Best techniques to control Genotoxities and Impact of ICH M7 guideline

1. BEST TECHNIQUES TO
CONTROL GENOTOXIC
IMPURITIES AND IMPACT
OF ICH M7 GUIDELINE
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core Committee
Cadila Pharmaceuticals Ltd.
Presented at the CPhI's 2nd Annual Advanced
API Convention, Mumbai, July 20-23
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2. CONTENTS
 ICH M7: Scope &General principles
 ICH M7: Consideration for marketed products
 Reactive or a proactive approach
 DS & DP GTI Risk assessment
 ICH M7: Impurities classification & Control
 ICH M7: Risk Characterization &Daily AIs
 ICH M7: Control options
 ICH M7: Documentation
 Clarifying the regulatory authority expectations for retrospective
application of ICH M7
 Conclusions
2

3. NOT ALL EARLY DEVELOPMENT DATA
SHOW LOW RISK OF PGTI: A RATHER
EXCEPTION
3
Roche

4. ICH M7: JUNE 23 2014 – INTENDED
SCOPE
 New DS & DP in clinical development & MA/NDA
application
 Certain post-approval products
 Changes to DS
 Changes to DP
 Changes in clinical use
 M7 does not apply to
 Biologicals
 Radipoharmaceuticls
 Herbal/animal products
 Flavours/colours/perfumes/excipients
 Drugs covered by ICHS9 (adv. cancer indication or where
DS itself is genotoxic)
 Appendix 1 of ICH M7 guideline gives all scope scenarios
for its application
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ICH M7

5. GENERAL PRINCIPLES OF
M7
 Focus on DNA-reactive impurities, i.e., mutagenic +ve
in bacterial mutagenicity test
 Threshold of Toxicological Concern (TTC ) concept
applies
 Less than lifetime (LTL) principle applies
 Clinical development and marketed products with shorter
treatment duration have higher acceptable levels
 Evaluate actual impurities and risk based subset of
PGIs
 When an impurity is also a metabolite, safety
evaluation is primarily on the metabolite
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ICH M7

6. THRESHOLD OF TOXICOLOGICAL
CONCERN (TTC)
 TTC for any unstudied chemical: 1.5 µg/person/day
 For later stage development & marketed products
 Based on an exposure of 1 x 10-6
upper bound lifetime risk of cancer
(“virtually safe dose”)
 Confirmed by evaluations expanding the database to more than 700
carcinogens
 However, TTC for genotoxic impurities in API of 10-5
lifetime risk of
cancer is justified as for pharmaceuticals a benefit exists
 TTC methods are very conservative; uses TD50 data for the most
sensitive species and most sensitive site (several “worst case”
assumptions)
 Less-Than-Lifetime (LTL) exposures
 During development & marketing can be higher and still maintain
comparable risk levels
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7. ASSESSMENT AND CONTROL OF DNA
REACTIVE IMPURITIES IN APIS TO LIMIT
CARCINOGENIC RISK
7Calculated daily dose of a mutagenic impurity corresponding to a theoretical
1:100,000 cancer risk as a function of duration of treatment & daily AIs
ICH M7

8. GTI RISK ASSESSMENT
8
Identification of Potential Impurities in Drug Substance and Drug
Product
Review the synthetic process - including starting materials or reagents or
intermediates/known impurities + drug substance and product degradants
Step 1
Conduct SAR evaluation
(DEREK/MCASE)
Safety Assessment
Chemistry
Step 2
Step 3
Step 4
Structural
Alert?
Assessment of Risk of Potential carryover of impurities –
Evaluate risk of carryover at levels of concern into DS/DP
Does the impurity pose any significant risk of carryover?
No
No further action
Yes
Yes
Next Slide
Classified as non-
genotoxic. Treat as
a general impurity
No
Teasedale A et al. (2010) Genotoxic Impurities: Strategies for Identifi cation and Control

9. GTI RISK ASSESSMENT..
9
Step 5
Finalize Risk Assessment
It the impurity genotoxic? Is the level >TTC?Step 6
Step 7
Define strategy to achieve acceptable limits Options:
1/ Modification of synthetic process
2/ Additional genotoxicity testing (typically in-vivo)
Previous Slide
Qualification
Analyze level of impurity
Safety Testing
Perform appropriate genotixicty
test : Typically AMES test
OR
Non-
Genotoxic Treat as a
general
impurity
Genotoxic
Level >TTC
Genotoxic
Level <TTC
Suitable for
Clinical use
Teasedale A et al. (2010) Genotoxic Impurities: Strategies for Identification and Control

10. GENOTOXIC COMPOUNDS
CLASSIFIED ON THE BASIS OF
REACTIVITY
10

11. STRUCTURA
L ALERTS
FOR
MUTAGENICI
TY
11

12. PURGE
FACTOR
S
12

13. TESTS TO INVESTIGATE THE IN
VIVO RELEVANCE OF IN VITRO
MUTAGENS
13

14. CONSIDERATIONS FOR
MARKETED PRODUCTS
14
Category (Section) Guidance for Re-Evaluation
Changes to Drug
Substance
• Post approval submissions with changes in synthesis or
process conditions after the starting material
• Not required for changing drug substance site of
manufacture, raw materials supplier
Changes to Drug Product • New or higher levels of existing mutagenic degradation
products when product submission involves change e.g.
composition, manufacturing process, dosage form
• Not required for changing site of manufacture
Changes to Clinical Use • Changes in clinical dose or duration of use, change in
indication e.g. life threatening disease to non-life
threatening disease or less serious condition
Other Considerations • (Q) SAR alert alone does not warrant re-evaluation,
unless it is a structure of ‘cohort-of-concern’ (CoC)
• Cause for concern 1) New mutagenicity or
carcinogenicity data for impurity 2) Newly discovered
impurity that is a mutagenic carcinogen or mutagen
Lifecycle • Newly identified impurities in products approved after
issuance of M7 would be assessed for mutagenicity

15. CLASSES OF GTIS & THEIR
CONTROL
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Class Definition Proposed action for
control
Class 1 Known mutagenic carcinogens ≤ compound-specific limit
Class 2 Known mutagens with unknown
carcinogenic potential
≤ appropriate TTC
Class3 Alerting structure, unrelated to
structure of DS, no mutagenicity
data
≤ appropriate TTC or
conduct Ames test (non-
mutagenic = Class 5,
mutagenic = Class 2)
Class4 Alerting structure, same alert in DS
or compounds related to DS which
have been tested and are non-
mutagenic
Non-mutagenic impurity
(ICH Q3A/B)
Class5 No structural alerts, or alerting
structure with sufficient data to
demonstrate lack of mutagenecity or
carcinogenicity
Non-mutagenic impurity
(ICH Q3A/B)

16. RISK CHARACTERIZATION AND
ACCEPTABLE INTAKE (AI)
 Compound-specific acceptable intake for Class 1
impurities
 M7 addendum of AIs for common reagents (Step 2, Dec 2014)
 TTC-based AI for Class 2, 3 impurities (next slide)
 Alternative approach described for Phase I trials up
to 14 days focus control on Class 1,2 and cohort of
concern
 All other impurities treated as non-mutagenic
 Risk approaches apply to all routes of administration
and all patient populations (including pregnant
women and children)
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ICH M7

17. ACCEPTABLE DAILY INTAKES FOR AN
INDIVIDUAL IMPURITY (DURING CLINICAL DEV.
& MARKETING)
 For intermittent dosing, AI should be based on the total number
of dosing days instead dosing span
 Number of dosing days should be related to the above table
 e.g., for a drug administered once/week for 2 years (104 dosing
days) AI per dose is 20μg
17
ICHM7
Single Impurity

18. ACCEPTABLE DAILY INTAKES
FOR MULTIPLE GIS
 For >3 Class 2 or Class 3 mutagenic impurities, above table
applies
 For combination products each active ingredient should be
regulated separately
 Degradation products should be controlled individually and a
total limit would not apply 18
ICHM7

19. EXCEPTIONS AND FLEXIBILITY IN
APPROACHES
 Higher acceptable intakes may be justified:
 When human exposure to the impurity is much greater from
other sources e.g. food or endogenous metabolism (e.g.
formaldehyde)
 Cases of severe disease, reduced life expectancy, late onset
but chronic disease, or with limited therapeutic alternatives.
 Based on a risk/benefit analysis when control efforts cannot
reduce levels below the acceptable limit and levels are as Low
as reasonably practicable (ALARP)
 Lower acceptable intake may be justified for some
structural classes of mutagens, i.e. aflatoxin-lie-, N-
nitroso-, and alkyl-azoxy structures which display
extremely high carcinogenic potency 19
ICH M7

20. OPTIONS FOR CONTROL OF
IMPURITIES
 Synthesis prior to SM will generally be managed under the
applicant’s quality system
 Removal of impurity can be monitored through starting
material, intermediate, or drug substance specifications, or
assured by the manufacturing process controls themselves
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Starting
Material
Synthetic
Intermediate
B
Drug
Substance
Synthetic
Intermediate
B
ICH M7

21. ADOPTED ALLOWABLE DAILY
INTAKES FOR GIS DURING CLINICAL
DEVELOPMENT
21
Teasedale A et al. (2010) Genotoxic Impurities: Strategies for Identification and Control

22. CLASSES OF GTIS & THEIR
CONTROL
22
Class Definition Proposed action for
control
Class 1 Known mutagenic carcinogens ≤ compound – specific
limit
Class 2 Known mutagens with unknown
carcinogenic potential
≤ appropriate TTC
Class3 Alerting structure, unrelated to
structure of DS, no mutagenicity
data
≤ appropriate TTEC or
conduct Ames test (non-
mutagenic = Class 5,
mutagenic = Class 2)
Class4 Alerting structure, same alert in DS
or compounds related to DS which
have been tested and are non-
mutagenic
Non-mutagenic impurity
(ICH Q3A/B)
Class5 No structural alerts, or alerting
structure with sufficient data to
demonstrate lack of mutagenecity or
carcinogenicity
Non-mutagenic impurity
(ICH Q3A/B)

23. CONTROL OPTIONS
 Option 1: Monitor the impurity in the drug substance
 Acceptance criterion at or below the TTC
 Option 2: Monitor the impurity in intermediate,
starting material or in-process control
 Acceptance criterion at or below the TTC
 Option 3: Monitor the impurity in intermediate,
starting material or in-process control
 Acceptance criterion above the TTC, with demonstrated
understanding of fate and purge and associated process
controls
 Option 4: Design robust process controls to reduce the
risk of impurity level above the TTC to negligible
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24. CONTROL OPTIONS..
 Considerations for periodic testing (re: ICHQ6A)
 Control of potential degradation products
 Use of accelerated stability studies or kinetically equivalent studies at
higher temperatures to determine relevance of PGTIs
 If results of these studies indicate levels of potential degradation
products approaching the acceptable limit, then further monitoring or
control is expected.
 Considerations for Clinical Development
 Product and process knowledge increases over the course of
development
 Data to support control strategies in clinical phases will be less than
for marketing registration
 Use a risk-based approach to prioritize assays on those impurities with
the highest likelihood of being present in DS or DP
 Efforts associated with drug product degradants will be limited in the
earlier phases
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ICH M7

25. DOCUMENTATION
25
Phase
(Section)
Recommended Documentation Elements
Clinical
Trial
Applicatio
ns (9.1)
• Ph 1 <14 days: Report Class 1 and 2 impurities, and those in
CoC along with control plans or chemistry arguments. Ph 1
≥14 days, Ph 2a: Report class 1, 2 and 3 impurities that
require analytical control
• Ph 2b, Ph 3: Report impurities by (Q)SAR and in silico, control
plans or chemistry arguments for Class 1, 2 or 3 actual and
potential impurities, bacterial mutagenicity results
CTD (9.2) • (Q)SAR assessments and classifications & rationale for actual
and potential impurities/degradants (all Classes): in silico
systems described, supporting bacterial mutagenecity reports
• Justification for proposed specifications and approaches to
control
ICH M7

26. IMPLEMENTATION OF M7
GUIDELINES
 Final version (Step 4) of M7 was published in July 2014
 Because of the complexity of the guideline, implementation of M7 is not
expected until 18 January 2016
 Applicants may adopt M7 or its portions e.g., <lifetime limits, approaches
to control, class-specific limits, until January ’16
 Ames tests should be conducted according to M7 irrespective of
the stage of development
 Ames tests conducted prior to publication of M7 need not be repeated
 If Ph 2B/3 clinical trials started before M7, M7 does not apply
 If Ph 2B/3 clinical trials started after M7, implement M7 choose
to follow the 18 month grace period (until January 2016)
 Due to complexity of commercial manufacturing process, M7
application to new marketing applications without Ph 2B/3 is not
expected until July 2017
 The 36 month implementation period is also appropriate for
applicable post-approved changes
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ICH M7

27. CASE STUDY 1: DEFERASIROX
(OPTION 1)
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28. CASE STUDY: DEFERASIROX..
 Deferasirox is an oral iron chelator; reduces chronic iron
overload from repeated blood transfusions
 Genotoxicity prediction using SAR/QSAR & Toxicophore
significance by ANOVA, 4-Hydrazino-Benzoic acid (4-HBA)
is genotoxic based on structural alerts, literature review
and QSAR models*
 4-HBA has been used in final stage of the process hence
possibility to get carry over in final API Deferasirox
 Purification of Deferasirox is achieved by crystallization
technique with the different solvent mixture (THF &
Methanol mixture)
 4-HBA removed from final API by acid - base purification 28
*Mutat. Res. (2008),659(3):248-61

29.  Limit of 4-HBA in Deferasirox final API is 4.0 (µg/ml) and
can be quantified using HPLC
 HPLC chromatograms of 4-HBA is as below where 4.0
(µg/ml) concentration can be quantified in Deferasirox.
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30. CASE STUDY 2: THIONYL
CHLORIDE (OPTION 4)
 Thionyl chloride is a highly reactive compound that is
mutagenic
 This reagent is introduced in step 1 of a 5-step
synthesis
 At multiple points in the synthesis, significant amounts of
water are used
 Since thionyl chloride reacts instantaneously with water,
no residual thionyl chloride would be present in the drug
substance
 An Option 4 control approach is suitable without the need
for any laboratory or pilot scale data
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31. CONCLUDING REMARKS
 M7 guidelines provide recommendations on how to assess and control
genotoxic, mutagenic impurities
 Selection of potential impurities is based on the risk of presence at
relevant levels in the drug substance or drug product
 Utilizes SARs to assess and predict mutagenecity potential (Hazard
Identification) and if warranted, control or determine risk (Risk
Assessment)
 Applies the concept of TTC and classifies impurities into 5 classes
based on mutagenecity and carcinogenicity
 Applies LTL (Less-Than-Lifetime) limits based on duration of use,
providing a flexible and practical approach during clinical development
and marketing
 Outlines flexible ways to control mutagenic impurities, and a staged
approach to documentation during development
 Because of the complexity of the guideline, implementation of M7 is
not expected until 18 January 2016; in some other cases until July 2017
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32. THANK YOU VERY MUCH
32
ACKNOWLWDGEMENT: DRS.
VAIBHAV BHATT AND NIKHIL
VAIDYA

33. BACKUP SLIDES
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34. Q3A THRESHOLDS
 Any impurity at a level greater than (>) the identification threshold (characterizing the
structure of actual impurities) in any batch manufactured by the proposed commercial process
should be identified
 The quantitation limit for the analytical procedure should be not more than (≤) the reporting
threshold
 Any impurity at a level greater than (>) the reporting threshold & total impurities observed in
these batches of the new drug substance should be reported with the analytical procedures
indicated. Below 1.0 percent, the results should be reported to two decimal places (e.g., 0.06
percent, 0.13 percent); at and above 1.0 percent, the results should be reported to one decimal
place (e.g., 1.3 percent).
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