1Process Validation of
Sterile Liquid Products
By
Weerayut Chirarutsami
23/08/2006
2Process Validation
Process validation is establishing documented evidence 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
3Process Validation
Type of Process Validation Prospective Conducted prior to market the product
Concurrent 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
4Validation 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.
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 or less filter, then filled and packaged using sterilized containers and closures in critical processing zones.
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.
7Pre-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
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
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
10
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
Validation of Sterile Product
11
Equipment 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 Dissolving Step pH adjustment step Final mixing step Filtering Step Filling Step Terminal Sterilization Step Leak Test Step
Validation of Sterile Product
12
Critical Processing Parameter
Mixing Speed
Mixing Time
Flushing Time
pH
Validation of Sterile Product
13
Critical Processing Steps
Validation of Sterile Product
Dissolved Active Ingredient
pH Adjustment
Final Mixing
Filtration
Filling
Sterilization
14
Acceptance Criteria
Dissolved Active Ingredient
pH Adjustment
Final Mixing
Filtration
Clear Solution
Filter Integrity, Sterility, pH, Holdtime
pH with in specification
pH, Appearance, Assay Content,Bioburden, Holdtime
Validation of Sterile Product
15
Acceptance 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
16
Product 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
17
Validation 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
18
Validation 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
19
Qualification 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
20
Validation of Sterile Product
Finish Product Testing after SterilizationUniformity 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.
Visual Evaluation Appearance, Color of solution
Other Testing Assay, pH, Density, Pyrogen or Endotoxin etc.
21
Validation of Sterile Product
Validation Report Validation Team must prepare the report
Report must be reviewed and approved by QA.
Written Notification or either successful completion or failure of the process validation must be issued to top management.
In case of failure, an investigation must be completed and documented
prior to repeat the validation study.
22
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
Validation of Sterile Product
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
24
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
Validation of Sterile Product
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
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 intermediateor finished product prior to packaging
Equipment change deemed intermediate by change control review
Validation of Sterile Product
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
28
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
Validation of Sterile Product
29
Conclusion Validation Protocol identifies critical process parameters to be
evaluated and predetermined acceptance criteria
Process must be continually monitored and change control used toidentify 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
30
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
31
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.
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)
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.
34
Process simulation studies (media fills)
Incubation Temperature It is generally accepted to incubate at 20-25C 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 20-25C for a minimum of 7 days followed immediately by incubation at a higher temperature range not to exceed 35C for a total minimum incubation time of 14 days.
35
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.
36
FILL MUST MEET THE ACCEPTANCE LIMITS FROM THE FOLLOWING TABLE:MAXIMUM ACCEPTABLECONTAMINATED UNITS NUMBER OF GOODOBSERVED IN THE LOT VIALS INCUBATED
0 30001 47502 63003 77604 91605 105206 118507 131508 144409 1571010 1697011 1821012 19440
Acceptance Criteria
Top Related