An Overview of IQ s Position Paper: Early Development GMPs for Small-Molecule Specifications

Transcription

1 An Overview of IQ s Position Paper: Early Development GMPs for Small-Molecule Specifications On behalf of Specifications Team Kirby Wong-Moon, Ph.D. Amgen Inc. Best Practices and Application of GMPs for Small Molecule Drugs in Early Development February 5,

2 2 Specifications Team Jamie McElvain Kythera (lead) Mike Coutant Pfizer Zhihong Ge Merck Scott Miller BMS Dennis O Connor - Boehringer-Ingelheim Frank Swanek - Boehringer-Ingelheim Mike Szulc Biogen Idec Mark Trone Millennium Kirby Wong-Moon Amgen Mehran Yazdanian Teva Pharmaceuticals Pete Yehl Genentech Shuhong Zhang Abbvie

3 3 Outline of Presentation General concepts of IQ specifications position paper Proposed drug substance specifications Proposed drug product specifications Specifications Breakout Sessions Summary Q&A

4 4 General Concepts of Position Paper (Pharmaceutical Technology, Oct 2012) ICH Q6A appropriate for commercial, not early development (ED) Process, formulation, and method changes expected in early development Commercial specifications should be tied to final process validation Risk-based, staged approach to phase appropriate specifications Specifications evolve as the clinical focus changes from safety to efficacy Staged approach analogous to that used for ICH M7 (mutagenic impurities) Early development: Safety focus wider acceptance criteria (AC) Specifications are used to control quality with an emphasis on patient safety since process and product understanding are limited. Late development: Growing process and product understanding maturing specifications Process and product understanding become more important to controlling quality, and specifications should focus more on clinical relevance. These ideas are intended to serve as a starting point to stimulate discussion at this GMP ED Workshop

5 5 Format and Scope of Position Paper Scope limited to small molecules, solid oral dosage forms, and US filings Differentiate ED specifications by standardizing typical tests and AC Release (submitted in regulatory filings) Internal (additional tests and/or tighter AC than release specification) Stability/Shelf-Life (to establish DS retest and DP expiry dates) Note on AC: Report Results and For Information Only (FIO) have same meaning and can be used interchangeably Drug Substance (DS) Single set of tests and AC for Phase 1 and 2a DS specs Drug Product Single set of tests and AC for PIB/PIC formulations (rely primarily on DS results) Single set of tests and AC for tablets & capsules Breakout Sessions Topic 1: Internal Control Strategies

6 6 A Single Set of Clinical DS Specifications is Proposed for Phase 1 and 2a The FIH enabling Tox Batch is a fundamental part in defining the DS specifications in ED For the Tox Batch, internal targets (not formal AC) are routinely used for characterization Ensure that the correct DS is administered to the test animals Determine correct potency value to ensure the proper dosing Quantitate impurities for Tox qualification For DS for clinical studies, additional testing and controls may be required may be similar to the Tox batch but with established AC Knowledge of the synthetic route and the DS is evolving Initial clinical acceptance criteria are often based on target specifications with the safety limits established from the Tox batch If the Tox batch is also intended to be used in a clinical study, the DS specification may be established based on the results of Tox batch testing since the impurities are inherently qualified

7 7 Description Proposed Specification for Clinical DS in ED Attribute Proposed Acceptance Criteria Range of color description (e.g., white to almostwhite to light yellow powder) Release Internal Stability X - X Identification by Spectroscopic Method Spectrum conforms to that of reference X - - Counterion Report results X X - Assay % anhydrous basis or anhydrous and solvent free basis if compound is a solvate X - X Impurities / Degradation Products Individual NMT 1.0% Total NMT 3.0% X X X Chiral Impurity NMT 1.0% X X X Residual Solvents ICH Limits or other justified limits for solvents used in the final step (tighten limits in later development) X X - Mutagenic Impurities Follow established guidance until ICH M7 is finalized - X - Inorganic Impurities NMT EMEA Limits/ADI - X - Water Content Report results - X X Solid Form Report results - X X Particle Size Report results - X - ROI NMT 1.0% - X - Single set of tests and AC for Phase 1 and 2a DS Specs

8 8 A Closer Look at Specification for DS Impurities Attribute Proposed Acceptance Criteria Release Internal Stability Impurities / Degradation Products Individual NMT 1.0% Total NMT 3.0% X X X Chiral Impurity NMT 1.0% X X X Residual Solvents ICH Limits or other justified limits for solvents used in the final step (tighten limits in later development) X X Mutagenic Impurities Follow established guidance until ICH M7 is finalized X Inorganic Impurities NMT EMEA Limits/ADI X

9 It is Proposed to Qualify & Identify DS Impurities at 3X ICH Q3A Levels Qualification threshold: lesser of 0.5% or 3 mg/day, for max dose < 2g/day ID threshold: 0.3% for unknowns not qualified in tox studies Internal targets could be used to trigger action at the proposed 3X ICH limits. 1.0% specification AC for individual impurities exceeds 0.5% qualification threshold. During batch disposition, review impurities against Tox batch profile to ensure qualification. Note: AC above 1.0% for specified impurities can be justified if sufficiently qualified The risk to patient safety is low due to small, short and well monitored clinical trials. As knowledge and program progress, specifications can be updated accordingly. Breakout Sessions Topic 2: Impurity Control Strategies 9

10 Qualification Limit* Identification Limit* ICH Q3A 0.15% or 1 mg 0.10% or 1 mg IQ Proposal (3X ICH) 0.5% or 3 mg 0.3% or 3 mg * For doses up to 2 g/day 10

11 11 Example DS Impurity Scenario Data in ED Impurity Lot A (used only for FIH enabling toxicology studies) Lot B (used for clinical studies through Phase 2a) Lot B Acceptability Considerations Impurity A (known ID) Impurity B (known ID) Impurity C (known ID) Impurity D (unknown ID) Impurity E (unknown ID) Impurity F (unknown ID) Impurity G (known ID) 0.40% 0.33% 0.83% 1.4% ND 0.45% ND 0.42% ND 0.22% 0.05% 0.55% ND 0.55% Level of impurity A is acceptable for early clinical use based on toxicology qualification Level of impurity B may be acceptable for early clinical use based on toxicology qualification Level of Impurity C is acceptable for early clinical use based on proposed Max 0.5% qualification limit Level of impurity D is acceptable for clinical use based on proposed Max 0.5% qualification limit but requires ID prior to clinical administration Level of impurity E is acceptable for clinical use without need for ID Level of impurity F may be acceptable for early clinical use based on internal company guidelines (e.g. safety margin) but requires ID prior to clinical administration Impurity meets specification. However, subject to disease category considerations, Lot B is not acceptable for use until toxicology qualification is completed

12 12 Proposed Early Development Specifications: Drug Products Quality attributes that affect DP performance are typically not known during the early stages of drug development Regulatory specifications should focus on ensuring that accurate and reproducible dosing can be achieved in the clinic and patient safety is not compromised. Characterization data should be acquired, reported and monitored to gain an understanding of the DP in the context of characterizing chemical, processing and packaging sensitivities. Staged approach: specifications evolve as additional knowledge is gained The scope of this paper limited to solid oral dosage forms powder-in-bottle (PIB) powder-in-capsule (PIC) tablets and capsules

13 13 Single Set of Tests and AC for PIB/PIC Formulations Description Attribute Same as DS for PIB Proposed Acceptance Criteria Capsule shell description for PIC Release Internal Stability X - X Identification Same as DS X X - Assay % X - X Degradation Products Use data from DS release (list degradation products only) X - X Uniformity of Dosage Units Conforms per USP<905> - X - Disintegration or Break Disintegration: Per USP <701> for capsules, NMT 15 Test 1 min X X X Single set of tests and AC for PIB/PIC formulations (rely primarily on DS results) The DP degradation products are monitored as part of the recommended DP stability program. DS process impurities are not included.

14 14 Proposed Specifications for Tablets & Capsules Tablets & capsules often employ fit for purpose approaches for rapid entry into FIH trials. Standardized specifications are frequently established for tablets and capsules used in early development Other tests may be added to the DP specification as required. For example, residual solvents should be tested if solvents are used in the DP manufacturing process. Propose that micro testing is not required in early development for oral products Breakout Sessions Topic 4: Microbiological

15 Single Set of Tests and AC for Phase 1 and 2a Capsules/Tablet Specifications 15 Attribute Proposed Acceptance Criteria Release Internal Description Describe color, shape and dosage form (e.g. white to almost-white round tablets) X - X Identification Conforms to standard For HPLC-based methods: The retention time and X - - UV absorption conforms to the standard Assay % X - X Degradation Products (do not include DS Individual unspecified NMT 1.0% X X X process impurities) Total NMT 5.0% Uniformity of Dosage Units Complies with USP<905> X - - Water Content Report results - X X Stability Dissolution or Disintegration Dissolution: Report results - X X Disintegration: Per USP<701> for capsules, NMT 15 min X - X Breakout Sessions Topic 3: Dissolution vs. Disintegration

16 16 It is Proposed to Qualify & Identify DP Degradants at 3X ICH Q3B Levels Similar to DS, 3X ICH Q3B limits are proposed for ID and qualification thresholds The proposed acceptance criterion for unspecified individual degradation products in ED is NMT 1.0%. Do not include DS process impurities. The limit of 5.0% for total degradation products is higher than the corresponding limit of 3.0% in DS due to the additional variability contributed by the formulation excipients, DP manufacturing process, and DP analytical methods. The risk to patient safety is low due to small, short and well monitored clinical trials As knowledge and program progress, specs will be updated accordingly Breakout Sessions Topic 2: Impurity Control Strategies

17 17 1. General Control Strategies 2. Impurity Control Strategies 3. Dissolution vs. Disintegration 4. Microbiological

18 18 Summary A standard, risk based approach has been presented for setting DS and DP specifications in early development for solid oral dosage forms for US filings. The recommendations ensure patient safety while allowing the flexibility to adapt to frequent product and process changes in early development. The goal is to promote clarity and consensus within the pharmaceutical industry and to establish a more detailed approach to specifications in ED that are aligned across industry and regulatory agencies. It is recognized that each company needs to evaluate these recommendations based on the objectives of their individual drug development programs and may choose not to adopt this industry proposal on phase appropriate specifications.

19 19 Acknowledgements Specifications Team members GMPs for Early Development Working Group Questions/Comments: