2005.03.03. Dr. Pogány - WHO, Shanghai 1/58 Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines János Pogány, pharmacist, PhD, consultant.

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Presentation transcript:

Dr. Pogány - WHO, Shanghai 1/58 Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines János Pogány, pharmacist, PhD, consultant to WHO Shanghai, 01 March QUALIFICATION and VALIDATION I.

Dr. Pogány - WHO, Shanghai 2/58 Subjects for Discussion 1.Regulatory background, definitions 2.Characteristics of processes 3.Validation master plan (VMP) 4.Pharmaceutical manufacturing process validation (tablet-making) 5.Concluding remarks

Dr. Pogány - WHO, Shanghai 3/58 WHO GMP and Guidelines  Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis.  WHO good manufacturing practices (GMP): main principles for pharmaceutical products – Section 4. Validation of manufacturing processes.  Supplementary guidelines on good manufacturing practices (GMP): Validation (2003) – Draft.

Dr. Pogány - WHO, Shanghai 4/58 Qualification  QUALIFICATION is the „Action of proving that any premises, (pharmaceutical utility) systems and items of equipment work correctly and actually lead to the expected results. The meaning of the word “validation” is sometimes extended to incorporate the concept of „qualification”.  REQUALIFICATION is the main part of the preventive maintenance programme of proving that any premises, (pharmaceutical utility) systems and items of equipment work correctly and keep on leading to the expected results. (normal wear and tear)

Dr. Pogány - WHO, Shanghai 5/58 Validation  VALIDATION is the „Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually leads to the expected results (see also qualification)”.  REVALIDATION is a part of the change control system of proving that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually keeps on leading to the expected results.

Dr. Pogány - WHO, Shanghai 6/58 Qualification - Validation Regulatory requirements DQ,IQ,OQ inputs DQ,IQ,OQ process DQ,IQ,OQ outputs Process Qualification Verification Validation Premises, equipment and supporting utilities must be qualified to operate in a validated process.

Dr. Pogány - WHO, Shanghai 7/58 Technical pharmacy  Pharmaceutical production system (from purchasing API to packaging FP)  Utility support system (HVAC, water, HPLC, etc. equipment containing many items)  Process (tablet making)  (Unit) operation (granulation, compression)  Step (sifting, sizing)  Procedure, method, technique (SOP)

Dr. Pogány - WHO, Shanghai 8/ Scientific approach  „Processes and procedures should be established on the basis of the results of the validation performed.” Objectives  To prove that the tests, measurements, results and interpretation of formal studies on (manufacturing) processes and procedures/methods are appropriate and accurate.  To stabilize new processes (to reduce variability, to increase batch to batch consistency of quality attributes of products).  To reduce defect levels (standardize yields).  To reduce production costs.

Dr. Pogány - WHO, Shanghai 9/58 Measure of variation (spread of data) 95.46% 68.26%

Dr. Pogány - WHO, Shanghai 10/58 Mean (average) chart Normal variation due to common causes UCL Upper control limit LCLLower control limit Abnormal variation of process – special causes average = mean

Dr. Pogány - WHO, Shanghai 11/58 Causes of variation  Man (different operators - lack of proper training)  Machine / equipment (variation of tablet weight)  Measurement (lack of calibration)  Method (accuracy of validated analytical methods)  Material (batch-to-batch variation of the same crystal form – different crystal forms (ASA)]  Environment (OoS T and RH in capsule filling)

Dr. Pogány - WHO, Shanghai 12/58 Process under control  Most points fall near the central line (68% within one σ)  A few points fall near the control limits (5% in the third σ)  Points shold balance on both sides of the mean  Points should cross the mean line often.  Points should show a random pattern (no trends, cycles, clustering)

Dr. Pogány - WHO, Shanghai 13/58

Dr. Pogány - WHO, Shanghai 14/58

Dr. Pogány - WHO, Shanghai 15/58 UNDER CONTROL OUT OF CONTROL

Dr. Pogány - WHO, Shanghai 16/58

Dr. Pogány - WHO, Shanghai 17/58

Dr. Pogány - WHO, Shanghai 18/58 Innovator FPPs Well-established, multisource, generic FPPs

Dr. Pogány - WHO, Shanghai 19/58 GMP, QUALIFICATION and VALIDATION STARTS WITH DESIGN + CONSTRUCTION OF FACILITIES AND PURCHASING EQUIPMENT

Dr. Pogány - WHO, Shanghai 20/58

VALIDATION MASTER PLAN (VMP) ILLUSTRATIVE ISSUES

Dr. Pogány - WHO, Shanghai 22/ Validation master plan 1.„In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled. 2.The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan (VMP).”

Dr. Pogány - WHO, Shanghai 23/58 Project oriented VMP  Construction of new premises  Major renovation or additions to existing premises  First time validation of previously unvalidated processes (ARV FPPs)  Automation or computerized implementations that span a number of applications

Dr. Pogány - WHO, Shanghai 24/58 Validation master plan  The VMP is a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as  Policy Documents (Quality Manual),  SOP's and  Validation Protocols/Reports.

Dr. Pogány - WHO, Shanghai 25/58 Content of VMP  Approval ( top management and all participating departmental heads )  Scope [ separate VMPs for manufacturing processes, pharmaceutical utility systems (e.g. HVAC, water)].  Responsibilities  Production and QC premises (including controlled environments)  Process and QC equipment  Pharmaceutical air (HVAC) and water systems

Dr. Pogány - WHO, Shanghai 26/58 Content of VMP  All critical utilities ( such as compressed air, steam and cooling liquids )  Computer control systems  Manufacturing processes  Product specifications including prospective IPC acceptance criteria  QC and IPC methods

Dr. Pogány - WHO, Shanghai 27/58 Content of VMP  Equipment cleaning  Validation requirements  Worker and environment safety  Change Control/Revalidation  Training requirements  Documentation requirements  Security plans

DESIGN, INSTALLATION and OPERATION QUALIFICATION

Dr. Pogány - WHO, Shanghai 29/ Documentary evidence (a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification or DQ); (b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications (installation qualification or IQ);

Dr. Pogány - WHO, Shanghai 30/58 DQ and IQ  DQ protocols and reports  GMP  VMP  National law  Engineering design and construction documents Do not start IQ before DQ has been completed!  IQ/OQ protocols and reports  Above inputs + machine manuals  Separate VMPs for HVAC and water systems Do not start OQ before IQ has been completed!

Dr. Pogány - WHO, Shanghai 31/ Documentary evidence (c) the premises, supporting utilities and equipment operate in accordance with their design specifications (operational qualification or OQ); (d) a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation or PV, also called performance qualification or PQ).

Dr. Pogány - WHO, Shanghai 32/58 Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines Tablets MANUFACTURING PROCESS VALIDATION

Dr. Pogány - WHO, Shanghai 33/58 Risks in manufacturing processes  Small quantity of waste creates serious danger to health (1/3 of 5% dextrose infusion was not sterile, Evans Medical, 1972)  Low chance that patient or doctor recognizes non- conformance to specification in time (DEG in glycerol, Haiti)  Limitations of sampling  Percent of nonconformance: 0,11,05,010,0  Percent probability of release:

Dr. Pogány - WHO, Shanghai 34/58 SAMPLING PROBLEM The whole batch is released to the patient But only the sample is tested BATCH Sample

Dr. Pogány - WHO, Shanghai 35/58 Types of process validation EXPERIMENTAL APPROACH PROSPECTIVE VALIDATION (R&D) CONCURRENT VALIDATION (FIRST ≥3 BATCHES) ANALYSIS OF HISTORICAL DATA RETROSPECTIVE VALIDATION (DIFFERS CONCEPTUALLY FROM THE EXPERIMENTAL APPROACH)

Dr. Pogány - WHO, Shanghai 36/ What should be validated? „Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated.”

Dr. Pogány - WHO, Shanghai 37/ Protocols and reports  Validation studies are an essential part of GMP and should be conducted in accordance with predefined and approved protocols.  A written report summarizing the results recorded and the conclusions reached should be prepared and stored.

Dr. Pogány - WHO, Shanghai 38/58 Essential parts of the process validation protocol  Short description of the process with a summary of the critical processing steps or critical parameters to be monitored during validation.  Additional testing intended to be carried out (e.g. with proposed acceptance criteria and analytical validation as appropriate).  Sampling plan — where, when, how and how many samples are taken.  Details of methods for recording and evaluation of results.

Dr. Pogány - WHO, Shanghai 39/58 Illustrative variables of wet granulation Process stepControl or manipulate (independent) variables Measured responses or output (dependent) variables Crystallization Micronization Particle size Bulk density Dissolution time Granulation and granule variables Pre-mixingSpeed, time, order of addition Blend uniformity Wet kneadingBatch (load) size Speed  Impeller  Chopper Spraying rate Volume of binder solution Granulation time End-point amperage  Impeller  Chopper Additional solvent volume

Dr. Pogány - WHO, Shanghai 40/58 Illustrative variables of wet granulation Process stepControl or manipulate (independent) variables Measured responses or output (dependent) variables DryingInlet air temperature (seasonal variation) Drying time (seasonal variation) Cooling time (if applicable) Outlet air temperature LOD Moisture content SizingScreen type and size Feed rate Granule size distribution (variation of sub-batches) BlendingBatch size (sub-batches) Speed Blending time Blend uniformity Bulk density  untapped  tapped Flowability Yield

Dr. Pogány - WHO, Shanghai 41/58 Illustrative variables of compression and film-coating Process stepControl or manipulate (independent) variables Measured responses or output (dependent) variables CompressionMachine speed Granule feed rate Precompression force Compression force Punches and dies Weight variation Content uniformity Friability Hardness Thickness Disintegration Dissolution time and profile Yield Film-coatingInlet air temperature (season) Inlet air flow Spray rate Spray atomizing pressure Outlet air temperature Tablet-bed temperature Coat quality Yield

Dr. Pogány - WHO, Shanghai 42/58 Illustrative variables of tablet packaging Process stepControl or manipulate (independent) variables Measured responses or output (dependent) variables BlisteringMachine speed Machinability of blister material Forming temperature Forming pressure Sealing temperature Sealing pressure Leak testing Appearance Minimum information is legible Yield Bulk packing Tablet counter Incomplete tablets Machine speed Number of tablets Detection, counting Pilfer-proof Labeling Yield

Dr. Pogány - WHO, Shanghai 43/58 Validation batches  Process validation reports should be submitted in the application for prequalification.  Formal studies of production scale batches (not less than three) are required to identify the critical variables.  Provisional equipment control parameters and the corresponding in-process acceptance criteria must be deduced from the results of experiments with the validation batches.  Critical parameters are to be monitored, non-critical ones should be tested occasionally.

Dr. Pogány - WHO, Shanghai 44/ Validation policy 5.Qualification and validation should not be considered as one-off exercises. An on-going programme should follow their first implementation and should be based on an annual review. 6.The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the quality manual or validation master plan. 7.The responsibility of performing validation should be clearly defined.

Dr. Pogány - WHO, Shanghai 45/58 Process approach CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM CUSTOMERCUSTOMER REQUIREMENTSREQUIREMENTS CUSTOMERCUSTOMER SATISFACTIONSATISFACTION Management responsibility Resource management Monitoring, improvement Manufacture Product Inputs

Dr. Pogány - WHO, Shanghai 46/58 Annual FPP quality review (1)  Starting materials used in the product, especially those from new sources.  Critical in-process controls and finished product results.  All batches that failed to meet established specification(s).  All critical deviations or non-conformances and related investigations.  All changes carried out to the processes or analytical methods.  Marketing Authorisation variations submitted, or granted, or refused, including those for third country dossiers.

Dr. Pogány - WHO, Shanghai 47/58 Annual FPP quality review (2)  Results of the stability monitoring programme.  All quality-related returns, complaints and recalls, including export only medicinal products.  Adequacy of previous corrective actions.  For new marketing authorisations, a review of post- marketing commitments.  A list of validated procedures and their revalidation dates.  A list of qualified equipment, support utility systems and their requalification dates, including calibration programs.

Dr. Pogány - WHO, Shanghai 48/58 Case summary of 20 batches (1) StatisticsAv. wt. mgDissolution %Assay % Mean347,699,698,2 Median346,9100,097,5 SD5, Range Minimum Maximum Conf. level, 95% Accept. Crit.350±5%75%, 40'90-110

Dr. Pogány - WHO, Shanghai 49/58 Case summary of 20 batches (2) 1.Acceptance criteria for assay and dissolution rate are loose and should be tightened. 2.Potential degradation products were not tested. 3.IPC data were not included in the retrospective analysis of batch records. 4.Failures were not reported, etc.

Dr. Pogány - WHO, Shanghai 50/ Analytical methods, computers and cleaning procedures  It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems and cleaning procedures.

Dr. Pogány - WHO, Shanghai 51/58 AUTOMATED SYSTEMS  Protection of records, backups  Access controls (use, read, write, execute, delete, or create)  Authentication (user ID and static passwords; user ID and dynamic passwords; and biometric devices)  Audit-trail controls, and many other issues.

52/58 Current WHO GMP Process performance Time 1992 version of WHO GMP Without/before GMP Parametric release Problems Stages of process validation

Dr. Pogány - WHO, Shanghai 53/58 BEST PROCESS MINIMUM REQUIRED INPUT MAXIMUM OUTPUT AT NO COST TO SOCIETY (industrial safety, labour safety, internal and external environment protection)

Dr. Pogány - WHO, Shanghai 54/58 Costs of quality Visible costs, e.g., waste and returned goods Hidden costs, e.g., wrong decisions, non-competitive manufacturing process, low yield, maintenance, idle machine time, workers attitude, etc.

Dr. Pogány - WHO, Shanghai 55/58 Main points again  High quality FPPs can be manufactured only with high quality processes under control.  Premises, equipment and supporting utilities must be qualified to operate in validated processes.  Testing QC samples of FPPs does not guarantee the quality of the whole batch, or the batch-to- batch consistency of quality.  Validation activities must be organized (VMP) and documented (protocols, records, reports, etc.)

Dr. Pogány - WHO, Shanghai 56/58 Main points again  Prospective and concurrent validations help to understand what is critical for quality and shows the level of quality, which can be achieved with the available resources.  Qualification and validation should not be considered as one-off exercises.  Quality of FPPs should be reviewed annually.  The best process is the most efficient both from technical and economic/financial points of view.

Dr. Pogány - WHO, Shanghai 57/58 Literature  Pharmaceutical Process Validation, edited by: R. A. Nash; Alfred H. Wachter, An International Third Edition, Revised and Expanded, Marcel Dekker, Inc. New York, Basel, Hong Kong (2003). Pharmaceutical Process Validation  Marjo-Riitta Helle et al.: A literature review of pharmaceutical process validation, 52 references, Pharmaceutical Technology Europe, August 2003.

Dr. Pogány - WHO, Shanghai 58/58 THANK YOU 谢谢 !