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
Trang 1Process Validation
of Sterile Liquid Products
By Weerayut Chirarutsami
Trang 2Process Validation
which demonstrate that the manufacturing process will consistently produce a product meeting its pre- determined 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
Trang 3 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
Trang 4Validation of Sterile Product
Total number of viable microorganisms on or in
pharmaceutical product prior to sterilization.
Trang 5Validation 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
Trang 6Validation 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
Trang 7Pre-validation Requirements :
Preventive Maintenance for Facilities and Utilities
Cleaning Validation
Equipment & System Qualification
Trang 8Validation 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
Trang 9Validation 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
Trang 10Validation 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
Trang 11Equipment Critical Process Parameter:
Mixing Speed
Mixing Time
Gas flushing time
Type and size of filter
Filtering Time and Pressure used
Filling Speed
Temperature and Duration for Terminal Sterilization
Critical Manufacturing Step
Terminal Sterilization Step
Leak Test Step
Validation of Sterile Product
Trang 12Critical Processing Parameter
Trang 13Critical Processing Steps
Validation of Sterile Product
Dissolved Active Ingredient
pH Adjustment Final Mixing Filtration Filling Sterilization
Trang 15Acceptance Criteria
Filling Sterilization
Leak Test
Visual Inspection
Appearance, Bioburden, Holdtime, Oxygen Headspace
No of Defected products
Sterility, Assay, pH, Endotoxin etc
No of Leaked products
Validation of Sterile Product
Trang 16Product Testing
Validation testing of bulk and F/G must be based on
testing standard release criteria and in-process testing
criteria
Typically involves non-routine sampling/testing throughout the entire process, with special emphasis on critical
process parameters.
Routine QC release testing should be performed on a
routine sample These samples should be taken
separately from the validation samples.
Validation of Sterile Product
Trang 17Validation Batch:
New product and product transfer, Prospective validation is required
Manufacturing Process, Formula, Equipment and Batch Size have to
be fixed during the validation trials.
Batch Size should be the same size as commercial production batch
The batch size must be fixed for production.
Different lots but same manufacturer of active ingredients should be used during validation trials
Validation of Sterile Product
Trang 18Validation Batch: Bulk Sampling and Testing
Samples may be taken by
Collecting during Transfer
Using a sampling device
Take at least 2 samples at top, middle and bottom
Individual Testing of sample must be done and the result must meet the testing standard specification
Validation of Sterile Product
Trang 19Qualification of Maximum Bulk Hold Time
The maximum period of time which the bulk can be held prior to filter, Fill and/or Sterilization
It will be counted after finished final mixing step until transfer to filter, finished filter until start filling and/or finished filling until start sterilization
One full scale batch should be held for most practical maximum time period prior to filter, fill and/or sterilization
If there is not enough support information / qualification done The period of 24 hours will be used
Hold time qualification must simulate actual storage condition
Validation of Sterile Product
Trang 20Validation of Sterile Product
Finish Product Testing after Sterilization
Uniformity of filled volume
Perform testing on filled containers.
Sterility
10 samples from each of the beginning and end of the filling run
Samples must represent all filling nozzles.
Trang 21Validation of Sterile Product
Validation Report
¾ Validation Team must prepare the report
¾ Report must be reviewed and approved by QA.
¾ Written Notification or either successful completion or failure of the process validation must be issued to top management.
¾ In case of failure, an investigation must be completed and documented prior to repeat the validation study.
Trang 22 Changes and Revalidation
Change of any of the following may need revalidation
Trang 23 Changes
Minor: It seems to have no impact on formulation
It is not necessary to validate
Intermediate : It could have significant impact on formulation
Depend on case-by-case (A minimum of 1 trial)
Major : It is likely to have significant impact on formulation
Revalidation is required (A minimum of 3 trials)
Validation of Sterile Product
Trang 24 Equipment change but same design, configuration
Validation of Sterile Product
Trang 25 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
Validation of Sterile Product
Trang 26 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
Validation of Sterile Product
Trang 27 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
Validation of Sterile Product
Trang 29 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
Validation of Sterile Product
Trang 30 Monitoring of environment, disinfection procedures,
equipment cleaning and sterilisation (including
containers and closures)
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
Trang 31Process 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.
Trang 32Process 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.
Trang 33Process 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.
Trang 34Process 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 7 days followed immediately by
incubation at a higher temperature range not to exceed 35°C for a total minimum incubation time of 14 days
Trang 35Process 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
Trang 36FILL MUST MEET THE ACCEPTANCE LIMITS FROM THE FOLLOWING TABLE:
MAXIMUM ACCEPTABLE
CONTAMINATED UNITS NUMBER OF GOOD
OBSERVED IN THE LOT VIALS INCUBATED