Regulatory and Compendial Standards for Drug Substances and Products - - PowerPoint PPT Presentation

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Regulatory and Compendial Standards for Drug Substances and Products - - PowerPoint PPT Presentation

Nov 20, 2023 273 likes •588 views

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

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  • J. Mark Wiggins, Merck Sharp & Dohme (MSD)

Adventures in Compliance: Converging on Global Regulatory and Compendial Standards for Drug Substances and Products

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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 – Pharmacopoeias – Industry

  • Benefit to:

– Patients

Multi-National / Local Companies

(Innovator / Generic / Excipient / API / Product) (Pharmaceuticals / Biologics / Vaccines)

Medicines with Good Quality Medicines that are Available Harmonized Quality Standards Review / Approval / Inspection

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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

Adventures in Compliance

Adventures can be exciting…daring…potentially dangerous…

Harmonization or Harmonisation?

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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
  • f 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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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)

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“A Single, Global Compendial Standard”:

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

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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

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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

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  • 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

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  • After Monograph Elaboration / Official
  • 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

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Ideal Pharmacopoeia   Harmonization

Prospective Harmonization

Pharmacopoeia Ideal Goal:

Prospective Harmonization: New Monographs for APIs/Products ▪ Goal: To create a harmonized monograph from the beginning. Retrospective Harmonization (PDG/ICH Q4B)

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Monograph Development: Prior to Prospective Harmonization

Separate monograph submissions

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USP

  • Ph. Eur.

Result: Different monographs

Pharmaceutical Company

USP monograph aligned with registrations

  • Apply different limits.
  • Run 2 different methods, or
  • Demonstrate method equivalence.

Ph.Eur. monograph differed from registrations

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Monograph Development: Prospective Harmonization (Pilot 1 – 2008)

Collaboration: monograph submission/development

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Pharmaceutical Company

USP

  • Ph. Eur.

Single monograph proposed Possible revisions discussed Possible revisions evaluated in lab Communication throughout development Intended Result: Harmonized monograph (Tests, Methods, Acceptance Criteria)

“Prospective Harmonization - API Pilot Project: Industry Perspective”, Pharmeuropa 22.4 (Oct. 2010), USP PF 36.6 (Nov. 2010), JPF 20.1 (Mar. 2011)

Scope: APIs

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Monograph Development: Prospective Harmonization (Pilot 1 – 2011)

Collaboration: monograph outcome

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Pharmaceutical Company

USP

  • Ph. Eur.

Actual Result: Harmonized monograph (Tests, Methods, Acceptance Criteria) Updates were required for product registrations in >150 countries to align with the new monograph

Scope: APIs

“Prospective Harmonization - API Pilot Project: Industry Perspective”, Pharmeuropa 22.4 (Oct. 2010), USP PF 36.6 (Nov. 2010), JPF 20.1 (Mar. 2011)

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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

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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

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Demonstrated success. Need to continue/expand effort.

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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. – 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

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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)

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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)

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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

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Practical Challenges – Monograph Impurity Limits

Is this peak

  • an API process impurity?
  • a degradate in the drug product?

Is this peak controlled as

  • a specified impurity?
  • unspecified impurity?

Address practical challenges associated with monograph development.

– Methods, Reference Standards, Limits – Overlapping? (Resolution)

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Consider: ICH Q3A/Q3B, GPhP for Limits

  • Safety-based limits (approved) vs. Process capability.
  • Control only degradates in drug product.

Peak identified? (Ref. Std.)

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  • After Monograph Elaboration / Official
  • Outcome / Compliance Decision

– Requested that USP NOT harmonize with Ph. Eur. – Requested revision for Ph. Eur., USP monographs – Requested regulatory agreement to use previously approved methods

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US EU (~30) MOW #150

Trying to Align: Product Registrations and Compendial Requirements

US (USP) MOW (USP)

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  • 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

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Recommendations: Vision for the Future

Shared Responsibility (Regulators, Pharmacopoeias, Industry): “We try never to forget that medicine is for the people.”

(George W. Merck, December 1950)

Converging on Global Regulatory and Compendial Standards: Imagine a world where there is no need for translation…

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Imagine…

  • …consistent standards published by pharmacopoeias in the

languages needed by their stakeholders.

  • …a global pharmaceutical industry that can ensure

compliance with these standards, because they contain consistent requirements.

  • …regulators who can use these globally consistent standards

to help ensure the quality of medicines.

  • …patients around the world who are able to receive

medicines with consistent quality, wherever the medicines are manufactured.

Imagine a world where there is no need for translation…

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  • No need for translation, because all the pharmacopoeias

are saying the same thing.

  • How do we get there?

– Global pharmacopoeia harmonization/convergence (e.g. Prospective/Informal harmonization) – Implementation of Good Pharmacopoeial Practices (pharmacopoeias and regulators) – Collaboration among pharmacopoeias, regulators, industry

  • Consistent pharmacopoeia standards for consistent quality
  • f medicines to benefit patients around the world.

Imagine a world where there is no need for translation…

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…medicine…for the people…

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Thank You

Gracias Děkuji Köszönöm どうも ありがとうہیرکش Ďakujem

дякую

Danke Tak Takk Рақмет Salamat Hvala Thank You

ًاركش

धनॎयवाद

감사합니다 Dziękuję Gracias Thank You Dank u Merci Kiitos Terima kasih Ačiū Obrigado Tack Cảm ơn Obrigado Merciنونمم 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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