Quality of Active Pharmaceutical Ingredients In collaboration with EMEA, EDQM, EU, FDA & WHO

Transcription

1 DIA International Conference Quality of Active Pharmaceutical Ingredients In collaboration with EMEA, EDQM, EU, FDA & WHO DIA paci Chair & DIA Board Member Disclaimer: The views expressed in this presentation are the personal opinions of the speaker and do not necessarily represent the views of the Organization

2 Presentation Flow Objectives of Regulations History of Indian regulatory requirements Acts & rules - which regulates Indian Pharmaceutical Industry Requirements for the Quality of API Regulatory approval processes 2/34

3 Objective of Regulation- Quality The Objective of Drugs & Cosmetics Act is to ensure that public (consumers) are supplied with safe and efficacious drugs and cosmetics. Responsibility of Manufacturers: Are responsible for quality of drugs manufactured by them. Responsibility of the Government Regulatory Agencies: Responsible to monitor the quality of drugs by periodic inspections of the manufacturing and sales premises for confirmation to the provisions of Drugs & Cosmetics Act and monitoring the quality of drugs moving in the market by carrying out post market surveillance. 3/34

4 History: Pre- Independence 1927 Henry Gidney s resolution to legislate the manufacture and sale of drugs Govt. appointed R. N. Chopra Committee to control menace of spurious, adulterated, misbranded drugs. (Cinchona bark) 1931 Committee submitted Report 1935 After passing Govt. of India Act, Drug became provincial subject Introduction of Drug Bill 1940 Drugs Act enacted 1945 In order to provide procedures to the industry rules were made under Drug Act 4/34

5 History: Post- Independence 1948 Pharmacy Act 1954 Drugs and Magic Remedies (Objectionable advertisement Act) 1955 Amendments to Drugs & Cosmetics Act, extension of definitions 1960 Amendments --- DTAB, Powers to central Govt., etc Amendments ---- Cosmetics manufacture regulated, misbranded, import prohibited etc Amendments ---- provision for Ayurvedic, Siddha Widened scope & definition, empowered 1985 Narcotics Drugs and Psychotropic Act 1986 Powers to consumers to draw samples Drugs Price Control Order (DPCO) 5/34

6 Chapter I Chapter II Chapter III Chapter IV Chapter V Chapter VI Composition of Drugs and Cosmetics Act Definitions Statutory committees and laboratories Import of drugs and cosmetics Manufacture of Drugs and Cosmetics Siddha and Unani drugs Miscellaneous Books on Standards: Indian Pharmacopoeia (Inclusion of HIV Drugs monographs) Homeopathic Pharmacopoeia Ayurvedic Pharmacopoeia and Indian Pharmacopoeia Veterinary 6/34

7 Schedule I Schedule II Schedule S Schedule R Schedule F Schedule FF Schedule V Schedule O Schedule M Schedule Y Schedule P Standards in Drugs and Cosmetics Act- Schedules Ayurvedic Drugs Other Drugs Cosmetics Condoms Vaccines Standards for Ophthalmic Preparations Patent & Proprietary Medicines Standards for Disinfectant Fluids Requirements for Manufacturing Requirements for New Drugs Requirements for Shelf Life and Storage Conditions 7/34

8 Requirement for the Quality of API Schedule M discusses about the GMP operations (especially Chapter IV) Rule No. 69, Rule No.122 and Schedule Y covers the filing requirements for a manufacturing license of New Drug / approval Assumption can lead to disaster 8/34

9 1.General Requirements Location & surroundings, Building and premises, Water System, Disposal of waste 2. Warehousing Area 3. Production area 4. Ancillary Areas 5. Quality Control Area 6. Personnel 7. Health, clothing and sanitation of workers Schedule M 8. Manufacturing Operations and Controls 9. Sanitation in the Manufacturing Premises 10. Raw Materials 11. Equipment 12. Documentation and Records 13. Labels and other Printed Materials 14. Quality Assurance 9/34

10 15. Self Inspection and Quality audit 16. Quality Control System 17. Specifications 18. Master Formula Records 19. Packing Records 20.Batch Packaging Records 21.Batch Processing Records 22.SOPs & Records for Receipt of materials, Sampling, Batch numbering, Testing Schedule M 23. Reference Samples 24. Reprocessing and Recoveries 25. Distribution records 26. Validation and Process validation 27. Product Recalls 28. Complaints and Adverse Reactions 29. Site Master Files 10/34

11 Buildings & Facilities Designed and constructed To facilitate cleaning, sanitizing, maintenance (incl. repairing), appropriate manufacturing operations (defined in physical areas or other control systems) To prevent mix-ups or contamination(chemical and microbiological) Utilities: e.g. Water Quality of the water used in the manufacture of APIs should be demonstrated to be suitable, for its intended use Increasing purity of the API along the process increasing quality of the water- Finally Purified water 11/34

12 Process Equipment Equipment shall be located, designed, constructed, adapted and maintained to suit the operations to be carried out The layout and design of the equipment shall aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid crosscontamination, build-up of dust or dirt To avoid accidental contamination, wherever possible, non-toxic / edible grade lubricants shall be used 12/34

13 Materials Material management Receipt Quarantine Sampling Testing (min. Identity) Reevaluation Storage Approved Reject - All incoming materials shall be purchased from approved sources - Evaluation of suppliers of critical materials shall be based on Historical experience, Questionnaire, Analytical verification of samples, Audit of the supplier Indian rules are somewhat silent on acceptance of hazardous materials and does not define the starting material 13/34

14 Manufacturing Stages of production operations: Chemical: Synthesis Physical: isolation/ purification/ drying/ Packaging/ labeling - Critical operations to be witnessed - Any deviation to be documented/explained In-process sampling and controls (IPC) Purpose IPC: monitoring/ adjusting process (reaction completion, ph control, water content, etc) Sample size Sampling method Sampling procedure 14/34

15 Manufacturing Blending of intermediates or APIs Combining materials with the same specifications to produce a homogeneous product Blend should be traceable back to all individual batches only contain individual batches that conform to specifications No blending of OOS batches Blending should include testing of parameters that may be affected: Particle size distribution Bulk density Tapped density (May be we should include Color) 15/34

16 Reprocessing and Recoveries Where reprocessing is necessary, written procedures shall be established and approved by the QA that shall specify the conditions and limitations of repeating chemical reactions. Such reprocessing shall be validated. (Scientific Rational is important) If the product batch has to be reprocessed, an investigation shall be carried out into the causes necessitating re-processing and appropriate corrective measures shall be taken for prevention of recurrence. Re-processed batch shall be subjected to stability evaluation. Recovery of the product residue may be carried out, if permitted, in the master production and control records by incorporating it in subsequent batches of the product. 16/34

17 Quality control Out of specifications (OOS) results to be investigated according to SOP including e.g., checklist of potential defects in laboratory checklist of potential defects in production check list of sampling and sampling devices guidance on re-sampling and re-testing testing of control (reserve) sample [RS, WRS and storage] Standards Reagents and standard solutions with use before date Primary reference standard: from documented source. If from official source and if stored as stipulated: no testing necessary Secondary reference standards (working standards): compared (by testing) to primary standard prior to first use Schedule L1 Effective from Nov will answer many of the questions 17/34

18 Quality control Stability monitoring Purpose: to confirm appropriate storage conditions and retest or expiry date Samples stored in containers simulating market container Normally, first 3 commercial production batches, then 1 batch/year placed on the on-going stability program Mention Expiration period instead of Retest period for APIs (?) 18/34

19 Validation Qualification: DQ, IQ, OQ, PQ Before starting process validation activities, appropriate qualification of facilities (rooms), equipment, systems (e.g., steam, gases, HVAC,...) should be completed. Validation of processes Processes and procedures shall be established on the basis of validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results Validation of analytical methods Degree of validation to be in relation to purpose of analysis and stage of production process (see also ICH Q2A, Q2B) Analytical methods from recognized pharmacopoeia: only suitability for use 19/34

20 Change control Any system needs to constantly be adapted/ optimized (deviations, OOS,..) Formal (written) proposal for change Approval of change by Quality Unit Implementation of change Evaluation of impact of the implemented change 20/34

21 Documentation All quality relevant activities should be described (written procedures, instructions) and documented (records) Life cycle of documents according to written procedure Issuance, review, approval, distribution, retention, withdrawal, revision history of documents Records on major equipment use and cleaning including date, signature and Use: product, batch-no. Cleaning (sanitization, sterilization): SOP Maintenance: preventative, during production, repair Water System Qualification and trending 21/34

22 Records on materials: traceability, i.e., origin and use Master production/ control instructions To ensure uniformity from batch to batch Issued and checked independently Batch production/ control records Should include all significant steps Batch production/ control records review To be performed accordingly to written procedure Review of critical steps such as OOS reports and deviation investigations and their impact on product quality, check for missing records, incomplete or illegible entries, compliance with specifications, before batch release Documentation 22/34

23 A typical Drug Development Cycle Discovery Development API Drug Product Packaged product for market 23/34

24 Regulatory approval processes Regulatory Authorities in India Central Drug Regulatory Authorities - CDSCO Central Drugs Standard Control Organization DCGI, DELHI Drugs Controller General of India - CBN Central Bureau of Narcotics NCI, GWALIOR Narcotics Commissioner of India State Regulatory Authorities - Each state is having state licensing authority e.g., DCA, Andra Pradesh - Director of Drugs Control Administration DC, Tamil Nadu Director of Drugs Control FDA, PONDY Licensing Authority, Food and Drugs Administration 24/34

25 Regulatory approval processes Drug Approval category in India: New drug First time in India Approved new drug- Approved by DCG(I), but not more than 4 years old Approved drug - Approved by DCG(I), but more than 4 years old Approved drugs details are Available at < > 25/34

26 Regulatory approval processes New drug, Approved new drug Application Approved drug Application (more than 4 years old drug) Form 44 Form 24 DCG(I), CDSCO Form 24 Mfg. License application Form 46A Approval State licensing authority Form 25 Mfg. License approval 26/34

27 Data requirements for filing Schedule Y Clinical trial Chemical and pharmaceutical information. Animal Toxicology Animal pharmacology Regulatory status in other countries Marketing information Post-marketing surveillance study Recently IPR status is also needs to be submitted along with the Pharmaceutical category and route of administration. 27/34

28 Clinical Trials Clinical trials required to be carried out in the country before a new drug is approved for marketing depend on the status of the drug in other countries. If the drug is already approved/marketed and internationally available, Phase III trials are required For new drug substances discovered in India, clinical trials are required to be carried out in India right from phase I 28/34

29 Chemical and Pharmaceutical Information Brief description of the drug and the therapeutic class Physiochemical data - Chemical name, Structure, Empirical formula Molecular weight - Physical properties Description, solubility, rotation, partition coefficient, dissociation constant, crystalline / amorphous, water of hydration, flow properties (even micro metrics) 29/34

30 Chemical and Pharmaceutical Information Analytical Data Elemental analysis Mass spectrum NMR spectra IR spectra UV spectra Polymorphic identification Particle size distribution Crystalline / amorphous, Water of hydration, Flow properties (even micro metrics) 30/34

31 Chemical and Pharmaceutical Information Complete monograph specification - Identification - Identity/quantification of impurities - Enantiomeric purity - Assay Validations - Assay method - Impurity estimation method - Residual Solvents/ OVI estimation method 31/34

32 Chemical and Pharmaceutical Information Stability studies - Study on final release specification 3 batches: Long term 30 C ± 2 C/ 65%RH ± 5%RH 12 months Accelerated 40 C ± 2 C/ 75%RH ± 5%RH 6 months Photo stability study on min of 1 batch is required 32/34

33 Quality System 33/34

34 Thank you!!! 34/34

35 Back up Slides

36 GROWTH OF PHARMACEUTICAL INDUSTRY : Imports, Simple Formulations (tinctures and mixtures) : APIs by chemical synthesis and fermentation, different dosage forms : Growth and sophistication : Research, Biotechnology and Exports 36/34

37 REASONS FOR INITIATIVES A) Globalization B) New Technologies C) New Therapies 37/34

38 REASONS FOR INITIATIVES CONTD.. A) Globalization Opportunities in: Contract Manufacturing Contract Clinical Research Contract R & D. 38/34

39 REASONS FOR INITIATIVES CONTD.. Contract Documentation & Testing. Neutraceuticals Herbal Medicines 39/34

40 REASONS FOR INITIATIVES CONTD.. B) New Technologies Vaccines Recombinant DNA Tissue Culture Cell Biology Fermentation Chemical Synthesis 40/34

41 REASONS FOR INITIATIVES CONTD.. C)New Therapies Stem Cells Genomics 41/34

42 INITIATIVES TAKEN BY THE GOVERNMENT Upgradation of G.M.P. requirements (Schedule M) Issuance of guidelines for clinical trials and bio-equivalance studies (GCPs) 42/34

43 INITIATIVES TAKEN BY THE GOVERNMENT CONTD.. Good Laboratory Practices for the Government as well as Private Testing Laboratories. Concepts of DMF for drugs imported into the country. G.M.P. for Ayurvedic Drugs. 43/34

44 IMPORTANT COMMITTEES CONSTITUTED BY THE GOVERNMENT HATHI COMMITTEE SPECIAL TASK FORCE AND MASHELKAR COMMITTEE 44/34

45 INITIATIVES IN THE PIPELINE Guidelines for manufacture, sale and distribution of medical devices. Guidelines for good distribution and storage practices for the hospitals. Guidelines for manufacture of biotech products. 45/34

46 INITIATIVES IN THE PIPELINE CONTD.. Guidelines for some of the important G.M.P. components i.e. stability testing, validation requirements etc. Guidelines for Neutraceuticals. 46/34