Batch Reworking and Reprocessing - PowerPoint Presentation

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Batch Reworking and ReprocessingSlide2

ContentsIntroduction

ScopeGlossary and Responsibilities

General Requirements

Specific Requirements on Reincorporation for Drug Products

Specific Requirements for APIs (according to ICH Q7/ EU GMP Part II)Slide3

Introduction and ScopeIntroduction: 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.Slide4

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.Slide5

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.Slide6

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).Slide7

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.Slide8

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).Slide9

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.Slide10

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.Slide11

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.Slide12

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.Slide13

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.Slide14

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. Slide15

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.Slide16

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.Slide17

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.Slide18

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.Slide19

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.Slide20

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)Slide21

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.Slide22

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.Slide23

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.Slide24

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. Slide25

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.Slide26

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. Slide27

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.Slide28

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.Slide29

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.Slide30

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.Slide31

Thank YouAny Questions