Company name DEPARTMENT Management of GMP Documentation

Batch Reworking and
• 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
Responsibilities (2)
• The Manufacturing Unit is responsible for
carrying out reworking, reprocessing and reincorporation 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
• Concurrent validation is normally
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
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).
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 reincorporation 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
reincorporation must be justified technically
and this must be documented
• The reasons for performing these operations
must also be documented.
Specific Requirements of ReIncorporation 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 ReIncorporation for Drug Product (2)
• Re-incorporation must be followed by a physical/
chemical operation in
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 reincorporated 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
generally acceptable
• But it should not be a routine process!
• Reprocessing normally improves the API
• There is a clear distinction
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
• The need of process validation for the reprocessing
steps has to assessed and decided on a case by case
• 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 should be validated.
Is API Rework Different from
• 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
• 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
• 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
• Re-filtration through a finer sized filter
• Re-milling using a different type of mill
• Chromatography under different
• Use of different drying device.
API Rework – Process
• 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 –
• 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
• Evaluate if stability studies are needed
(normally accelerated studies)
• Estimate rework costs before you start
(feasibility study)
• Rework should remain exceptional.
API Rework – Regulatory
• 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
• 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 nonconformance and appropriate evaluation
of the quality of the product reworked
• Reworking procedures normally require
approval from Authorities.
Thank You
Any Questions

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