Adventures in Compliance: Converging on Global Regulatory and Compendial Standards for Drug Substances and Products J. Mark Wiggins, Merck Sharp & Dohme (MSD)
Overall “Guiding” Principle To promote public health by providing safe and effective medicines with consistent quality to extend and improve the lives of patients around the world. • Roles for: – Regulators Review / Approval / Inspection – Pharmacopoeias Harmonized Quality Standards – Industry Multi-National / Local Companies (Innovator / Generic / Excipient / API / Product) • Benefit to: (Pharmaceuticals / Biologics / Vaccines) – Patients Medicines with Good Quality Medicines that are Available 2
Adventures in Compliance Adventures can be exciting…daring…potentially dangerous… Convergence Harmonization • Convergence – to unite in a common interest or focus; move toward uniformity; tend to a common result or conclusion • Harmonization – process and results of adjusting differences or inconsistencies to bring significant features into agreement Harmonization or Harmonisation? 3
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 4
Pharmacopoeia Harmonization: Long-Term Vision • The "Ideal Pharmacopoeia" would contribute to product quality: – By providing appropriate standardization – By facilitating drug registration – By supporting regulatory agencies – Through a single, global compendial standard. * “The Ideal Pharmacopoeia – A Model for the Future” Pharmaceutical Technology, Vol. 32, No. 11, pp. 122-125 (November 2008) 5
“A Single, Global Compendial Standard”: 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 6
Good Pharmacopoeial Practices (GPhP) / WHO NEW! WHO Technical Report No. 996 Published May-2016 Source: www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex01.pdf?ua=1 7
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. 8
Adventures in Compliance Which came first? Source: Google Images The Monograph – or – The Approval? Depends on “who” you are! 9
Drug Substance/Product Specifications: Tests, Methods, Acceptance Criteria Before Pharmacopoeia Monograph After Pharmacopoeia Monograph Source: Google Images 10
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 Registrations / QS EU (~30) (Updates / Renewals / Change Control) MOW #1 MOW #150 Product Life-Cycle 11
Trying to Align: Product Registrations and Compendial Requirements • After Monograph Elaboration / Official • Challenge: Resolve differences between monograph and global registrations (≥ 150) • ≥ 49 specific pharmacopoeias US EU (~30) MOW #150 Product Life-Cycle 12
Ideal Pharmacopoeia Harmonization Goal: Ideal Retrospective Prospective Pharmacopoeia Harmonization Harmonization (PDG/ICH Q4B) Prospective Harmonization : New Monographs for APIs/Products ▪ Goal: To create a harmonized monograph from the beginning. 13
Monograph Development: Prior to Prospective Harmonization Separate monograph submissions Pharmaceutical Company USP monograph aligned with registrations Ph.Eur. monograph differed from registrations USP Ph. Eur. Result: Different monographs - Apply different limits. - Run 2 different methods, or - Demonstrate method equivalence. 14
Monograph Development: Prospective Harmonization (Pilot 1 – 2008) Collaboration: monograph submission/development “Prospective Harmonization - Scope: Pharmaceutical API Pilot Project: Industry Perspective”, APIs Company Pharmeuropa 22.4 (Oct. 2010), USP PF 36.6 (Nov. 2010), JPF 20.1 (Mar. 2011) Single monograph proposed Possible revisions discussed Possible revisions evaluated in lab Communication throughout development USP Ph. Eur. Intended Result: Harmonized monograph (Tests, Methods, Acceptance Criteria) 15
Monograph Development: Prospective Harmonization (Pilot 1 – 2011) Collaboration: monograph outcome “Prospective Harmonization - Scope: Pharmaceutical API Pilot Project: Industry Perspective”, APIs Company Pharmeuropa 22.4 (Oct. 2010), USP PF 36.6 (Nov. 2010), JPF 20.1 (Mar. 2011) Updates were required for product registrations in >150 countries to align with the new monograph USP Ph. Eur. Actual Result: Harmonized monograph (Tests, Methods, Acceptance Criteria) 16
Prospective/Informal Harmonization: Current Perspective Collaboration… then Expansion Scope: Pharmaceutical APIs and Products Company Primary Harmonization Work Ph. Eur. USP + BP IP ChP FBras PhRus KP JP Secondary Work: PDG, MOUs, Observers GPhPs (Adopt / Adapt) 17
Prospective/Informal Harmonization: Monographs Completed (USP/Ph. Eur./BP) Monograph Monograph Rizatriptan Benzoate Aprepitant Capsules Montelukast Sodium Sitagliptin Phosphate Montelukast Tablets Sitagliptin Tablets Montelukast Chewable Tablets Raltegravir Potassium Dorzolamide Eye Drops Raltegravir Tablets Dorzolamide-Timolol Eye Drops Raltegravir Chewable Tablets Demonstrated success. Need to continue/expand effort. 18
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. – 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 19
Compliance with Monograph Requirements: Options/Approaches (Flexibility/Complexity) • Focus on Compliance: We have developed a new compendial review process to 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) 20
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) 21
Monograph Development: Adventures in Compliance 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 – 3 different methods for Assay/Degradates in approved registrations 22
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