Anda registration in us eu


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Anda registration in us eu

  1. 1. Drug GMPs Worldwide andANDA Registration in US and EU Dr.J.B.Dave 29.4.2010
  2. 2. Definition of GMP …. GMP is that part of Quality Assurance which ensures that product are consistently manufactured and controlled for the purpose of their intended use or as required by the marketing authorization -2-
  3. 3. Drug GMPs Worldwide….. WHO GMP Guideline TGA Guideline (Therapeutic Goods Administration) US FDA Guideline (US Federal Drug Administration) ANVISA (Brazilian National Health Surveillance Agency) EC Guideline Schedule M -3-
  4. 4. Quality System….Six Systems Model - Quality System Management - Facilities & Equipment System Environment - Material System - Production System - Packing & Labeling System - Laboratory Control Operations System -4-
  5. 5. Comparison…..Inspection ApproachEU USAssessment oriented Enforcement orientedExample: Example:Primary interest is in justification for the Primary interest is in methodology for resolvingresolution of the deviations deviationsOperations focused System & document focused Spend more time out in the conference roomSpend more time out in the plant at shop floor reviewing documents Issues FD 483, You may have a warning letterIssues Post-inspection letters that lists of and then respond to it. It is a less formal thanproblems they have found. EU.Inspector Driven – Conclusion are really Higher level authority reviewwritten by the inspectors May contact your distributor but don’t ask youConcern with “Good Distribution Practices” once the material leaves your company -5-
  6. 6. Comparison…..Batch release processEU USFor European Market : For US Market :Batch released to the market by Qualified No such requirementPerson (QP) at Europe after reviewing BatchManufacturing Record & complete testing inEurope -6-
  7. 7. Life Cycle…..Controlled Process Design & develop Product • With trained staff • Using confirmed quality Scale-up the process materials following• Design plant validated processes and• Install equipment in accordance with the• Develop relevant Validate Process – As scale up preestablished formulas &• Documentation methods(Formulas, Mfgmethods, material & Make & Package Productproduct specifications,maintenance schedules Carry out In-Processetc…) Checks & Controls Record all process details On the basis of, Record all In – process • End product test results • Review of batch mfg & checks & controls details packaging records • Review of In-process Test end product against control records established specification • All other information relevant to the quality of the product Make release/reject decision -7-
  8. 8. Product Registration & Post Approval Changes -8-
  9. 9. Organisation of….. ANDA & CTD Module ANDA / CTD Module 1 Administrative and legal information Module 2 QoS (Quality overall summary) in FDA format Module 3 CMC For generic application not applicable Module 4 • Toxicological & Pharmacological – Non clinical study Module 5 Bioequivalence studiesNote : All modules of ANDA are in electronic format hyperlinked as per FDA eCTD format -9-
  10. 10. Generic Product Registration Process…..US Drug Development Exhibit Batches Pivotal BE Studies / Stability 3 Months ANDA Submission to FDA Facility InspectionANDA Review by FDA (PAI) by FDA ANDA Approval Post Approval Changes Validation Batches (Scale Up to 10 Times)FDA Post approval Product Launchinspection at least once in every Post Approval Changes 2 years Commercial Production -10-
  11. 11. Generic Product Registration Process…..EU Drug Development 2 Pilot + Exhibit Batches 1 Commercial Pivotal BE Studies / Stability 6 Months CTD Submission Facility Inspection CTD Review by EU (PAI) by EU Product Approval Post Approval Changes Validation Batches EU Post approval Product Launchinspection at least once in every Post Approval Changes 2 years Commercial Production -11-
  12. 12. Post Approval Changes….. GenericConcern of Regulatory Agencies:Demonstrate that changes do not lead to dilution of quality, either at the in-process stage,batch release or during the storage. Also the change should not adversely effect on safetyor efficacy of the product. Common Post Approval Changes / Variations Change Change in in Batch size Shelf life Change Change in in Equipment Container/ Closure Change Quantitative Change in of Change vendor Manufacturing in for raw materials Site Excipients -12-
  13. 13. Examples…..Post Approval changes (US)  Site change for labeling operation or secondary packaging.Annual  Change in equipment of same design and operating principle.Reportable  Addition or deletion of embossing / debossing in tablet dosage form.  Extension of expiration dating based on complete shelf life data.  Change in manufacturing site for the final intermediate of drug substance.CBE 0  Change in test method or controls for assuring better product quality.  Change or addition/deletion of a desiccant.  Site changes to different manufacturing site for drug product, drug substance which has satisfactory GMP status within 2 years  The placement of equipment with another equipment of different designCBE 30 that does not alter process operating parameters.  A change in analytical procedure with an equivalent procedure at the in- process stage of drug product manufacturing (e.g., from HPLC to UV method)  Site change to a difference site which does not have a satisfactory cGMP inspection within 2 years.  For non-sterile dosage forms any fundamental change in the process (forPAS e.g., Wet granulation to Dry granulation or vise versa).  Change in the route of synthesis for a drug substance.  Changing an analytical procedure for the finished product if the change is not compendial. -13-
  14. 14. Examples…..Post Approval changes (EU)  Deletion of test procedure, if an alternative test procedure is already authorized  Change in imprinting / embossing & other markingType IA  Change in the dimension or shape in the immediate release solid dosage(Minor Changes) form.  Change in the coating weight of immediate release product  Minor change in the mfg process not have significant effect on safety, quality & efficacy.  Addition or replacement of test procedure.  Change in the dimension or shape in the prolong release solid dosage form.Type IB  Replacement of a single excipient with the a comparable one with the same(Minor Changes) functional characteristics and at a same level  Addition or replacement of the In-process test  Introduction of new manufacturer of API  Change in scoring /break line intended to divide into equal doses  Qualitative or quantitative change in one or more excipients that may haveType II significant impact on safety, quality & efficacy of the product(Major Changes)  Deletion of in-process test  Change in the coating weight of the prolonged release products  Change in the mfg process have significant effect on safety, quality & efficacy. -14-
  15. 15. Post Approval Changes….. Generic US EU Minor Changes Moderate Changes Major Changes Minor Changes Major Changes Not likely to have Could have likely to have Not likely to have likely to have any detectable Significant Significant any detectable Significant effect on quality effect on quality effect on quality effect on quality effect on quality and performance and performance and performance and performance and performance of the product of the product of the product of the product of the product 3 Batch accelerated & 1 Batch 1 Batch accelerated & Type I A Type I B Type II long term stability data long term stability datalong term stability data Revised Documents Revised Documents Revised Documents Dissolution Profile Dissolution Profile Full BE Study File & submit Prior approval CBE – 0 Day changes to Annual with tacit CBE – 30 Days PAS regulatory in PAS Reportable acceptance & PAS annual report after 30 days Within 12 months -15-
  16. 16. Modern Quality System…. The basic philosophy on which all modern quality systems are based is that,  Quality should be built into the product  Testing alone cannot be relied on to ensure product quality Product quality and performance achieved and assured by design of effective and efficient manufacturing processes Product specifications based on mechanistic understanding of how formulation and process factors impact product performance Continuous “Online (Real Time)" assurance of quality -16-
  17. 17. Tools For Online Quality Review …. PAT – NIR, Acoustics, Check weigher LIMS BMS Continuous environmental monitoring Online TOC Audio/Visual alarm for monitoring AHUs Risk Assessment Self Inspections & External Audits Scheduler for calibration, preventive maintenance, sterility testing, APRs Stagewise online batch reviewAnd many more ……. -17-
  18. 18. Fully developed & effectivelymanaged quality system willlead to consistent, predictableprocesses that ensure theavailability of safe and effectiveproduct for the consumer all thetime. -18-
  19. 19. References “The Gold Sheet”, Pharmaceutical & Biotechnology Quality Control. Guidance for Industry – Quality System Approach to Pharmaceutical CGMP regulation. US. Dept of Health & Human Services, FDA. Good manufacturing practices and requirements of premises, plant and equipment for pharmaceutical products (Schedule M) International Pharmaceutical Quality (IPQ) – Inside the global regulatory dialogue. Centre for Drug Evaluation and Research Good Pharmaceutical Manufacturing Practice : Rationale & Compliance -19-
  20. 20. Acknowledgement• Mr.S.G.Belapure, President, Operations, Zydus Cadila Healthcare Ltd, presentation made on 11.2.10 at CSIR sponsored national seminar on GMP at SSPC. -20-
  21. 21. -21-