GPhA Fall Technical Conference Nov 2-5, 2015 Bethesda, MD ICH M7 Guidance Overview and Current FDA Perspectives

GPhA Fall Technical Conference Nov 2-5, 2015 Bethesda, MD ICH M7 Guidance Overview and Current FDA Perspectives Stephen Miller, Ph.D. CMC-Lead; Office of New Drug Products Office of Pharmaceutical Quality CDER / FDA 1

Presentation Overview 1. Scope/Content of the ICH M7 Guideline 2. Implementation Periods 3. Current FDA Perspectives 2

General Principles Focus on DNA-reactive impurities, i.e. mutagenic impurities typically positive in the bacterial mutagenicity assay Threshold of Toxicological Concern (TTC) concept applies 1x10-5 lifetime risk Less than Lifetime (LTL) principle applies Clinical development and marketed products with shorter treatment durations have higher acceptable levels Evaluate actual impurities plus risk-based subset of potential impurities 3

Guideline General Framework Sections 1-4 Scope etc. Section 5: Impurity Assessment Section 6: Hazard Assessment Scope, General Principles Considerations for Marketed Products What impurities need to be assessed? actual, potential, degradation products Is the impurity mutagenic? QSAR + Ames Section 9: Documentation Section 8: Control Section 7: Risk Characterization Expectations for regulatory filings Expectations, options for impurity control, lifecycle What is the acceptable intake? (TTC, compound specific, less than lifetime exposures) 4

Scope: Intended New drug substances and new drug products in clinical development and subsequent application for marketing Certain post approval submissions of marketed products and to new marketing applications (drug substance previously approved): Changes to the drug substance Changes to the drug product Changes in clinical use See M7 Appendix 1: Scope Scenarios 5

Considerations For Marketed Products When a new drug substance supplier is proposed, evidence that the drug substance produced by this supplier using the same route of synthesis as an existing drug product marketed in the assessor s region is considered to be sufficient evidence of acceptable risk/benefit regarding mutagenic impurities and an assessment per this guideline is not required. 6

Impurity Assessment Section 5: Drug Substance and Drug Product Impurity Assessment Describes an assessment process for actual impurities plus risk-based subset of potential impurities These structures are then evaluated for mutagenic potential 7

Synthetic Impurities and Degradation Products Category (Section) Synthetic Impurities in DS (5.1) From Starting Material (SM) to DS Degradation Products in DS and DP (5.2) Guidance for Assessment Actual impurities in drug substance that are identified (Note: identification would be expected when impurities exceed ICH Q3A identification thresholds) Potential impurities to assess can include SMs, reagents and intermediates. Potential impurities are those reasonably expected to form during the reaction and are a risk based sub set of all potential impurities Assess risk of carryover into DS of identified impurities in SMs and intermediates, and impurities that are reasonably expected by-products in synthesis route However for SMs introduced late in synthesis, where the route of synthesis of SM is known, the final steps of SM synthesis should be assessed Actual degradation products identified in DS and DP under long-term storage conditions (Note: identification would be expected when impurities exceed ICH Q3A/B identification thresholds) Potential degradation products in DS and DP reasonably expected to form under long term storage conditions (e.g., above ICH Q3A/B identification thresholds at accelerated or confirmatory photo-stability studies) 8

Hazard Assessment Known mutagen - evaluate literature and databases Structure of unknown mutagenicity - perform a computational toxicology assessment using (Q)SAR methodologies that predict bacterial mutagenicity Optionally, perform Ames study Mark Powley s and Naomi Kruhlak s talks Additional flexibility during the implementation period to follow pre-m7 approaches to Hazard Assessment 9

Risk Characterization TTC approach can be generally used for compounds predicted to be mutagenic Less-Than-Lifetime concept now includes marketing phase in addition to clinical development phase Tables 2 and 3 in ICH M7 Dave Green s presentation 10

Table 2: Acceptable Daily Intakes for an Individual Impurity (during clinical development and at marketing)* Duration of treatment < 1 month >1-12 months >1-10 years >10 years to lifetime Daily intake [µg/day] 120 20 10 1.5 Intermittent dosing can be based on the total number of dosing days Compound-specific Acceptable Intake (AI) can be adjusted proportionally for shorter durations 11

The treatment duration categories with acceptable intakes in Table 2 for marketed products are intended to be applied to anticipated exposure durations for the great majority of patients. (Section 7.3.2) Examples of Clinical Use Scenarios (Table on Page 19) 12

Control Options (8.1) 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 13

Documentation (M7 Section 9) Section 9.1 outlines a risk-based approach to documentation during clinical development phases Section 9.2 outlines recommendations for the marketing application 14

Implementation of M7 Guideline The final (Step 4) version of M7 was published on the ICH website in July 2014. Because of the complexity of the guideline, implementation of M7 is not expected until 18 months after ICH publication (i.e., January 2016). Applicants may adopt all or portions of the M7 guideline at any time (e.g., less-than-lifetime limits, approaches to control, class-specific limits), until January 2016 when full implementation is expected. The following slides show exceptions to 18 month timeline 15

Implementation (cont.) Ames tests should be conducted according to M7 irrespective of the stage of development of the Application. However, Ames tests conducted prior to publication of M7 need not be repeated. When development programs have started phase 2B/3 clinical trials BEFORE publication of M7, these programs can be completed up to and including marketing application submission and approval without following M7 (i.e., M7 does not apply; may follow pre-m7 guidance). When development programs have started phase 2B/3 clinical trials AFTER publication of M7, these programs have the option to implement M7 or choose to follow the 18 month grace period (full implementation in January 2016). 16

Implementation (cont.) Given the complexity and lead-time for development of a commercial manufacturing process, application of M7 to new marketing applications that do not include Phase 2B/3 clinical trials is not expected until 36 months after ICH publication of M7 (e.g., new dosage forms, or new DMFs supporting generic drug applications, may follow pre-m7 guidance until July 2017). The 36 month implementation period is also appropriate for applicable post-approval changes (i.e., may follow pre-m7 guidance until July 2017). 17

Clinical Development (e.g., IND) M7 Implementation Timeline New Marketing Applications Requiring Clinical Efficacy & Safety Data (e.g., NDA) New Marketing Applications Without Clinical E & S Data (e.g., new dosage forms, generic drugs)* Applicable Post-Approval Changes (e.g., new synthetic route) Full implementation of M7 not expected until January 2016 Full implementation of M7 not expected until July 2017 * This will be addressed by regional regulatory processes Programs in Phase 2b or 3 before July 2014 may continue to follow Pre-M7 guidance until the marketing application is submitted and approved 18

FDA Case Studies Presented to show diversity of approaches consistent with M7 guidance Outcomes were specific to these cases, and may not apply to other situations with different mutagenic impurities, risk-benefit to patients, etc The control strategy and its risk-based justification must fit its context for each application or master file 19

Case Study 1 Starting Material Step 1 A Step 2 B Step 3 C Step 4 Final Drug Substance Crude Drug Substance Step 5 [ D ] xtal = crystallization 20

Case Study 1 - continued Starting Material Step 1 A Step 2 B* 1 -sulfonate Step 3 C 1 -chloride Imp * Step 4 Final Drug Substance Crude Drug Substance Step 5 [ D ] 21

Case Study 1 - continued Starting Material Precursors to SM Ar-NO 2 * Ar -NO 2 * Step 1 A Step 2 B* 1 -sulfonate Step 3 1 -chloride Imp * C Step 4 Final Drug Substance Crude Drug Substance Step 5 [ D ] 22

Case Study 1 - continued Starting Material Precursors to SM Ar-NO 2 * Ar -NO 2 * Step 1 A Step 2 B* 1 -sulfonate Step 3 1 -chloride Imp * C Step 4 Final Drug Substance Crude Drug Substance Step 5 [ D ] Spike & Purge studies on nitro and chloride impurities support Option 3 control (at intermediate C) Option 1 control on residual sulfonate intermediate in DS Spike & Purge studies could support Option 3 testing or Periodic Verification Testing with Option 1 23

Case Study 2 SM-1 SM-2 Step 1 A Step 2 precip B Reagent Final Drug Substance SM-3 Step 1 C Step 2 precip D 24

Case Study 2 - continued SM-1 SM-2 Step 1 2 Precursors* to SM-2 A Step 2 precip B Reagent* Final Drug Substance SM-3 Step 1 C Step 2 precip D CH 3 Cl By-product* 25

Case Study 2 - continued SM-1 SM-2 Step 1 2 Precursors* to SM-2 A Step 2 precip B Reagent* Final Drug Substance SM-3 Step 1 C Step 2 precip D CH 3 Cl By-product* Acceptable intake > 1.5 ug/day based on clinical use Structures in 2 steps prior to SMs evaluated for mutagenicity Spike & Purge studies, predicted purge factors, and analytical data support Option 4 control for precursors to SM-2 Spike & Purge plus analysis of CH 3 Cl at D supports Option 4 8 of 8 commercial-scale batches shows Reagent < 10% of AI in drug substance; Spike & Purge; supports Option 4 26

Conclusions FDA Perspectives 1) In NDAs, ANDAs and master files, we are seeing many of the approaches to controlling mutagenic impurities that are consistent with the intent of the M7 guidance Options 1-4 control approaches Less-Than-Lifetime acceptable intakes Compound-specific Permitted Daily Exposures Class-specific acceptable intakes (e.g., mono-chloro alkanes) Intermittent use scenarios 27

Conclusions FDA Perspectives 2) Some types of mutagenic impurities (e.g., nitroaromatics, unsaturated ketones) can in some cases persist through a surprising number of reactions and purge points Value of knowledge for specific impurity/synthesis 3) For possible discussion in Q&A: How have applicants/holders been handling situations where there is a significant difference between the loading dose and the subsequent maintenance doses? 28

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