Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA

Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDAĐề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDAĐề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA Đề cương thẩm định quy trình sản xuất thuốc tiêm của FDA

Process Validation of Sterile Liquid Products By Weerayut Chirarutsami 23/08/2006 Process Validation ‰ Process validation is establishing documented evidence which demonstrate that the manufacturing process will consistently produce a product meeting its predetermined specifications and quality Characteristics New Product Trial Batch, Development Batch Transferred Product Products produced at the sending site Revalidation Product The original product before revalidation Process Validation Type of Process Validation ‰ Prospective „ ‰ Concurrent „ ‰ Conducted prior to market the product Based on information generated during actual implementation of the process (each batch will be released separately) Retrospective (Not recommended for sterile product) „ Based on accumulated historical production, testing and control data „ Generally requires data from 10-30 batches „ Use data only from batches made by the same process Validation of Sterile Product Sterile Product : The Products which free of any viable organisms Sterility : Viable microorganisms are absent Bioburden : Total number of viable microorganisms on or in pharmaceutical product prior to sterilization Validation of Sterile Product Terminal Sterilization : Operation whereby the product is sterilized separately by autoclave after filled and packaged using sterilized containers and closures in critical processing zones Aseptic Operation: Operation whereby the product is sterilized separately by filtering through 0.2 µ or less filter, then filled and packaged using sterilized containers and closures in critical processing zones Validation of Sterile Product Validation Team: Production, QC, QA, Engineer,Planner # To prepare the validation protocol # Verify the calibration and maintenance status of equipment # Perform qualification for equipments and system # Verify change control # Schedule the validation activities # Training production operators # Conduct validation study # Monitor the critical steps in manufacturing process # Assure that the approved testing standard is being used # Evaluate all test results, # Prepare the validation report Validation of Sterile Product Pre-validation Requirements : ‰ Preventive Maintenance for Facilities and Utilities ‰ Calibration of Equipment ‰ Cleaning Validation ‰ Equipment & System Qualification ‰ Raw Materials/Components/Test Methods ‰ Process Justification ‰ Change Control ‰ Training operators All must be proven suitable and reliable for the manufacturing process before the process can be validated Validation of Sterile Product Process Justification: ‰ To identify critical process steps & process parameter of Mixing process ‰ To determine the suitable Hold time Period ‰ To confirm the analytical tests that will have to be performed ‰ To define the optimal parameters throughout the overall ampoule filling process to consistently produce the finished products(filled ampoules) which meet the established specifications ‰ To assure that the product is sterile after sterilization process Validation of Sterile Product Validation Protocol A document stating how validation will be conducted, including test parameters, product characteristics, production equipment to be used and decision points on what constitutes acceptable test results Validation of Sterile Product Validation Protocol should contain : ‰ Title Page, Review/Approval Page ‰ Purpose and Overview ‰ Equipment List ‰ Ingredients and Component List ‰ Qualification List of Equipment and System ‰ Process Flow Diagram and Description ‰ Equipment Critical Process Parameter ‰ Process Validation Sampling Plan/Testing Requirements ‰ Acceptance Criteria ‰ Stability Requirements ‰ Process for evaluation of any deviations occurring during validation ‰ Conclusion 10 Validation of Sterile Product „ Changes and Revalidation ‰ Change of any of the following may need revalidation „ Formula Composition „ Raw Material Source „ Manufacturing Process „ Manufacturing Location „ Equipments „ Batch Size „ Testing Specification 22 Validation of Sterile Product „ Changes ‰ Minor: It seems to have no impact on formulation „ ‰ Intermediate : It could have significant impact on formulation „ ‰ It is not necessary to validate Depend on case-by-case (A minimum of trial) Major : It is likely to have significant impact on formulation „ Revalidation is required (A minimum of trials) 23 Validation of Sterile Product „ Minor Change „ Qualitative inactive excipient change deemed minor by change control review „ Process change deemed minor by change control review „ Manufacturing location change with in same building, same equipment, personnel, procedure and utilities are used „ Equipment change but same design, configuration 24 Validation of Sterile Product „ Intermediate Change „ Active ingredient source or synthesis change deemed intermediate by change control review „ Qualitative inactive excipient change deemed intermediate by change control review „ Manufacturing location change to a different building on the same site and same utilities, same equipment, personnel, and procedure are used 25 Validation of Sterile Product „ Intermediate Change „ Process changes, such as mixing times or operating speeds for solutions „ Change in release specification to a tighter limit caused original validation results to be out of specification „ Extension of the qualified in process hold time for intermediate or finished product prior to packaging „ Equipment change deemed intermediate by change control review 26 Validation of Sterile Product „ Major Changes „ Quantitative or qualitative formulation change deemed major by change control review „ Inactive excipient or active ingredient source change deemed major by change control review „ Transfer product from on site to another „ Significant change in process „ Equipment change to a different design, configuration or operating principle 27 Validation of Sterile Product „ Major Changes „ New Dosage „ Rework Procedure „ Process changes deemed major by change control review such as mixing times or operating speeds for suspensions „ Change in release specification to a tighter limit caused original validation results and routine production results to be out of specification 28 Validation of Sterile Product „ Conclusion Validation Protocol identifies critical process parameters to be evaluated and predetermined acceptance criteria Process must be continually monitored and change control used to identify need for process revalidation Production and QA have to review and approve the validation result Product must be held until the validation get approval 29 Re-validation „ „ „ „ „ Regular performance of process simulation studies Monitoring of environment, disinfection procedures, equipment cleaning and sterilisation (including containers and closures) Routine maintenance and re-qualification of equipment, e.g autoclaves, ovens, HVAC (heating, ventilation and air conditioning) systems, water systems, etc Regular integrity testing of product filters, containers, closures and vent filters Re-validation after changes 30 Process simulation studies (media fills) Process simulation studies (media fills) are simulating the whole process in order to evaluate the sterility confidence of the process Process simulation studies include formulation (compounding), filtration and filling with suitable media Simulations are made to ensure that the regular process for commercial batches repeatedly and reliably produces the finished product of the required quality However, each process simulation trial is unique and so it is not possible to extrapolate these results directly to actual production contamination rates 31 Process simulation studies (media fills) „ Where filling takes place over extended periods, i.e longer than 24 hours, the process simulation test should extend over the whole of the standard filling period In order to prevent excessively high numbers of units being filled it is usually acceptable to just run the machine for a reasonable time, if the validity of the simulation is not diminished by this procedure „ The fill volume of the containers should be sufficient to enable contact of all the container-closure seal surfaces when the container is inverted and also sufficient to allow the detection of microbial growth 32 Process simulation studies (media fills) „ Where filling takes place over extended periods, i.e longer than 24 hours, the process simulation test should extend over the whole of the standard filling period In order to prevent excessively high numbers of units being filled it is usually acceptable to just run the machine for a reasonable time, if the validity of the simulation is not diminished by this procedure „ The fill volume of the containers should be sufficient to enable contact of all the container-closure seal surfaces when the container is inverted and also sufficient to allow the detection of microbial growth 33 Process simulation studies (media fills) Incubation Temperature „ It is generally accepted to incubate at 20-25°C for a minimum of 14 days without having collected data to support this incubation schedule „ It is similarly acceptable for firms who prefer a two temperature incubation schedule to incubate at 20-25°C for a minimum of days followed immediately by incubation at a higher temperature range not to exceed 35°C for a total minimum incubation time of 14 days 34 Process simulation studies (media fills) Acceptance Criteria „ Ideally the contamination rate should be zero However currently the accepted contamination rate should be less than 0.1 % with a 95 % confidence level according to the Annex I to the EU/PIC/S Guide to GMP 35 Acceptance Criteria FILL MUST MEET THE ACCEPTANCE LIMITS FROM THE FOLLOWING TABLE: MAXIMUM ACCEPTABLE CONTAMINATED UNITS OBSERVED IN THE LOT 10 11 12 NUMBER OF GOOD VIALS INCUBATED 3000 4750 6300 7760 9160 10520 11850 13150 14440 15710 16970 18210 19440 36