What are Reworking and Reprocessing?

Introduction

All pharmaceutical manufacturing sites must implement a system designed to identify, document, investigate and control all activities of reprocessing and reworking to ensure that quality, safety, purity, and efficacy are maintained and that the activities are in accordance with local and if applicable, corporate change control requirements.

Scope

This training applies to all pharmaceutical manufacturing sites for API's, Drug Products, medical devices, and intermediates.

Responsibilities

• Site Management and site Quality Management are responsible for ensuring that all reworking, reprocessing, and re-incorporation are conducted according to company procedures, pertinent regulatory, GMP, and Health, Safety, and Environment (HSE) requirements
• Site Quality Management must approve all reworking and reprocessing, and all associated procedures/documents in relation to these operations before implementation.
• The Manufacturing Unit is responsible for carrying out reworking and reprocessing when applicable, as defined and approved by site Quality Management
• Site Quality Management is responsible for ensuring that all reprocessing, reworking, and reincorporation activities are documented. (including the reasons).

General Requirements

• Reworking or re-processing must be validated.
• Concurrent validation is normally the best validation approach for reworking
• Reprocessing and Reworking of each material/product must be pre-authorized by site Quality Management through a change control process after investigation of the potential quality impact and checking for compliance with regulatory requirements.
• Any reprocessing and reworking must be reviewed to determine if additional testing, stability studies, validation works or regulatory filings are required.
• When reprocessing of a material/product within the established specifications and/or reincorporation is/are often part of the routine manufacturing process, there must be appropriate documents established and applied for these operations (e.g. batch manufacturing records).

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• Reprocessing of an intermediate or an active pharmaceutical ingredient is acceptable:

when it is a repetition of a chemical/physical operation, which is an integral part of the manufacturing process as described in the registration dossier.

• Reprocessing when not part of the routine process and reworking of rejected finished products:

must only be performed under exceptional circumstances.

• These activities can only be performed if the finished product quality is not adversely affected by these operations and if the formula and specifications described in the registration dossiers are fully met.
• Batches arising from these operations must be part of the stability program of the final product.
• In addition, these steps must be considered to be part of the process validation.
• Reprocessing and reworking processes that are not approved by authorities must be appropriately assessed and documented and informed to the authorities where applicable.
• All batches resulting from reworking and reprocessing activities must be fully traceable and reconciled.
• In addition, traceability and reconciliation of all batches, which have been partly or completely reworked and reprocessed, must be also achieved in order to be able to know in which batch(es) these have been introduced.
• Each reprocessing and reworking must be justified technically and this must be documented.
• The reasons for performing these operations must also be documented.

What are Reworking and Reprocessing?

Reworking

The rectification of a material/ product that does not conform to established standards or specifications using a process different from the established manufacturing process to obtain a compliant material/ product.

The intermediate or a batch of a product (Part or full) which upon failing to meet the predefined specification may be subjected to a different manufacturing process that is not part of a previously validated manufacturing process.

This process of subjecting the non-conforming material to a different manufacturing process to get a product that meets all the predefined specifications is called Reworking. Adding additional purification or milling steps etc. that are not part of the established manufacturing process to improve the product characteristics or to make it meet the predefined specifications are categorized as reworking.

ALSO READ: SOP for Handling of Rejected Batches

Reprocessing

The rectification of a material/product that does not conform to established standards or specifications, using method(s) that are part of the approved manufacturing process

The intermediate or a batch of a product (Part or full) which upon failing to meet the predefined specification may be introduced again to a previous step in the validated manufacturing process.

This process of reintroducing the non-conforming material into the previous step of a validated manufacturing step to get a product that meets all the predefined specifications is called Reprocessing. Repeating a filtration or crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, chromatography, milling) that are part of the established manufacturing process to improve the product characteristics or to make it meet the predefined specifications is considered acceptable.

As the saying goes, "Mistakes are sure to happen," and so do non-conformances in the production of pharmaceuticals. The chance of noticing non-conformance or failing to meet pre-defined standards may not be totally eliminated even if you have validated processes, qualified vendors, qualified equipment, calibrated instruments, in-process inspections, SOP's, etc. in place.

Does this imply that the entire batch must be disposed of? What if a manufacturing company is unable to absorb the losses because the product is too expensive? What if certain actions, like reworking or reprocessing, carried out within the parameters of the rules, may save the batch? Can each batch undergo reworking or reprocessing? What distinguishes reworking from reprocessing? If reprocessing or reworking is just applicable to the production of APIs, or if final formulations can also use it.

Let's start by addressing all the questions that any manufacturer would have, starting with the distinction between reprocessing and reworking.

The reworking cannot be pre-approved as part of the marketing authorization because it results from an unforeseen outcome.

Important information (Reprocessing)

• Upon discovering any non-conformance, it must be reported right away to the Quality Unit and escalated to higher-level management.
• To determine the precise cause of the failure, an inquiry may be conducted.
• After consulting with the cross-functional team and management, the quality unit may approve or reject the suggestion of reprocessing based on the kind and severity of the non-conformance as well as the findings of the investigation.

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• The following requirements must be met before permission to perform reprocessing is granted:

1. Reprocessing procedures must first receive approval from the Quality Unit.
2. The final items' quality must not be compromised.
3. The reprocessed batch shall be assigned a new batch number. Distinct batch numbers should be provided whenever possible for quick identification.
4. If necessary, quality control may conduct extra tests to determine the product's quality.
5. Before beginning the reprocessing, the company must perform a thorough risk assessment.
6. By-product generation and over-reacted components must be taken into account.
7. The complete reprocessing process must be well documented.
8. The reprocessing procedures may be validated as needed.

• Reprocessing must be regarded as an uncommon occurrence.
• It should be noted that reprocessing may be incorporated into the batch production process if it is repeated and is of a similar type for the majority of batches of a product.
• Before being released, the reprocessed batch must pass a comprehensive inspection across all quality indicators.
• Reprocessed batches ordinarily do not need regulatory approval before product distribution, but they must be mentioned in the yearly notifications to the regulatory authority.

Important information (Reworking)

• Reworking should only be considered in extraordinary cases and should be avoided at all costs.
• Any non-conformance that is noticed should be reported right away to the Quality Unit and escalated to the highest level of management.
• To determine the precise cause of the failure, an inquiry may be conducted.
• After discussing the idea of reworking with the cross-functional team and management, the quality unit may approve or reject it depending on the type and severity of the non-conformance as well as the findings of the inquiry.
• The following requirements must be met before permission to carry out reworking is granted:

1. The reworking procedure shall be approved by Quality Unit beforehand.
2. The quality of the finished products shall not be affected. Documentation shall be done to show that the reworked product is of equivalent quality to that produced by the original process.
3. A new batch number shall be allotted to the reworked batch. If possible distinct batch numbers shall be given for easy identification.
4. If required Quality control may perform additional testing to ascertain the quality of the product. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.
5. The firm shall carry out a proper risk assessment before initiating the reworking.
6. The entire reworking procedure shall be thoroughly documented.
7. The firm shall carry out concurrent validation. The protocol shall define the work procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, a report can be written and the batch released once it is found to be acceptable.

• Before being released, the modified batch must pass a rigorous inspection on each quality criterion.
• In accordance with the continuing stability program, the reworked batch must undergo stability testing.
• The procedures should allow for comparing each reworked batch's impurity profile to batches produced using the established technique.
• Following regulatory approval for the alteration, regularly reworked batches must be distributed.

Reworking in the case of finished formulations

It has been reported that most regulatory agencies are not really interested in performing any reworking in the case of finished formulations, but they are quite at ease with reprocessing. Reprocessing may be permitted as long as it is done under exceptional conditions, is done after a thorough investigation, and the finished product is of an equal caliber to the original product, etc. Examples of reprocessing include performing additional sifting or, in some cases, repacking after de-blistering.

Recovery is permitted in some circumstances as well. Recovery is the act of adding all or a portion of earlier batches (or of redistilled solvents and related products) of the requisite quality into a new batch at a certain point in the manufacturing process. It entails recovering wasted resources for a different application or purifying waste to produce a pure substance. After assessing the hazards involved, including any potential impact on shelf-life, the recovery should be carried out in line with a predetermined protocol. Recording the recovery is necessary.

Important Considerations

1. Although the USFDA and EU permit reworking of APIs, their respective guidelines make no mention of the reworking of completed formulations.
2. Reprocessing is believed to occur when unreacted material is added back into a process and a chemical reaction is repeated unless it is a required step in the established process. To prevent the production of by-products and overreacted elements from negatively affecting the quality of the intermediate or API, such reprocessing should be preceded by a rigorous evaluation.
3. It is thought to be a regular process practice to continue with a process step even if an in-process control test reveals that the step isn't complete. Reprocessing is not thought to be taking place here.
4. Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.

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