BEST TECHNIQUES TO CONTROL GENOTOXIC IMPURITIES AND IMPACT OF ICH M7 GUIDELINE

Dr. Bhaswat S. Chakraborty Sr. VP & Chair, R&D Core

CommitteeCadila Pharmaceuticals Ltd.

Presented at the CPhI's 2nd Annual Advanced API Convention, Mumbai, July 20-

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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

Conclusions2

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

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Roche

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 scenariosfor its application

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ICH M7

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 5

ICH M7

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 levels6

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

GTI RISK ASSESSMENT

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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

ChemistryStep 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

GTI RISK ASSESSMENT..

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Step 5

Finalize Risk AssessmentIt the impurity genotoxic? Is the level

>TTC?

Step 6

Step 7Define 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 TestingPerform appropriate

genotixicty test : Typically AMES test

OR

Non-Genotoxic

Treat as a general impurity

GenotoxicLevel >TTC

GenotoxicLevel <TTC

Suitable for Clinical use

Teasedale A et al. (2010) Genotoxic Impurities: Strategies for Identification and Control

GENOTOXIC COMPOUNDS CLASSIFIED ON THE BASIS OF REACTIVITY

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STRUCTURAL ALERTS FOR MUTAGENICITY

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PURGE FACTORS

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TESTS TO INVESTIGATE THE IN VIVO RELEVANCE OF IN VITRO MUTAGENS

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CONSIDERATIONS FOR MARKETED PRODUCTS

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Category (Section) Guidance for Re-EvaluationChanges 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 manufactureChanges 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

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)

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

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

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

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

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ICH M7

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

ADOPTED ALLOWABLE DAILY INTAKES FOR GIS DURING CLINICAL DEVELOPMENT

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Teasedale A et al. (2010) Genotoxic Impurities: Strategies for Identification and Control

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 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)

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 negligible23

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 24

ICH M7

DOCUMENTATION

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Phase (Section)

Recommended Documentation Elements

Clinical Trial Applications (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

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

CASE STUDY 1: DEFERASIROX (OPTION 1)

OH

COOH

+

OH

CONH2

O

N

O

OH

2-(2-Hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one

C14H9NO3Mol. Wt.: 239.23

C7H7NO2Mol. Wt.: 137.14

C7H6O3Mol. Wt.: 138.12

O

N

O

OH

2-(2-Hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one

C14H9NO3Mol. Wt.: 239.23

+

NHNH2

COOH

N

N

N COOH

OH

HO

4-[3,5-Bis-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid

C21H15N3O4Mol. Wt.: 373.36

DEFERASIROX

C7H8N2O2Mol. Wt.: 152.15

4-Hydrazino-benzoic acid

ROS OF DEFERASIROX

Salicylic acid Salicylamide

[4-HBA]

DFX-1

DFX-127

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

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*Mutat. Res. (2008),659(3):248-61

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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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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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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THANK YOU VERY MUCH

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ACKNOWLWDGEMENT: DRS. VAIBHAV BHATT AND NIKHIL

VAIDYA

BACKUP SLIDES

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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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