Process Validation of Semisolids. Weerayut Chirarutsami 23/8/2006

Transcription

1 Process Validation of Semisolids By Weerayut Chirarutsami 23/8/2006

2 Semisolids: A pharmaceutical dosage form category that includes ointments, cream emulsions, pastes, gels, and rigid foams. Their common property is the ability to cling to the surface of application for reasonable duration before they are washed or worn off. The adhesion is due to plastic rheologic behavior, which allows the semisolid to retain shape and cling as a film until acted upon by an outside force, in which case it will deform and flow

3 Validation Team: Production, QC, QA, Engineer,Planner To prepare the validation protocol Verify the calibration and maintenance status of equipment 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.

4 Pre-validation Requirements : Cleaning Validation Preventive Maintenance for Facilities and Utilities Calibration of Equipment Equipment Qualification Raw Materials/Components/Test Methods Process Justification Documentation Change Control Training operators All must be proven suitable and reliable for the manufacturing process before the process can be validated

5 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

6 Validation Protocol should contain: Title Page, Review/Approval Page Purpose and Overview* Equipment List Ingredients and Component List 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 *minimum requirements

7 The commercial scale pre-validation trials may be evaluated for identification of critical manufacturing steps, determination of critical process parameters Equipment Critical Process Parameter: Mixing Speed Homogenizing Speed Mixing Time Heating / Cooling Time Pumping Speed (Flow Rate) Critical Manufacturing Step Dissolving Step Melting Step Homogenizing Step

8 Critical Parameters Semi-Solids Solids Mixing Critical Steps Homogenizing Critical Parameters Mixing time Mixing speed Mixing volume (batch size) Homogenizing time Homogenizing speed

9 Critical Processing Parameter Mixing Speed Mixing Time Heating Time Cooling Time Pumping Speed Homogenizing Speed Homogenizing Time

10 Critical Processing Steps Preparing Internal and External Phase Mixing two phase together Homogenizing Final Mixing

11 Acceptance Criteria Prepare Internal & External Phase Clear Solution Mixing Homogeneity of product Homogenizing Appearances, Texture Final Mixing ph, Vicosmeter, Appearance, Assay Content

12 Equipment Critical Process Parameter: Mixing Speed Homogenizing Speed Mixing Time Heating / Cooling Time Pumping Speed (Flow Rate) Vacuum Critical Manufacturing Step Dissolving Step Melting Step Homogenizing Step Vacuum Step

13 Number of Validation Trials For New Product, Product Transfer Generally at least three consecutive successful batches at commercial scale are required For Revalidation as a result of change control, the number of trials to be determined by validation team

14 Product Testing Validation testing of bulk and F/G must be based on testing standard release criteria and in-process testing criteria Routine QC release testing should be performed on a routine sample. These samples should be taken separately from the validation samples.

15 Validation Batch: New products 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. However, it can be changed up to 10% with the on-going study by using the same equipment.

16 Validation Batch:Continued Different lots but same manufacturer of active ingredients should be used during validation trials At least 2 portions of this bulk quantity must be filled in to 2 batches of any size container. The portions should be from different bulk trials. 1 entire bulk should filled in to 1 batch of the smallest container size to demonstrate the largest filling run time. The validation study should include the smallest and largest size of the same type of filled container

17 Validation Batch:(Continued) Raw materials, in-process product and finished product must pass all in process and testing standard release requirements Cleaning procedure for all relevant equipment must be evaluated for cleaning validation Product may not be released to the market until the validation report is approved and issued

18 In-process Monitoring Record temperature of melted ingredients, mixtures, incoming liquids and final product, and rates of heating or cooling for comparison against the product development batch information Record critical processing parameters for pumping, mixing, comminution and transfer of the product Check the product for foaming, presence of unusual lumps, or discoloration. Determine if there is any residue in the tanks after emptying. Examine the filters and screens for unmixed or undissolved material

19 Validation Batch: Bulk Sampling and Testing Take 10 samples from the mixer, tank, or during product transfer to the storage/filling vessels. The samples must represent the top, middle and bottom of the vessel If sampling from the mixer/tank using an specific equipment, samples should be taken immediately adjacent to blades, baffles, and shafts where product movement during mixing may restricted The bottom of the tank and any potential dead spots should be sampled and examined for unmixed or undissolved material, if possible

20 Sampling Plan & Acceptance Criteria

21 Establishing Bulk Homogeneity Acceptance Criteria: Semi-Solids Solids Product Parameters Bulk Homogeneity Acceptance Criteria UPL & LPL within % LA * RSD 3.6% (n=6) or 4.2% (n=10) Sampling Plan Take samples from 2 3 levels to get 6 10 samples depending on batch size/mixer design For bulk in mixing, storage or holding tank; * Prod Specs = % LA; LPL & UPL = Lower & Upper Prediction Limits

22 RSD Limits for Bulk Samples (Semi-Solids) Solids)

23 RSD Limits for Bulk Samples (Semi-Solids) Solids)

24 Qualification of Maximum Bulk Hold Time The maximum period of time which the bulk can be held prior to fill One full scale bulk batch should be held for most practical maximum time period prior to filling If there is not enough support information / qualification done. The period of 24 hours will be used Hold time qualification must simulate actual in-process conditions and handling The qualified hold time used in routine production must be specified in the manufacturing batch record

25 Finish Product Testing Net Contents Perform testing on filled containers across the filling run. Perform testing per testing standard Microbiology Samples from each of the beginning and end of the filling run and perform testing per Testing Standard Preservative Efficacy testing should be tested. Content Uniformity Other Testing Assay, ph, Viscosity, Preservative Content etc.

26 Sampling Samples must be representative of each filling nozzle For single filling size Take a minimum of 3 fill containers from each of the beginning, middle and end of the filling run. The total number of samples must be not less than 10. All samples must be tested Multiple filling size Take 3 samples each at the beginning and end of the filling size Multiple Tanks and Multiple filling size Take 10 samples each at the beginning and end of the filling tank and take 10 samples each at the beginning and end of the filling size.

27 Sampling Other pattern Ten equidistant points across the filling run must be samples. The beginning and end of filling must be represented. Samples should be taken in triplicate

28 Filled Product: Content Uniformity (Semi-Solids Solids) Product Parameters Content Uniformity Acceptance Criteria (n = 10) UPL & LPL within % LA * RSD 4.2% Sampling Plan 3 4 units from beginning, middle and end of filling cycle; total = 10 units The average result of 10 individual results must meet the release limit for assay

29 Changes and Revalidation Change of any of the following may need revalidation Formula Composition Raw material Source Manufacturing Process Manufacturing Location Equipment Batch Size

30 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)

31 Minor Change Delete or Decrease quantity of colorant, flavor Qualitative inactive excipient change deemed minor by change control review Process change deemed minor by change control review such as change in order of addition Change in batch size of 10% using the same equipment Manufacturing location change with in same building, same equipment, personnel, procedure and utilities are used Equipment change but same design, configuration

32 Intermediate Changes Active ingredient source or synthesis change deemed intermediate by change control review Qualitative inactive excipient change deemed intermediate by change control review Change in formulation overage / excess (filling or stability) Change in batch size 10% < batch size 100% using the same equipment Manufacturing location change to a different building on the same site and same utilities, same equipment, personnel, and procedure are used

33 Intermediate Change Process changes deemed intermediate by change control review, such as mixing times or operating ranges outside of previously validated capacity Extension of the qualified in process hold time for intermediate or finished product prior to packaging Equipment change deemed intermediate by change control review

34 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 Change in batch size > 100%

35 Major Change Rework procedure New dosage Equipment change to a different design, configuration or operating principle.

36 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.

37 Conclusion Process must be continually monitored and change control used to identify need for process revalidation Validation Protocol identifies critical process parameters to be evaluated and predetermined acceptance criteria Production and QA have to review and approve the validation result Product must be held until the validation get approval