Drug Substance/Product Specifications: Tests, Methods, Acceptance Criteria

Compendial Affairs: Adventures in Compliance – Impediments to Monograph Development

J. Mark Wiggins

Owner and Compendial Consultant Global Pharmacopoeia Solutions LLC

Director, Compendial Affairs (Retired) Merck & Co., Inc.

October-2018 Purpose and Significance: Pharmacopoeia / Monographs

• A pharmacopoeia’s core mission…protect public health …creating and making available public standards…help ensure the quality of medicines. • Pharmacopoeias…reflect specifications approved by the regulatory body.

• Pharmacopoeial monographs…an important tool for assurance of the quality of pharmaceutical ingredients and products… through testing of their quality. • Specifications in pharmacopoeias…a list of tests, references to analytical procedures, and appropriate acceptance criteria…

Source: www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex01.pdf?ua=1

2 Compendial End-to-End Process

Compendial Affairs: Ensure ongoing compliance with new / revised compendial requirements through an end-to-end process.

Compliance

Strategy Surveillance Implementation (proactive advocacy (review, (on-time, for compliance) planning) in-use)

3 Adventures in Compliance

• Compliance with official compendial requirements is a legal and regulatory requirement in those countries/ regions in which the pharmacopoeia is applicable.

• A company must comply with: – approved product registration and – appropriate compendial requirements.

• HOW a company complies…there is flexibility…and there is complexity…

• CONSIDER: Publication of a NEW monograph.

4 Adventures in Compliance

Which came first?

Source: Google Images

The Monograph – or – The Approval? Depends on “who” you are!

5 Drug Substance/Product Specifications: Tests, Methods, Acceptance Criteria

Before Pharmacopoeia Monograph After Pharmacopoeia Monograph

Source: Google Images 6 Trying to Align: Product Registrations and Compendial Requirements

• Before Monograph Elaboration • Quality Standard (QS) reflects global product registrations (methods, limits) • ≥ 150 country-specific registrations

US EU (~30) Registrations / QS (Updates / Renewals / Change Control)

MOW #1

MOW #150 Product Life-Cycle

7 Trying to Align: Product Registrations and Compendial Requirements

• After Monograph Elaboration / Current State • Challenge: Resolve differences between monograph and global registrations (≥ 150) • ≥ 49 specific pharmacopoeias

US EU (~30) MOW #150 Product Life-Cycle

8 Trying to Align: Product Registrations and Compendial Requirements

• Desired outcome / Future state • Convergence of global registrations (≥ 150) and monographs (≥ 49) • Requires planning, collaboration

US Registrations / QS / Monographs EU (~30) MOW #150 US (USP) MOW (USP) EU (Ph.Eur./BP) MOW (Ph.Eur./BP) Japan (JP) China (ChP)

Product Life-Cycle

9 Prospective/Informal Harmonization: Current Perspective

Collaboration…then Expansion

Scope: Pharmaceutical APIs and Products Company

Primary Harmonization Work Ph. Eur. USP + BP

FBras IP ChP PhRus KP JP Secondary Work: PDG, MOUs, Observers GPhPs (Adopt / Adapt) 10 Monograph Development: Adventures in Compliance Successes / Collaboration / Convergence: • Prospectively harmonized monographs – API/Prod (Ph. Eur., BP, USP) • Expansion of harmonized monographs – Natl. Pharms. (JP, IP, ChP, KP) • Developed improved methods and new reference standards

Challenges / Compliance: • Changes to approved limits (assay widened; impurities tightened) • Changes to approved methods (isocratic hold; system suitability) • Introduced new methods (not in approved registration, e.g. identity) • For a particular product family, Ph. Eur. monograph applied method from one dosage form to another dosage form, which impacted current product and new formulation/strength in development – Requested that USP NOT harmonize with Ph. Eur…

11 Compliance with Monograph Requirements: Lessons Learned

• Monograph development is not just about setting specifications, but also about practical considerations for methods, reference standards. • In our experience, 80 – 90% of all questions/issues during monograph development are related to limits/controls for impurities/degradates.

• Change control to comply with compendial requirements: – is difficult and time consuming. – requires multiple impacted stakeholders (technical, site, central…). – impacts multiple products, registrations (≥ 150 countries).

• There is flexibility in approaches to compendial compliance, but must balance Quality Standard, Product Registrations, Site/External Quality Testing and Release, Material Control…

Flexibility Complexity 12 Compliance with Monograph Requirements: Options/Approaches (Flexibility/Complexity)

• Focus on Compliance: Compendial review process should enable impact assessment with implementation planning/execution.

• Test-by-Test Consideration: Limits / Methods • Differences in Limits – Adopt/Not adopt the updated limits • must apply tighter limits from monograph (compliance) • may choose not to apply wider limits from monograph (consider impact to global product registrations)

13 Compliance with Monograph Requirements: Options/Approaches (Flexibility/Complexity) • Differences in Methods (“MARK” Principle) – Merge • Incorporate additional requirements from monograph into registered method (e.g. system suitability) – Add • Include monograph method in addition to registered method (e.g. additional identification test) – Replace • Switch from registered method to monograph method – Keep • Maintain registered method instead of monograph method

(NOTE: “Replace” or “Keep” options require equivalency)

14 Compendial End-to-End Process

Compendial Affairs: Ensure ongoing compliance with new / revised compendial requirements through an end-to-end process.

Compliance

Strategy Surveillance Implementation (proactive advocacy (review, (on-time, for compliance) planning) in-use)

15 Surveillance: Global Pharmacopoeias USP, PhEur, BP: 40 Publications/ Website Postings per year (review, planning)

3,000 Total Items for Review

500 Items with Potential Impact/ Possible Change Control (CRM) Filter: TOC (Tool) 400 Items with Minor Impact/No TR Filter: Major Impact

100 Items with Filter: Minor Impact Minor Impact (CRs)

100 Items with 300 Items with Major Impact No Impact (TCTeams, CRs) (No CRs) 16 Scope Expansion / Challenges to Surveillance: 49 Active Pharmacopoeia Commissions / 36 Pharmacopoeias

Czech Argentina Hungary Japan Pakistan Slovakia Ukraine Republic

United Austria Denmark Iceland Kazakhstan Philippines Slovenia Kingdom

United Belarus Egypt India Korea Poland Spain States

Belgium Finland Indonesia Lithuania Portugal Sweden Viet Nam

Brazil France Iran Mexico Romania Switzerland Europe

Russian China Germany Ireland Montenegro Thailand Africa Federation

Croatia Greece Italy Norway Serbia Turkey WHO

Source: WHO/2012 17 Surveillance: National Pharmacopoeias XP: ? Publications per year (language) (review, planning)

??? Total Items for Review

Items with Potential Impact/ Possible CRs (CRM) In-Country Partners

Items with Minor Impact/No CR Filter

Items with Filter Minor Impact • Japan (CRs) • Brazil • Russia • India • China Items with Items with • Korea Major Impact No Impact (TCTeams, CRs) (No CRs) 18 Scope Expansion / Challenges to Surveillance: Amount of New / Revised Content in USP • Compendial Affairs groups typically summarize compendial changes in communication to stakeholders

• PF: 6 per year • Accelerated Revs: 12 per year Scope Expansion / Challenges to Surveillance: Amount of New / Revised Content in USP

• USP scope and breadth challenges the compendial review process (and impacts ability to submit monographs) • Recommendation: Improvements to “Briefing” to enhance industry efficiency and effectiveness – Provide all specific changes in detail (“from…to…”) – Very helpful for all revisions (major, minor, editorial) – Especially important for total re-write of general chapter • Could Establish “Best Practice” among Pharmacopoeia • Huge benefit to stakeholders (industry, regulators) – Avoids redundant effort by MANY Compendial Affairs groups

20 Compendial End-to-End Process

Compendial Affairs: Ensure ongoing compliance with new / revised compendial requirements through an end-to-end process.

Compliance

Strategy Surveillance Implementation (proactive advocacy (review, (on-time, for compliance) planning) in-use)

21 Monograph Development – What is Required for Submission? • Appropriate Product Portfolio • Willingness to Submit / Sponsorship by Leadership • Compendial Affairs Resources – Time to Submit / Time to Follow-Up • Internal Stakeholders Resources / Time • Method Availability – Method Validation – Specifications (Limits) Availability / Justification of Specs – Data Availability: Release / Stability / Structures • Reference Standard Availability / Support

22 Compendial Affairs – Responsibilities 1. Review – official compendial revisions 2. Review / Response – proposed revisions 3. Internal support 4. External advocacy – Global Pharmacopoeias (USP, PhEur, BP) – National Pharmacopoeias (JP, ChP, PhRus, IP, etc.) – Trade Associations (IPEC, PhRMA, PDA, NJPQCA, RDPAC, etc.) 5. Reference standard support 6. Monograph development That was then…

23 Compendial Affairs – Responsibilities 1. Review / Response / Planning – proposals 2. Review – official compendial revisions 3. Monograph development 4. Reference standard support 5. External advocacy – Global Pharmacopoeias (USP, PhEur, BP) – National Pharmacopoeias (JP, ChP, PhRus, IP, etc.) – Trade Associations (IPEC, PhRMA, PDA, NJPQCA, RDPAC, etc.) 6. Internal support PLUS: …and this is “now” • Change Control • Filing Updates 24 …medicine…for the people… 25 Thank You

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