guidelines on variations to a registered pharmaceutical product

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Guidelines on Variations to a Registered Pharmaceutical Product6. Justification/risk-assessment showing that the parameter is non-significant.7. Evidence of process validation and/or evaluation studies for sterilization, where applicable.8. Information on impurities, if applicable.9. Copy of currently accepted specifications of API (and intermediates, if applicable).10. Description of the batches, certificates of analysis or batch analysis report and summary of results,in a comparative tabular format, for at least two batches (minimum pilot scale) for all specificationparameters.Description of changeConditions tobe fulfilledDocumentationrequiredReportingtype14 Change in batch size of the active pharmaceutical ingredient involving:14aup to 10-fold compared to the currentlyaccepted batch size1-2,4,6 1,3-4 AN14b downscaling 1-4 1,3-4 AN14c any change in scale (APIMF procedure) 5 1-2, 4-5 AN14dmore than 10-fold increase compared to thecurrently accepted batch sizeConditions to be fulfilled1-2,4,6 1,3-4 Vmin1. No changes to the manufacturing process other than those necessitated by changes in scale (e.g. useof different size of equipment).2. The change does not affect the reproducibility of the process.3. The change is not necessitated by unexpected events arising during manufacture or due to stabilityconcerns.4. The change does not concern a sterile API.5. API manufacturing site and batch size is currently accepted through the WHO PQP APIMF procedure.6. The proposed batch size increase is relative to either the originally accepted batch size, or the batchsize accepted through a subsequent major or minor variation.Documentation required1. A brief narrative description of the manufacturing process.2. Where applicable, evidence of process validation and/or evaluation studies for sterilization.3. Copy of the currently accepted specifications of the API (and of the intermediate, if applicable).4. Batch analysis data (in tabular format) issued by the FPP manufacturer for a minimum of two batcheseach of the currently accepted batch size and the proposed batch size.5. A copy of the WHO letter of acceptance for APIMF amendment.Doc. No.: DAR/GDL/005 Revision Date: 8 th July 2013 Review Due Date: 16 th July 2016Revision No.: 1 Effective Date : 16 th July 2013 Page 24 of 70
Guidelines on Variations to a Registered Pharmaceutical ProductDescription of changeConditions tobe fulfilledDocumentationrequiredReporting type15 Change to the specifications or analytical procedures applied to materials used in themanufacture of the active pharmaceutical ingredient (e.g. raw materials, starting materials,reaction intermediates, solvents, reagents, catalysts) involving:15a any change 1 No variation is required, suchchanges are handled asamendments to the APIMF by theAPIMF holder15b tightening of the specification limits 2-4 1-3 AN15c minor change to an analytical procedure 5-7 2-3 AN15d15e15f15g15haddition of a new specification parameterand a corresponding analyticalprocedure where necessary.deletion of a specification parameter ordeletion of an analytical procedureaddition or replacement of a specificationparameter as a result of a safety orquality issuerelaxation of the currently acceptedspecification limits for solvents, reagents,catalysts and raw materialsrelaxation of the currently acceptedspecification limits for API startingmaterials and intermediatesConditions to be fulfilled2,7-9 1-3 AN2,10 1-4 ANNone 1-3,5 Vmin4,7,9-10 1,3-4 INNone 1-3,5 Vmaj1. API manufacturing site is currently accepted through the WHO PQP APIMF procedure.2. The change is not necessitated by unexpected events, resulting in failure to meet specifications,arising during manufacture or because of stability concerns.3. Any change is within the range of currently accepted limits.4. The analytical procedure remains the same.5. The method of analysis is based on the same analytical technique or principle (e.g. changes to theanalytical procedure are within allowable adjustments to column length, etc., but do not includevariations beyond the acceptable ranges or a different type of column and method).Doc. No.: DAR/GDL/005 Revision Date: 8 th July 2013 Review Due Date: 16 th July 2016Revision No.: 1 Effective Date : 16 th July 2013 Page 25 of 70
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