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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

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Compendial End-to-End Process

Implementation (on-time,

in-use)

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

Surveillance (review,

planning)

Strategy (proactive advocacy

for compliance)

Compliance

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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.

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Which came first?

The Monograph – or – The Approval?

Source:

Google Images

Depends on “who” you are!

Adventures in Compliance

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

Before Pharmacopoeia Monograph After Pharmacopoeia Monograph

Source: Google Images 6

• Before Monograph Elaboration

• Quality Standard (QS) reflects global product registrations (methods, limits)

• ≥ 150 country-specific registrations

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US

EU (~30)

MOW #1

MOW #150

Registrations / QS (Updates / Renewals / Change Control)

Trying to Align: Product Registrations and Compendial Requirements

Product Life-Cycle

• After Monograph Elaboration / Current State

• Challenge: Resolve differences between monograph and global registrations (≥ 150)

• ≥ 49 specific pharmacopoeias

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US

EU (~30)

MOW #150

Trying to Align: Product Registrations and Compendial Requirements

Product Life-Cycle

• Desired outcome / Future state

• Convergence of global registrations (≥ 150) and monographs (≥ 49)

• Requires planning, collaboration

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US

EU (~30)

MOW #150

Trying to Align: Product Registrations and Compendial Requirements

US (USP)

EU (Ph.Eur./BP)

MOW (USP)

MOW (Ph.Eur./BP)

Japan (JP) China (ChP)

Registrations / QS / Monographs

Product Life-Cycle

Prospective/Informal Harmonization: Current Perspective

Collaboration…then Expansion

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Scope: APIs and Products

USP

KP JP IP

Ph. Eur. + BP

ChP

Secondary Work: PDG, MOUs, Observers

GPhPs (Adopt / Adapt)

Pharmaceutical Company

FBras PhRus

Primary Harmonization Work

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…

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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…

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Flexibility Complexity

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)

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• 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)

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

Compendial End-to-End Process

Implementation (on-time,

in-use)

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

Surveillance (review,

planning)

Strategy (proactive advocacy

for compliance)

Compliance

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Surveillance: Global Pharmacopoeias (review, planning)

Filter: TOC (Tool)

3,000 Total Items for Review

Filter: Major Impact

Filter: Minor Impact

500 Items with Potential Impact/ Possible Change Control (CRM)

400 Items with Minor Impact/No TR

100 Items with Major Impact

(TCTeams, CRs)

100 Items with Minor Impact

(CRs)

USP, PhEur, BP: 40 Publications/ Website Postings per year

300 Items with No Impact

(No CRs) 16

Scope Expansion / Challenges to Surveillance: 49 Active Pharmacopoeia Commissions / 36 Pharmacopoeias

Argentina Czech

Republic Hungary Japan Pakistan Slovakia Ukraine

Austria Denmark Iceland Kazakhstan Philippines Slovenia United

Kingdom

Belarus Egypt India Korea Poland Spain United

States

Belgium Finland Indonesia Lithuania Portugal Sweden Viet Nam

Brazil France Iran Mexico Romania Switzerland Europe

China Germany Ireland Montenegro Russian

Federation Thailand Africa

Croatia Greece Italy Norway Serbia Turkey WHO

Source: WHO/2012 17

Surveillance: National Pharmacopoeias (review, planning)

In-Country Partners

??? Total Items for Review

Filter

Filter

Items with Potential Impact/ Possible CRs (CRM)

Items with Minor Impact/No CR

Items with Major Impact

(TCTeams, CRs)

Items with Minor Impact

(CRs)

XP: ? Publications per year (language)

Items with No Impact

(No CRs)

• Japan • Brazil • Russia • India • China • Korea

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• Compendial Affairs groups typically summarize compendial changes in communication to stakeholders

Scope Expansion / Challenges to Surveillance: Amount of New / Revised Content in USP

• PF: 6 per year • Accelerated Revs: 12 per year

• 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

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Scope Expansion / Challenges to Surveillance: Amount of New / Revised Content in USP

Compendial End-to-End Process

Implementation (on-time,

in-use)

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

Surveillance (review,

planning)

Strategy (proactive advocacy

for compliance)

Compliance

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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

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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

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That was then…

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

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…and this is “now”

PLUS:

• Change Control

• Filing Updates

25 …medicine…for the people…

Thank You

Gracias Děkuji Köszönöm どうも

ありがとう Ďakujem дякую شکریہ

Danke Tak Takk Рақмет Salamat Hvala Thank You

شكراً धन्यवाद 감사합니다 Dziękuję Gracias Thank You

Dank u

Merci Kiitos

Terima

kasih Ačiū Obrigado Tack Cảm ơn

Obrigado Merci ممنون Gracias Mulțumesc Merci

Danke

Thank You

Merci

Danke Thank You Hvala

Хвала Cпасибо ขอบคุณ

Dankie

Asante

Hvala ευχαριστώ Grazie Takk Хвала Teşekkür

ederim

Merci

Thank You

谢谢

Дзякуй

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