Batch Reworking and Reprocessing

Contents Introduction Scope Glossary and Responsibilities General Requirements Specific Requirements on Reincorporation for Drug Products Specific Requirements for APIs (according to ICH Q7/ EU GMP Part II)

Introduction and Scope Introduction: All pharmaceutical manufacturing sites must implement a system designed to identify, document, investigate and control all activities of reprocessing/ reworking/ re-incorporation to ensure that quality, safety, purity and efficacy is 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 APIs, Drug Product, medical devices and intermediates.

Glossary (1) 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 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 Re-incorporation: The introduction of a part of a batch within the specifications into another batch of the same product at a predetermined stage of the manufacturing process.

Responsibilities (1) 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, reprocessing and re-incorporation and all associated procedures/documents in relation to these operations before implementation.

Responsibilities (2) The Manufacturing Unit is responsible for carrying out reworking, reprocessing and re-incorporation 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 (1) Reworking or re-incorporation processes must be validated Concurrent validation is normally the best validation approach for reworking Reprocessing, reworking or re-incorporation of each material/product must be pre-authorized by site Quality Management through change control process after investigation of the potential quality impact and checking for compliance with regulatory requirements.

General Requirements (2) Any reprocessing, reworking or re-incorporation 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 re-incorporation 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).

General Requirements (3) 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.

General Requirements (4) 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.

General Requirements (5) 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, reprocessing and/or re-incorporation activities must be fully traceable and reconciled In addition, traceability and reconciliation of all batches, which have been partly or completely reworked, reprocessed or reincorporated, must be also achieved in order to be able to know in which batch(es) these have been introduced.

General Requirements (6) Each reprocessing, reworking and reincorporation must be justified technically and this must be documented The reasons for performing these operations must also be documented.

Specific Requirements of Re-Incorporation for Drug Product (1) The maximum quantity, which can be reincorporated into another batch, must be specified and expressed as a percent in relation to the full production batch size The maximum number of partial batches that can be incorporated into one other batch must be limited and that maximum number determined on a case by case basis.

Specific Requirements of Re-Incorporation for Drug Product (2) Re-incorporation must be followed by a physical/ chemical operation in order to ensure homogeneity of the batch A shelf-life must be specified for the products to be reincorporated based on stability tests performed on bulk products at the given manufacturing step. Any batch of drug product which contains reincorporated material must not itself be re-incorporated into another batch of drug product.

Specific Requirements for APIs – Based on ICH Q7 (1) Intermediates and APIs failing to meet established specifications should be identified and quarantined These intermediates or APIs can be reprocessed or reworked as described in the following slides The final disposition of rejected materials should be recorded.

Specific Requirements for API Reprocessing – Based on ICH Q7 (2) If reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process and should not be called reprocessing Introducing un-reacted material back into the process and repeating a chemical reaction is considered to be reprocessing unless it is part of an established process. Such reprocessing should be carefully evaluated that the quality is not adversely impacted due to the potential formation of by-products and over reacted materials.

API Reprocessing (1) Reprocessing in API manufacturing is generally acceptable But it should not be a routine process! Reprocessing normally improves the API quality There is a clear distinction between reprocessing and reworking.

API Reprocessing (2) In most cases reprocessing is related to a physical operation, such as: Crystallization Filtration Purification (Chromatography, Distillation) Drying Milling Typically if more than 10% of the batches have to be “reprocessed”, then the process should be checked for its robustness.

API Reprocessing (3) Reprocessing is Introducing an intermediate or API, including one that does not conform to standards and specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps that are part of the established manufacturing process. Reprocessing is not Continuation of a process step after an in-process control test has shown that the initial step was incomplete.

API Reprocessing - Examples Re-crystallization from the same solvent Re-filtration through the same type of filter Re-milling using the same type of mill Introducing material to the process that conforms to specifications (e.g. tailings)

API Reprocessing – Process Validation The need of process validation for the reprocessing steps has to assessed and decided on a case by case basis Especially for biotech products and proteins process validation activities should be considered When the number of reprocessed batches is small, a concurrent validation approach should be used When reprocessing is performed routinely, reprocessing should be validated.

Is API Rework Different from Reprocessing? Yes, it is different However in former times, especially by FDA inspectors it was considered to be the same or similar FDA Definition in 1996: “Reprocessing is a system of reworking batches that do not conform to standards or specifications” Why is it different? Because it normally uses process conditions that are different from those of the original process.

API Rework – ICH Q7 Definition Subjecting an intermediate or API that does not conform to standards and specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API Therefore only non-conforming batches should be reworked And using processing steps different from the original process.

API Rework 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.

API Rework - Examples Re-crystallization from a different solvent Re-filtration through a finer sized filter Re-milling using a different type of mill Chromatography under different conditions Use of different drying device.

API Rework – Process Validation Validation of reworking procedures is critical and should clearly show that reworking does not adversely affect the quality or purity of the product (PIC/S Draft from April 1998) 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 an interim report can be written and the batch released, once it is found to be acceptable.

API Rework – Recommendations Check the impurity profile of each reworked batch against batches manufactured by the established process Consider if additional analytical methods should be used to characterize the reworked batch Evaluate if stability studies are needed (normally accelerated studies) Estimate rework costs before you start (feasibility study) Rework should remain exceptional.

API Rework – Regulatory Aspects Reworking procedures require “Prior Approval” from the Authorities unless potential reworking processes were described in the original submission (MAA, NDA, DMF, ASMF, etc.) Recommendation: File one or more rework procedures in the original dossiers whenever data from process development are available or create at least data on lab scale and submit Evaluate always, if rework is possible from regulatory viewpoint.

Summary of API Processing Reprocessing in API manufacturing is an acceptable way of treating materials that may not have met the specifications But it should not be performed routinely to cover-up intrinsic deficits in the process Reprocessing is normally covered by the existing filed procedures.

Summary of API Rework Rework in API manufacturing is an alternative way of treating materials that do not conform to specifications It should not be performed without investigation into the reasons of non-conformance and appropriate evaluation of the quality of the product reworked Reworking procedures normally require approval from Authorities.

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