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.
Thank You

Any Questions