Overview of Regulatory Requirements for API and Formulations

Transcription

1 Overview of Regulatory Requirements for API and Formulations Sangeeta Sardesai 4-Dec-2010

2 Definition - Regulatory Requirement The restrictions, licenses, and laws applicable to a product or business, imposed by the government. Regulatory requirements describe what is necessary for a new drug to be approved for marketing in any particular country. 7-Dec-10 Sangeeta Sardesai - sanofi aventis 2

3 Various Regulatory Agencies- Drugs and Cosmetics Act, 1940 and Drugs and Cosmetics Rules, India Food and Drug Administration (FDA) US European Medicines Agency (EMA) EU Medicines & Healthcare products Regulatory Agency (MHRA)-UK Therapeutic Goods Administration (TGA) Australia Pharmaceutical and Medicines Agency (PMDA) Japan Health Canada - Canada World Health Organisation (WHO) International Conference on Harmonization (ICH) 7-Dec-10 Sangeeta Sardesai - sanofi aventis 3

4 Systems covered Quality System Facilities and Equipment System Materials System Manufacturing System Packaging and Labelling System Laboratory Control System Information System. 7-Dec-10 Sangeeta Sardesai - sanofi aventis 4

5 State of Control Detailed inspection of a system so that the findings reflect the state of control in that system for every product (profile) class If one of the six systems is out of control, the firm is considered out of control A system is considered out of control based on GMP deficiencies which suggest lack of assurance of quality 7-Dec-10 Sangeeta Sardesai - sanofi aventis 5

6 Quality System Assures overall compliance with cgmps and internal procedures and specifications. Includes Quality Control Unit and all of its review and approval duties Quality Unit which is independent from Production 7-Dec-10 Sangeeta Sardesai - sanofi aventis 6

7 Quality System Includes- Batch Release Product Quality Reviews Complaint reviews Discrepancy/ failure investigations Change Control CAPA (Corrective And Preventive Action) Reprocess/ Rework Validation/ Revalidation Rejects Stability Failures/ Out of trend data Quarantine products Documented GMP & Job Related Training Reprocessed, reworked, returned, salvaged product 7-Dec-10 Sangeeta Sardesai - sanofi aventis 7

8 Facilities & Equipment System Includes measures and activities which provide an appropriate physical environment and resources used in the production of the drugs or drug products. Facilities Equipment Utilities HVAC Water System Separate facilities or containment where needed (penicillins, highly potent compounds etc.) 7-Dec-10 Sangeeta Sardesai - sanofi aventis 8

9 Facilities & Equipment System- Facilities Location, design, construction appropriate to facilitate cleaning, maintenance, operations Prevent cross-contamination Layout and air handling design and construction Containment Positive / Negative pressures as required by product Flow of materials & personnel Linear and uni-directional Adequate space for placement of equipment and materials 7-Dec-10 Sangeeta Sardesai - sanofi aventis 9

10 Facilities & Equipment System- Facilities Defined areas and other control systems Quarantine (intermediates, APIs) Released materials Rejection areas Sampling / Dispensing areas Production operations Packaging and labeling operations Laboratory operations Adequate washing and toilet facilities Separate gowning areas primary / secondary 7-Dec-10 Sangeeta Sardesai - sanofi aventis 10

11 Facilities & Equipment System- Equipment Appropriate design, size, location, non-reactive product contact surfaces Identification clearly marked Qualification (DQ, IQ,OQ, PQ) Calibration Schedule, procedures and records Preventive Maintenance Schedule, procedures and records Regular checks Cleaning procedures and validation (CIP / SIP) Records of use, cleaning, maintenance Lubricants, heating fluids or coolants (not contact/alter product quality) Closed or contained equipment (where required) 7-Dec-10 Sangeeta Sardesai - sanofi aventis 11

12 Facilities & Equipment System- Utilities (HVAC & pipelines) Designed and constructed to prevent contamination / crosscontamination Drawings should be available Qualification / Validation / Calibration Routine cleaning / replacement / maintenance Regular testing Trends Alert / Action Limits Permanently installed pipework identified Drains of adequate size with air break should be appropriately 7-Dec-10 Sangeeta Sardesai - sanofi aventis 12

13 Facilities & Equipment System- Water Process water at minimum meeting WHO guidelines for potable water Justify quality of water used to achieve stated Quality Qualified / Validated Water systems Regular program for sanitization Established specifications Testing at fixed intervals Chemical / Microbiological Trends Alert / Action levels 7-Dec-10 Sangeeta Sardesai - sanofi aventis 13

14 Materials System Includes receipt, Identification, storage, handling, sampling, approval / rejection of raw materials, components, drug product containers and closures Handling and Storage Requirements Preference for computerized inventory control processes Handling and storage to prevent degradation, contamination and mix-up Separate storage space for Quarantine and Approved Appropriate storage conditions (Freezer, Cold storage etc.) Appropriate identification at all stage of storage and usage (Quarantine, Under Test, Approved, Rejected) Separate access-restricted area for rejected / return goods Cartons, bags, boxes off the floor, away from walls 7-Dec-10 Sangeeta Sardesai - sanofi aventis 14

15 Materials System Sampling / Dispensing Representative sampling Statistically based Written sampling plan with justification Sampling to prevent contamination / cross-contamination Identification of sampled containers Re-evaluation / Retest Date First In, First Out / First Expired, First Out FIFO / FEFO 7-Dec-10 Sangeeta Sardesai - sanofi aventis 15

16 Materials System Supply Chain evaluation Supplier Evaluation Criticality of material Transportation requirements Purchased against agreed specification Change control process for changing suppliers 7-Dec-10 Sangeeta Sardesai - sanofi aventis 16

17 Manufacturing System Includes measures and activities to control the manufacture of drugs and drug products. Training (documented; job-related) Batch Documentation Master & Batch production and control records Accurate and complete batch production documentation Implementation and documentation of in-process controls, tests Adequate written procedures & practice Identification of equipment with contents, stage of manufacturing, status Equipment usage and cleaning records 7-Dec-10 Sangeeta Sardesai - sanofi aventis 17

18 Manufacturing System Manufacturing Process To ensure prevention of contamination and cross-contamination Established time limits for completion of production steps/ stages Critical weighing and manufacturing operations should be witnessed Justification and consistency of in-process specifications and final product specifications Process validation based on knowledge of process Identify CPP Yields should be calculated Deviations should be documented and investigated Reprocessed / Reworked materials should be appropriately controlled. Data/ information documented and available to Quality Unit for review (trending, investigations etc.) 7-Dec-10 Sangeeta Sardesai - sanofi aventis 18

19 Packaging and Labeling System Includes measures and activities that control the packaging and labeling of drugs and drug products. Process Validation Written procedures for- Receipt, identification, quarantine, sampling, examination and/or testing Reconciliation; investigation if discrepancy 7-Dec-10 Sangeeta Sardesai - sanofi aventis 19

20 Packaging & Labeling System Packaging Operations Packaging and labeling areas must be designed to prevent mix-up and cross-contamination. Access to label storage area limited Controls / procedures in place for packaging and labeling operations Adequate identification of labeling and packaging materials Documented procedures to ensure correct packaging materials and labels are used Examination of labeling and packaging materials prior to use Line clearance Stereo Controls Control on over-printing / embossing 7-Dec-10 Sangeeta Sardesai - sanofi aventis 20

21 Packaging & Labeling System Records / Documents- Approved Specifications - should conform to specifications Master and Batch Packing Records Print labels checked against master and a copy placed into the batch record Records maintained for each shipment (showing receipt, examination & result) Destruction - All printed packaging and labels with batch number to be destroyed at site. Obsolete labels to be destroyed at site 7-Dec-10 Sangeeta Sardesai - sanofi aventis 21

22 Laboratory Control System Includes measures and activities related to laboratory procedures, testing, analytical methods development, validation / verification, stability program Adequate laboratory facilities Adequately staffed laboratories (supervisory and bench personnel) Qualified and trained Reference Standards (primary; secondary) Microbiological cultures Instrumentation as per testing requirements Adequate Microbiology facility to support the site requirements Qualified Microbiologist Retention Sample Handling and Controls Stability Management Program 7-Dec-10 Sangeeta Sardesai - sanofi aventis 22

23 Laboratory Control System Written Documents- Approved specifications Approved procedures for sampling, testing, approval / rejection Trending OOT Laboratory controls followed and documented Out of Specifications (OOS) Approved procedure (SOP) covering OOS Investigation of OOS results in a timely manner as per SOP and documented. CAPA identified and implemented. OOS review included in Product Quality Reviews 7-Dec-10 Sangeeta Sardesai - sanofi aventis 23

24 Laboratory Control System Validation / Qualification Method validation/ revalidation Equipment Qualification / Maintenance - AMC Calibration: written procedures, schedule, documentation - OOC Validation and Security for computerized handling of test results and related data Excel sheet usage and validation 7-Dec-10 Sangeeta Sardesai - sanofi aventis 24

25 Systems Approach Goal Evaluate whether management with executive responsibility ensures that an adequate and effective quality system has been established and maintained 7-Dec-10 Sangeeta Sardesai - sanofi aventis 25

26 Most Common GMP Deficiencies by System Packaging and Labeling 13% Materials 5% Laboratory 17% Production 10% Facilities and Equipment 15% Quality 41% 7-Dec-10 Sangeeta Sardesai - sanofi aventis 26

27 GMP Guide for API (ICH Q7) Provides guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. Intended to help ensure that APIs meet the requirements for quality and purity Applicable to all APIs manufactured by chemical synthesis, extraction, cell culture / fermentation (separate section) Not applicable to sterile APIs, vaccines, whole blood and plasma, gene therapy APIs More Widely used by Regulators worldwide EU Volume 4 Part II Basic requirements for Active substances used as starting materials WHO, TRS No. 957, 2010 Annex 2- WHO GMP for API 7-Dec-10 Sangeeta Sardesai - sanofi aventis 27

28 Questions???? 7-Dec-10 Sangeeta Sardesai - sanofi aventis 28