Process Validation

= The selection of number of batches for process validation shall be defined in individual protocol. All protocols shall be as per the Format given in Annexure.

= A validation team shall be consisting of multi-disciplinary team of personnel primarily responsible for conducting and or supervising validation studies. A team shall comprise Production, Quality assurance, Validation, Quality Control, Engineering and R &D personnel.

= The validation activity shall be carried out according to authorized product specific Protocol. A comprehensive in depth validation study will be done for product intended to supply to the highly regulated market. Products supplied to the local market only required to fulfill the local regulatory requirements.

= For products supplying in the highly regulated market, process validation with the agreed API (e.g. DMF grade) to be done.

= The product & stage (granulation, compression/coating/capsule filling/product concentrate manufacturing & filling, packing) specific protocol shall contains Table of content (Index), approval, objective, scope, product details, validation team, responsibility, validation methodology, batches under validation, list of critical equipments & utilities, list of raw materials, process flow diagram, process stages, list of critical process parameters, control variables & measuring response /justification, manufacturing and packing process, sampling plan, test parameters, acceptance criteria, environmental control, list of packaging materials, batch yield, deviation summary, process summary and conclusion.

= The validation and / or qualification status of all-relevant equipments & system checks as Status of calibration of different gauges, thermometers, sensors, balances, etc shall be verified.

= Training should be given to supporting staff who shall perform the validation and shall get engaged in manufacturing activities.

= Following considerations shall be exercised while conducting the process validation.

= Use same source of components for validation batches.

= The use of same equipment and facilities dedicated for commercial production & their operating ranges of critical processes.

= During processing of the validation batches, extensive sampling and testing shall be performed. Mixing/blending time will be fixed based on the process optimization/validation data. From the process validation batches the blend samples will be collected at 1 to 3 time points (based on the active and excipients ratio) from 10 different points. If active quantity is low (Less than 50%) 2/3 time points will be followed other wise 1 time point will be considered.

However if blending uniformity is achieved at first time point, the blending of multiple time point may not be required to avoid demixing.

In case of pMDI products, the mixing time and the rpm of the stirrer will be fixed based on the process optimization/process validation data.

= For blend uniformity / homogeneity sample analysis the sample size of the blend material should be not less than 1X and not more than 3X of unit dosage form. Samples for blend uniformity analysis (BUA) to be collected either from the High shear mixer or IBC. The samples from 10 locations (Considering top, middle and bottom layer) to be collected in 10 vials specifying the product name , batch number, stage of the sampling, locations, sets, tare weight, sample weight & vial number with appropriately signed & date. The vials will be closed and then sent to QC for analysis. For inhaler products atleast 3(three) stage sampling should be done considering start, middle & end.

= For manufacturing common blend/granules the sample quantity should be not less than 1X and not more than 3X of unit dosage form of the lowest strength where X is average weight of the lowest strength of products.

= The %RSD value of drymix/blended samples collected for uniformity analysis from the different locations of High shear mixer or IBC should be either ≤ 5.0 %(for first set sample) or ≤ 6.0 %(for second and third set sample including the first set sample).

= The %RSD value of finished products (core/coated tablets) collected for dose uniformity analysis should be used to clarify the testing results as either readily pass (RSD ≤ 4.0 %), marginally pass (RSD ≤ 6.0 %).

= Complete analysis shall be done on the final product of all batches under study for pMDI products in addition to complete analysis the uniformity of content will also be analysed.

= For transferring Beximco products from other unit (track I to track II) the process validation will be of less extensive. This is because products have been selling in the local market for long time without any quality issue, moreover the manufacturing procedure for these batches also kept same with the exception of only batch size change.

= Hence during dry mixing /final blending with lubricant, validation samples from top, middle & bottom to be sampled for checking blend uniformity analysis. Compression speed stage validation will be done for high/medium/low speed, high and low hardness and finally the pooled bulk product will be supplied for checking assay & dissolution. However if the product is uncoated the full pharmacopoeial
analysis will be done for bulk tablet. For coated tablets sample will be tested against product specification for release.

= After compilation of batches; review the results, parameters etc. standardize the critical parameters.

= Three consecutive batches shall be considered for the studies. Any intermittent deviation shall be investigated and study should be further continued with evaluation.

= Validation protocols shall be used for the purpose and a conclusion for the process under consideration shall be drawn in validation report for all the three batches.

= The report shall specify the acceptance criteria and shall contain conclusions derived from the scientific study.

= Upon consideration of the review, recommendations shall be made on the extent of monitoring and the in-process controls necessary for routine production.

= The approved recommendation on the extent of monitoring and the in-process controls shall be incorporated into the Master Formula Record and Batch Production Record (Batch Manufacturing Record & Batch Packing Record) or into appropriate standard operating procedures.

= Required number of samples shall be collected as per product specific stability protocol for stability study during the process validation study.

= Revalidation shall be considered under following conditions.

= Whenever there is change in vendor for active ingredient and/or such excipients, which are more than 50 % by weight of the batch size.

= Change in site.

= Change in equipment (which can have impact on product quality).

= Change in batch size.

= Major change in the process.

= For liquid product where a clear solution is produced, e.g. MDI Inhaler, process validation need not always to be repeated for change of API sources if the process validation had been completed earlier. This is because the manufacturing process is unlikely to be affected by the different source of API. This is applicable only for locally supplying products. There is no requirement of the local regulatory authority to perform process validation for changes in API source.

= Validation Review: The frequency of validation review report will be three years and the report will include the parameters like introduction, scope, batch manufacturing data, equipment maintenance history, change control history, deviation history, failure investigation, audit recommendation, market complaints, summery report and conclusion. The process validation review status will be documented in the Annexure – II and process validation review will be documented in Annexure.

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