Process Validation

1.0    PURPOSE 
        To lay down the procedure to perform the process validation for the manufacturing of Intermediates and Active Pharmaceutical Ingredients.

2.0    SCOPE 
2.1    This procedure is applicable to the Validation of processes of Intermediates and Active Pharmaceutical Ingredients manufactured 
3.0    RESPONSIBILITY
3.1    In charge – Production
3.2    In charge – Quality control

4.0    ACCOUNTABILITY
4.1    Head - Quality Assurance

5.0    PROCEDURE:

5.1    Process Validation is establishing documented evidence that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.
5.2    Trial batch MPCR and BPCR shall be prepared based on the Technology Transfer Document as per the Standard Operating Procedure xxxxx (Preparation of MPCR and BPCR)
 
5.3    Trial batch (es) shall be planned and through which sufficient data shall be collected on the suitability of equipment, raw material quality, critical supporting systems. Evaluation of process parameters, which affect the quality and yield of the product.
5.4    Trial Batch Report shall be prepared by production department (as per   Annexure-I) based on the evaluation, review and conclusions arrived on trial batch performance data and shall be reviewed, describe the action plan for the preparation of MPCR and BPCR for validation batches  & approved by Quality Assurance. 
5.5    Based on the trial batch report, through change control procedure MPCR and BPCR shall be revised (SOP Change Control) and a protocol shall be prepared for Prospective Process Validation.
5.6    Prospective Process validation shall be carried out for all the intermediate stages and Active Pharmaceutical Ingredients. 
5.7    Intermediates which are not isolated for some structural instabilities and using in solution form (through-put intermediates) shall be considered as a chain process for validation up to its isolation stage.
5.8    PRE-REQUISITES FOR PROSPECTIVE PROCESS VALIDATION: 
5.8.1    Approved Master Production and Control Record and Batch Production and Control Record that are prepared based on the evaluation of trial batch data.
5.8.2    An approved validation protocol which specifies how validation shall be conducted including the following:
5.8.2.1    Selection of batches, batch size and raw material input details. 
5.8.2.2    Process flow, brief process description, equipment details, Critical parameters with justifications and excursions.
5.8.2.3    Sampling procedures     indicating extensive tests for in process controls.
5.8.2.4    Test parameters, specification references for in process, all raw materials and final product, 
5.8.2.5     Product characteristics and data to be collected 
5.8.2.6     Identification of execution team.
5.8.3    Prospective Process Validation shall be carried out in equipment which are qualified for design, installation, operation and performance. 
5.8.4    Critical supporting systems such as HVAC, Nitrogen system and Vacuum system shall be validated prior to the validation study.
5.8.5    Prospective Process Validation shall be carried out with the        Process and monitoring equipment (instruments) such as Resistance Thermal Devices, Digital Temperature Monitors, RPM Meters, Pressure Gauges, Vacuum Gauges, Compound Gauges etc., which are calibrated.
5.8.6    All the raw materials, which are to be used in the process validation study, shall be approved.
5.8.7    Training for all the personnel who are involved in the process validation shall be given on the topics such as charging of materials, critical process steps, sampling procedures, sampling plan, holding and packing of the materials etc., 
 
5.9    DOCUMENTS REQUIRED FOR THE VALIDATION STUDY:
5.9.1    Process Validation Protocol. (Annexure – II).
5.9.2    Process Validation Form. (Annexure – III).
5.9.3    Process Validation Report. (Annexure – IV).

5.10    Production department shall prepare Process Validation Protocol in the format given in Annexure – II.
    The contents of the process validation Protocols shall be as follows

    The protocol header consists of the following information in the respective     cells of the format given in Annexure-II

5.10.1    Protocol Approval
5.10.2    Objective
5.10.3    Scope
5.10.4    Responsibility
5.10.5    Equipment list    
5.10.6    Calibration of equipment and instruments  
5.10.7    Raw material used and their quality data
5.10.8    Process Flow Chart
5.10.9    Brief manufacturing process
5.10.10    Critical process parameters (With justifications and excursions)
5.10.11    Execution of the protocol 
5.10.12    Acceptance Criteria
5.10.13    Report and conclusion

5.11    PROCESS VALIDATION DATA FORM:
5.11.1    This form shall be used to record the results of the process validation batches during execution.
5.11.2    The content of the process validation format shall be based on the type of the data to be collected for execution of process validation protocol and shall be prepared as per Annexure – III and shall include the following:
5.11.2.1    Ensuring the calibration status of the instruments before validation run.
5.11.2.2    Brief comments on batch operation, cleaning and preventive maintenance.
5.11.2.3    Observations made on In-process, Quality parameters of the product
5.11.2.4    Output / Yield of the product
5.11.2.5    Brief comments on review of BPCR. 
 
5.12    PROCESS VALIDATION REPORT:
5.12.1    Production Department shall prepare the process validation report after the completion of the validation batches execution. 
5.12.2    Report shall summarise the whole exercise and shall draw final conclusion stating, acceptance or rejection. It shall clearly establish:

5.12.2.1    The quality and quantity of raw materials, suitability of equipment.
5.12.2.2    Critical Process parameters 
5.12.2.3    In-process and final product specifications.
5.12.2.4    Deviations if any. 

5.12.3    Data shall be presented in the form of graphs, trend charts etc., 

5.12.3.1    The contents of the report is as follows, but not limited to 

5.12.3.1.1    Report approval
5.12.3.1.2    Objective
5.12.3.1.3    Equipment used
5.12.3.1.4    Calibration status of the instruments
5.12.3.1.5    Manufacturing process
5.12.3.1.6    Acceptance criteria
5.12.3.1.7    Validation results including review and discussion.
5.12.3.1.8    Results of In- process parameters
5.12.3.1.9    Results of Quality parameters.
5.12.3.1.10    Output / Yield 
5.12.3.1.11    Deviations, if any
5.12.3.1.12    Summary and Conclusion

5.12.4    After approval of Process validation report MPCR & BPCR shall be finalized. 

5.13    ACTION PLAN WHEN BATCH FAILS:
    
5.13.1    When a quality parameter fails with respect to the specification, a deviation report shall be raised and the investigation shall be conducted immediately for the identification of failure.
5.13.2    If the reason for failure is identified, one more consecutive batch shall be considered for the validation run by taking preventive actions to avoid those failures (If necessary revise the MPCR and BPCR).
5.13.3    If the reason is unidentified, another three consecutive batches shall be taken for validation.

5.14    REVALIDATION CRITERIA: 

5.14.1    Re-validation shall be carried out in the following cases:

5.14.1.1    Change in Raw materials / solvents 
5.14.1.2    Change in Major equipment
5.14.1.3    Change in critical process parameters 
5.14.1.4    Scale-up or Scale-down.
 
5.15    CONCURRENT VALIDATION:
5.15.1    Concurrent Validation shall be done for the validated process only.
5.15.2    Concurrent validation shall be done when a minor change in the process which is not affecting the quality or yield of the product (such as changes in non-critical operational parameters), change in the like to like equipment in the same block or in different block for the validated and established process of a particular stage.
5.15.3    Concurrent validation shall be done for any further powder processing for a batch (such as milling, pulverizing, micronizing and blending etc.,) as per the customer requirement.

5.15.4    A protocol shall be prepared as per the format of prospective process validation protocol (Annexure – II) by giving the title as ‘Concurrent Process Validation’. For the chemical process validation, no need to conduct the extensive in-process tests.

5.15.5    For powder processing concurrent validation, the entire process shall be validated as per the prospective process validation methodology.

5.15.6    Data shall be compiled and concluded for each individual batch and after approval the batch can be released / dispatched.

5.15.7    If any failure with respect to the specification, the proposed change and validation shall be withdrawn / cancelled / rejected.

5.15.8    Final report and conclusion shall be made after completion of three batches.

5.16    RETROSPECTIVE VALIDATION:
5.16.1    Retrospective validation is that the representative of all batches produced during the review period and should be sufficient in number to demonstrate process consistency.
5.16.2    A minimum of 30 consecutive batches or batches manufactured in a calendar year shall be considered for the retrospective validation.
5.16.3    The data shall be compiled for the critical parameters, quality and yield details.      
5.17    PROTOCOL NUMBERING SYSTEM:
5.17.1    Protocol number shall be a sequential number for each product as given in the following format.

Typical Example:

MPV/MZ/301 indicates first process validation protocol of Mirtazapine in the calendar year 2003.

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Process validation, quality assurance