Chapter 48: Reprocessed and Reworked Materials

Reprocessing

The reprocessing of any lot or batch of drug is given approval by quality control (QC). Approval of a reprocessed lot or batch of a drug by QC is based on documented scientific data, which may include validation. The reprocessing of products that fail to meet their specifications, or rejected product, is generally a rare occurrence. Materials to be reprocessed should be appropriately controlled/quarantined to prevent unauthorized use.

Good manufacturing practices (GMP) state that reprocessing is permitted only when the following conditions are met:

• Reprocessing shall not be performed without the review and approval of the quality unit (QU).

• The quality of the finished product is not affected.

• The reprocessed lot meets specifications.

• The reprocessing is done in accordance with a defined procedure approved by QC.

• All risks have been evaluated, including the consideration of potential formation of by-products and/or overreacted materials.

• Complete records of the reprocessing are kept.

• A new batch number is assigned.

• Validation demonstrates that the quality of the finished product is not affected.

Reprocessing activities including introducing an intermediate or active pharmaceutical ingredient (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 (for example, distillation, filtration, chromatography, milling) that are part of the established manufacturing process are generally considered acceptable. 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.

If reprocessing of a specific step is used for most batches, this information 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 action is not considered to be reprocessing.

Reworking

Reworking is the process of performing additional manufacturing process steps on in-process or final material that does not meet standards or specifications, which is typically performed when there is an unexpected occurrence, and this new additional processing step is not preapproved as part of the marketing authorization. The reworked lot may be subject to additional regulatory approvals before release for distribution. Materials to be reworked should be appropriately controlled or quarantined to prevent unauthorized use. The GMP for reworking are:

• Written procedures shall be established and followed, prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to ensure that the reprocessed batches will conform with all established standards, specifications, and characteristics.

• The reworking of any lot or batch of drug is given approval by the quality control department.

Approval of a reworked lot or batch of a drug by the quality control department is based on documented scientific data, which may include validation. The reworking of products that fail to meet their specifications is undertaken only in exceptional cases. Reworking is permitted only when:

• An investigation into the reason for nonconformance of batches to established standards or specifications is performed prior to reworking batches.

• All risks have been evaluated, and a new batch number is assigned.

• The lot is reworked in accordance with a defined procedure approved by QC.

• The quality of the finished product is not affected.

• The reworked lot meets specifications. 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.

• Complete records of the reworking are kept.

• The reworked lot is included in the ongoing stability program.

Before acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria. Concurrent validation is often the appropriate validation approach for rework procedures, and 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.