CURRENT CHALLENGES IN GLOBAL REGULATORY COMPLIANCE QUALITY OF PHARMACEUTICAL INGREDIENTS PHARMACOPOEIAL HARMONISATION PROCESS

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1 CURRENT CHALLENGES IN GLOBAL REGULATORY COMPLIANCE QUALITY OF PHARMACEUTICAL INGREDIENTS PHARMACOPOEIAL HARMONISATION PROCESS Dr. Vinay G Nayak President, Technical Operations Alembic Pharmaceuticals Limited

2 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

3 DEFINATION Harmonized: 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

4 Harmonization By Attribute Applied 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) as opposed 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.

5 LIST FOR HARMONISATION Carboxymethylcellulose 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 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

6 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

7 Pharmacopoeial Harmonisation 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

8 PHARMACOPOEIAL DISCUSSION GROUP In 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)

9 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 Expert Committees (a few monographs assigned to Small Molecules Monograph Expert Committees)

10 The PDG: its mission Drives International Harmonization of requirements in parallel and in co co-ordination with the ICH activity Has focused on: Excipients General Chapters

11 PDG process Stage 1: identification Stage 2: investigation Stage 3: expert committee review of first draft Stage 4: forum publication Stage 5: consensus Stage 6: regional adoption, implementation and indication of harmonisation Stage 7: inter-regional acceptance (by Q4B)

12 PDG procedure stage 6 Stage 6: Regional adoption and implementation 6A: Adoption and publication 6B: Implementation 6C: Indication of harmonisation - but highlight residual differences - (Ph.Eur. chapter 5.8)

13 Achievements: excipients 40/62 Excipients monographs Harmonisation by attribute:recognise sticking points. (Non-harmonised-attributes) Publish core harmonisation result Co-operation with Tri-PEC

14 Achievements: General Chapters 27/35 General Chapters10 of 11 Q6A general chapters 6 biotech general chapters 11 powder characterisation general chapters

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

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

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

18 Achievements: General Chapters 27/35 General Chapters10 of 11 Q6A general chapters 6 biotech general chapters 11 powder characterisation general chapters

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

20 Indication of Harmonisation Status PDG agreement to review previously published harmonised excipient monographs to indicate harmonisation status highlight residual differences achieve harmonisation at a higher level

21 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)

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

23 Summary: PDG harmonisation process improved Regulatory scrutiny of sign-off and published texts (ICH Q4B) has sharpened the process First texts can be used as interchangeable in the ICH regions Scope of Q4B widened Work on dosage-form general chapters and excipients is the priority Currently EP/USP bilateral pilot project on prospective API harmonisation

24 Chapter <231> Heavy Metals -Issues 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

25 TOXICOLOGY USP 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

26 GLOBAL HARMONISATION Benefits 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

27 SUMMARY As 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 27

28 SUMMARY Pharmacopoeias are key-players in ensuring safe standards to protect public health Pharmacopoeias can react quickly to newly arising challenges Application of the new ICH concepts is already possible in the present framework of pharmacopoeial requirements, further guidance being developed Changes to the present paradigm in setting specifications will need to be closely followed by the pharmacopoeias however: safety first!! 28

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