Dr. Vinay G NayakPresident, Technical OperationsAlembic Pharmaceuticals Limited

PHARMACOPOEIAL HARMONISATION PROCESS

CURRENT CHALLENGES IN GLOBAL REGULATORY COMPLIANCEQUALITY OF PHARMACEUTICAL INGREDIENTS

Why Is a Public Standard Important?�Ensure a consistent approach to quality for innovator and generic products �Assess the quality of drug products in commerce �Provide specifications that new manufacturers can target�Monitor for counterfeit and substandard products�Monitor the quality of imported drug products�Provide information for compounding pharmacists

DEFINATIONHarmonized: A pharmacopeial general chapter or other pharmacopeial document is harmonized when a pharmaceutical substance or product tested by the document’s harmonized procedure as published in EP, JP and USP yields the same results, and the same accept/reject decision is reached.Harmonized by Attributes: If a monograph or general chapter is not completely harmonized with the corresponding texts of the Japanese Pharmacopoeia and the European Pharmacopoeia, it is considered to be harmonized by attributes. Definition of Harmonization

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Harmonization By AttributeApplied retrospectively when agreement was unable to be reached on specific tests in a monograph, or parts of a General Chapter.�Instituted as a means to move items forward where there was agreement on the main attributes (i.e. assay, identification) asopposed to delaying entire monograph or chapter.�Attributes may have been determined to be non-harmonized by PDG for the following reasons–(1) Differing regulatory or legal requirements–(2) Non-harmonized methodology for procedures–(3) Differences in scientific expert opinions�PDG have committed to work transparently in clearly identifying which specific attributes in a monograph or chapter are harmonized.�PDG have committed to working on eliminating non-harmonized attributes where possible.

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LIST FOR HARMONISATIONCarboxymethylcellulose�Carboxymethylcellulose Calcium�CroscarmelloseSodium�Crospovidone�Cellulose, Microcrystalline�Cellulose, Powdered�Cellulose Acetate�Cellulose Acetate Phthalate�Citric Acid, Anhydrous�Citric Acid, Monohydrate�Ethylcellulose�Hypromellose�Hypromellose PhthalateLactose, Anhydrous�Lactose Monohydrate�Magnesium Stearate

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�Methylcellulose�Butyl, Ethyl, Methyl, Propyl Paraben�Polysorbate 80�Povidone�Saccharin�Saccharin Calcium�Saccharin Sodium�Sodium Chloride�Sodium Starch Glycolate�Starch, Corn�Starch, Potato�Starch, Rice�Starch, Wheat�Stearic Acid�Sucrose�Talc

GENERAL CHAPTERS FOR HARMONIZATION

Analytical Sieving�Bulk Density and Tapped Density�Gas Pycnometric Density of Solids�Powder Flow�Tablet Friability�Optical Microscopy�Powder Fineness�Specific Surface Area�Porosimetry by Mercury Intrusion�X-Ray powder diffraction�Amino acid determination�Capillary electrophoresis�Isoelectric focusing�Protein determination

peptide mapping�Polyacrylamide Gel Electrophoresis�Extractable Volume�Residue on Ignition�Particulate Matter�Sterility�Dissolution�Disintegration�Uniformity of Content/Mass�Microbial Contamination�Laser Diffraction Measurement of Particle Size�Bacterial Endotoxins�Water-Solids Interaction

• Starting point: Industry is more and more developing products intended for submission worldwide

•Aim: “single set of global specifications”

(see ICH Q6A Guideline objective) • Avoid redundant testing by suppliers and pharmaceutical industry to meet differing standards

Pharmacopoeial Harmonisation

PHARMACOPOEIAL DISCUSSION GROUPIn response to proposals from industry:�PDG was formed in 1989�PDG is an informal body and consists of representatives from –United States Pharmacopeia (non-governmental)–European Pharmacopoeia, (European Directorate for the Quality of Medicines in the Council of Europe) –Japanese Pharmacopoeia (Ministry of Health, Labour and Welfare)

PHARMACOPOEIAL HARMONISATION

Pharmacopeial Discussion Group (PDG) �Participants include USP and the European and Japanese Pharmacopoeias�Focuses on selected official, broad-impact General Chapters and excipient monographs �Eliminate/minimize industry’s need to perform multiple tests and procedures and to comply with multiple acceptance criteria for the same article�Slow process, specific stages and terminology�Affects primarily General Chapter and Excipient Monograph ExpertCommittees (a few monographs assigned to Small Molecules Monograph Expert Committees)

The PDG: its missionDrives InternationalHarmonization ofrequirements in parallel and in coco-ordination with the ICH activityHas focused on:• Excipients• General Chapters

PDG process Stage 1: identificationStage 2: investigationStage 3: expert committee review of first draftStage 4: forum publicationStage 5: consensusStage 6: regional adoption, implementation and indication of harmonisationStage 7: inter-regional acceptance (by Q4B)

PDG procedure stage 6 Stage 6: Regional adoption and implementation6A: Adoption and publication6B: Implementation6C: Indication of harmonisation- but highlight residual differences- (Ph.Eur. chapter 5.8)

Achievements: excipients 40/62 Excipients monographsHarmonisation by attribute:Recognise sticking points.(Non-harmonised-attributes)Publish “core” harmonisation resultCo-operation with Tri-PEC

Achievements: General Chapters 27/35 General Chapters10 of 11 Q6A general chapters6 biotech general chapters11 powder characterisation general chapters

Why evaluation by ICH EWG Q4B ? Despite PDG efforts general chapters remained effectively unharmonizedImplementation of sign-off texts as agreed ?Need for formal declaration of regulatory acceptance to be expedited, to facilitate achieving true harmonization in practiceConsidered critical to attain full utility of ICH Q6A GLIndustry and regulators promoted such greater cooperation to ICH SC 2003

PDG Achievements in Brussels Sign Off Topics – GeneralChapters/ExcipientsLaser diffraction measurements of particle size (new)Carmellose (new)Dissolution Testing: Rev. 2Bacterial Endotoxin: Rev. 1Additional minor revisions

PDG Achievements in Brussels Process improvements since Portland:Small working group to monitor and communicate PDG topics on a regular basis beneficial for progressDevelopment of online repository of PDG documents ongoingContinuous Process Improvement as standing agenda item.

Achievements: General Chapters 27/35 General Chapters10 of 11 Q6A general chapters6 biotech general chapters11 powder characterisation general chapters

Current Status of Q4B evaluation Residue on Ignition (Annex 1) step 5Extractable Volume (Annex 2) Particulate Matter (Annex 3) step 4Microbial Contamination (Annexes 4A, 4B, 4C)Disintegration (Annex 6)Uniformity of Dosage Units (Annex 5)Dissolution (Annex 7) step 2Sterility (Annex 8)

Indication of Harmonisation StatusPDG agreement to review previouslypublished harmonised excipient monographs toindicate harmonisation statushighlight residual differencesachieve harmonisation at a higher level

Interaction PDG/Q4B SC approved future Q4B activities:Tablet friability (PDG Stage 6)Analytical Sieving (PDG Stage 6)Bulk Density and Tapped Density (PDG Stage 6)Capillary electrophoresis (PDG Stage 6)Polyacrylamide gel electrophoresis (PDG Stg 6)

Interaction PDG/Q4B Possible future PDG activities under discussion:Chromatography pHSpectrophotometry (including NIR)Water determination

Summary:PDG harmonisation process improvedRegulatory scrutiny of sign-off and published texts (ICH Q4B) has “sharpened” the processFirst texts “can be used as interchangeable” in the ICH regionsScope of Q4B widenedWork on dosage-form general chapters and excipients is the priorityCurrently EP/USP bilateral pilot project on prospective API harmonisation

�Difficulties in reproducibility–Monitor solutions/standards change with time, recovery issues�Difficulties with reagents –safety issues–All procedures generate H2S (USP via thioacetamide reaction with base). H2S more toxic than cyanide–Thioacetamide not allowed in California and several European countries (EP uses Na2S)�Nondiscriminatory screening test–Not element specific–Sensitivity varies by element–Only a few elements respond at required sensitivities�Visual comparison test –Limits based on visual acuity, not toxicology

Chapter <231> Heavy Metals -Issues

TOXICOLOGYUSP is proposing an approach to elemental impurity control that is both health based and risk based

�Control metals that are toxic�At limits that are toxicologically relevant�At all times during a drug product’s shelf life�With a risk-based approach as to what and when to test

GLOBAL HARMONISATIONBenefits to stakeholders–Elimination of redundant testing–Multi-compendial compliance�Benefits to the pharmacopeias–Stronger monographs with a global set of experts setting and reviewing standards–Specifications (test methods) are representative of the global supply chain

SUMMARYAs pharmaceutical companies move from Regional to

Global markets there is an increasing trend to move from

diverse to commonly accepted standards.

Also the advancements in science and tachnology have

promoted meaningful standards of Quality Measurement

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SUMMARYPharmacopoeias are key-players in ensuring safe standardsto protect public healthPharmacopoeias can react quickly to newly arising challengesApplication of the new ICH concepts is already possible in the present framework of pharmacopoeial requirements, further guidance being developedChanges to the present paradigm in setting specifications willneed to be closely followed by the pharmacopoeias –however: safety first !!

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