mutagenic; no further action
`Outcome: (potential) mutagenic; check impurity profile on
`actual presence and control below relevant TTC
`
`Within the range above the identification TH and below the
`qualification TH:
`These have already been identified and require assessment for
`(potential) mutagenicity
`
`Outcome: non-mutagenic; no further action
`3a
`3b Outcome: (potential) mutagenic; purify and control level
`below relevant TTC
`
`Impurities in the range above the qualification TH:
`These have already been identified and require assessment for
`(potential) mutagenlcity
`
`4a Outcome: non-mutagenic; requires qualification as a non(cid:173)
`mutagenic impurity
`
`4b Outcome: (potential) mutagenic; purify and control level
`below relevant TTC
`
`ent ofirnpuritiel
`Figure 6.1 Examples of how ICH Q3A [1) and ICH M7 (5) interact,for a~s~ss:ential irnpur'.t,e;
`
`in the DS. The examples are divided into two scenarios, one dealing_ wit /on the y-a~esa,e
`(scenario 1) and one dealing with actual impurities (scenario 2). lnd'~ateh os,aswe11 35t~~
`the ranges for (relative/absolute) amounts of impurities/degradants in 1 ,!ptable intake le
`
`various thresholds (TH). The TIC in this context relates to the relevant :-~e one.
`as defined in ICH M7 [SJ, the 1.5 µg/day level being the most conserva 1
`
`I ....
`. . . . . . . .
`Eton Ex. 1034
`17 of 43
`
`·1• • , • • • •• f
`
`• • • • • . • ~ ,
`
`.0
`
`A
`
`

`

`.. C " 0 e .. • D
`
`.!!
`!
`0
`Cl "' C .. a:
`
`~
`
`~
`r
`~
`
`.
`•
`•
`•
`.
`
`Impurities In New Drug Substances and New Drug Products
`
`1173
`
`s cenario 2: Actual lmp url tlee
`
`Oualificatlon TH
`
`ldenhficahon TH
`
`I
`
`Reporting TH
`
`I
`
`I
`
`•
`•
`
`TTC
`
`•
`•
`•
`•
`.
`•
`•
`•
`•
`•
`•
`Actual Impurities o r degradents can Include those
`observed In the drug eubetence above the ICH 0 3A
`reporting thres holds. For any of these which are:
`1 Actuats (excluding potential impurities covered under scenario 1)
`within the range below the reporti