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

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

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 QualityMedicines 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 ComplianceAdventures 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 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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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

ArgentinaCzech

RepublicHungary Japan Pakistan Slovakia Ukraine

Austria Denmark Iceland Kazakhstan Philippines SloveniaUnited

Kingdom

Belarus Egypt India Korea Poland SpainUnited

States

Belgium Finland Indonesia Lithuania Portugal Sweden Viet Nam

Brazil France Iran Mexico Romania Switzerland Europe

China Germany Ireland MontenegroRussian

FederationThailand Africa

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

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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 10

• 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 Registrationsand Compendial Requirements

Product Life-Cycle

• 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 Registrationsand Compendial Requirements

Product Life-Cycle

Ideal Pharmacopoeia Harmonization

ProspectiveHarmonization

PharmacopoeiaIdeal

Goal:

Prospective Harmonization: New Monographs for APIs/Products

▪ Goal: To create a harmonized monograph from the beginning.

RetrospectiveHarmonization(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

PharmaceuticalCompany

USP monograph alignedwith registrations

- Apply different limits.

- Run 2 different methods, or

- Demonstrate method equivalence.

Ph.Eur. monograph differedfrom registrations

Monograph Development:Prospective Harmonization (Pilot 1 – 2008)

Collaboration: monograph submission/development

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PharmaceuticalCompany

USP Ph. Eur.

Single monograph proposedPossible revisions discussed

Possible revisions evaluated in labCommunication 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

Monograph Development:Prospective Harmonization (Pilot 1 – 2011)

Collaboration: monograph outcome

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PharmaceuticalCompany

USP Ph. Eur.

Actual Result: Harmonized monograph

(Tests, Methods, Acceptance Criteria)

Updates were required for productregistrations 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)

Prospective/Informal Harmonization:Current Perspective

Collaboration…then Expansion

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Scope:APIs and Products

USP

KP JPIP

Ph. Eur.+ BP

ChP

Secondary Work: PDG, MOUs, Observers

GPhPs(Adopt / Adapt)

PharmaceuticalCompany

FBras PhRus

Primary Harmonization Work

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.

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

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)

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 – MonographImpurity 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.)

• 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 Registrationsand Compendial Requirements

US (USP) MOW (USP)

• 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 Registrationsand Compendial Requirements

US (USP)

EU (Ph.Eur./BP)

MOW (USP)

MOW (Ph.Eur./BP)

Japan (JP) China (ChP)

Registrations / QS / Monographs

Product Life-Cycle

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 wherethere 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 of medicines to benefit patients around the world.

Imagine a world wherethere is no need for translation…

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29…medicine…for the people…

Thank You

Gracias Děkuji Köszönömどうも

ありがとうشکریہ Ďakujem дякую

Danke Tak Takk Рақмет Salamat Hvala Thank You

شكراً धन्यवाद 감사합니다 Dziękuję Gracias Thank You

Dank u

MerciKiitos

Terima

kasihAčiū Obrigado Tack Cảm ơn

Obrigado Merci ممنون Gracias MulțumescMerci

Danke

Thank You

Merci

Danke Thank YouHvala

ХвалаCпасибо ขอบคณุ

Dankie

Asante

Hvala ευχαριστώ Grazie Takk ХвалаTeşekkür

ederim

Merci

Thank You

谢谢

Дзякуй

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