Reprocessing Biotech Products Workshop Session 4 January 31, 2013

Some stuff on the web…. From Compliance Firm website: “Reprocessing is taking a material (in-spec or out-of-spec) and reintroducing it to an existing (validated) process.” “Reworking is taking an out-of-spec product and running it through a non-standard process to bring it back into spec. Concurrent validation is required.” “I would add that if it can be done on the same batch record, it is a reprocess. A rework will always require another batch record.”

From Regulatory chat boards… “Scott is right on the definitions... Just to cite an official definition from the CEFIC.pdf “ “Reprocessing is the treatment of a batch or sub-batch of materials of unacceptable quality by repeating the same process steps from a defined stage of production so that its quality may be made acceptable.” “NOTE: The occasional repeating of one or more process steps during manufacture after it was known that the pre-set limits had not been met, or there was an unexpected process problem, is an acceptable part of the process and a rational reaction to the results obtained.”

From Regulatory chat boards… “Reworking is the treatment of a batch or sub-batch of materials of unacceptable quality by using a process other than that used to produce the original material so that its quality may be made acceptable. In general there is no objection to occasionally reprocessing materials not meeting specification by repeating all or part of the same process, however if this becomes a routine procedure, investigations should be conducted into the adequacy of the original process.”

Questions What do you consider the true definition of reprocessing to be? Likewise what is not considered reprocessing? What would be examples of each? What are current industry practices with regard to reprocessing? What systems and requirements are needed for reprocessing to be acceptable in: - Clinical products? - Commercial products? To what extent is reprocessing applied by industry?

Adventures in Reprocessing…

Case Study 1 - Scenario Mega Monoclonals has labeled zmab for use in the US but in order to manage supply, they decide to take some of the labeled stock for US and relabel it for use and distribution in Canada. The relabeling process involves the removal of the old label and application of the new label. All relabeling activities are done with quality oversight. A protocol is in place that has been approved by the QA team and is based on small scale studies as well as a documented risk assessment that there is no impact to product quality and safety.

Case Study 1 - Questions Is this considered reprocessing? Is it reportable and if so, what category? Does this differ if zmab is a clinical product or a licensed product?

Case Study 2 - Scenario During the manufacture of zippitydodamab (zmab), a product in global clinical phase 2 trials made by Mega Monoclonals, a disposable bag used to collect product between manufacturing steps, was discovered to be leaking. The decision was made to refilter the product into a new bag. RA and QA are brought in to assess the refiltration. It is discovered upon review that the ability to refilter at this particular manufacturing step is not captured in the master batch record or in any regulatory filing(s) as part of the normal manufacturing process. Zmab is manufactured at a contract manufacturing company – Bigtime Biotech (BB) - that has a platform process for the manufacture of monoclonals. One of the standard operating procedures in place at BB for their platform processes allows for reprocessing for this kind of situation and it is referenced in the master batch record.

Case Study 2 - Questions Is the described scenario a reprocessing step? Why or Why not? What, if any information needs to be filed to global health authorities? If Zmab were a licensed product, would this change anything with regard to classification and reporting categories? What do you consider the true definition of reprocessing to be? Likewise what is not considered reprocessing? What would be examples of each? What are current industry practices with regard to reprocessing? What systems and requirements are needed for reprocessing to be acceptable in: - Clinical products? - Commercial products? To what extent is reprocessing applied by industry?

Back-up

ICH Q7 - Reprocessing Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing. Introducing unreacted material back into a process and repeating a chemical reaction is considered to be reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful evaluation to ensure that the quality of the intermediate or API is not adversely impacted due to the potential formation of by-products and over-reacted materials.

ICH Q7 - Reworking Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for non-conformance should be performed. Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is often the appropriate validation approach for rework procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, then a report can be written and the batch released once it is found to be acceptable. Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.

WHO Annex 4 The reworking or recovery of rejected products should be exceptional. It is permitted only if the quality of the final product is not affected, if the specifications are met, and if it is done in accordance with a defined and authorized procedure after evaluation of the risks involved. A record should be kept of the reworking or recovery. A reworked batch should be given a new batch number. The introduction of all or part of earlier batches, conforming to the required quality, into a batch of the same product at a defined stage of manufacture should be authorized beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelflife. The recovery should be recorded. The need for additional testing of any finished product that has been reprocessed, reworked or into which a recovered product has been incorporated, should be considered by the quality control department.