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
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
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
Which came first?
The Monograph – or – The Approval?
Source:
Google Images
Depends on “who” you are!
Adventures in Compliance
5
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
7
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
8
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
9
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
10
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…
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…
12
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)
13
• 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
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
15
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
18
• 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
20
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
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
23
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
24
…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
26