Reprocessing Biotech Products
Workshop Session 4
January 31, 2013
Some stuff on the web….
From Compliance Firm website:
“Reprocessing is taking a material (in-spec or out-of-spec)
and reintroducing it to an existing (validated) process.”
“Reworking is taking an out-of-spec product and running it
through a non-standard process to bring it back into spec.
Concurrent validation is required.”
“I would add that if it can be done on the same batch record,
it is a reprocess. A rework will always require another batch
record.”
From Regulatory chat boards…
“Scott is right on the definitions... Just to cite an official
definition from the CEFIC.pdf “
“Reprocessing is the treatment of a batch or sub-batch of
materials of unacceptable quality by repeating the same
process steps from a defined stage of production so that its
quality may be made acceptable.”
“NOTE: The occasional repeating of one or more process steps
during manufacture after it was known that the pre-set limits
had not been met, or there was an unexpected process
problem, is an acceptable part of the process and a rational
reaction to the results obtained.”
From Regulatory chat boards…
“Reworking is the treatment of a batch or sub-batch of
materials of unacceptable quality by using a process other
than that used to produce the original material so that its
quality may be made acceptable.
In general there is no objection to occasionally reprocessing
materials not meeting specification by repeating all or part of
the same process, however if this becomes a routine
procedure, investigations should be conducted into the
adequacy of the original process.”
Questions
1. What do you consider the true definition of
reprocessing to be?
2. Likewise what is not considered reprocessing?
3. What would be examples of each?
4. What are current industry practices with regard to
reprocessing?
5. What systems and requirements are needed for
reprocessing to be acceptable in:
- Clinical products?
- Commercial products?
6. To what extent is reprocessing applied by industry?
ADVENTURES IN
REPROCESSING…
Case Study 1 - Scenario
• Mega Monoclonals has labeled zmab for use in the US but in
order to manage supply, they decide to take some of the
labeled stock for US and relabel it for use and distribution in
Canada. The relabeling process involves the removal of the
old label and application of the new label.
• All relabeling activities are done with quality oversight. A
protocol is in place that has been approved by the QA team
and is based on small scale studies as well as a documented
risk assessment that there is no impact to product quality and
safety.
Case Study 1 - Questions
1. Is this considered reprocessing?
2. Is it reportable and if so, what category?
3. Does this differ if zmab is a clinical product or a licensed
product?
Case Study 2 - Scenario
• During the manufacture of zippitydodamab (zmab), a product in
global clinical phase 2 trials made by Mega Monoclonals, a
disposable bag used to collect product between manufacturing
steps, was discovered to be leaking. The decision was made to
refilter the product into a new bag.
• RA and QA are brought in to assess the refiltration. It is discovered
upon review that the ability to refilter at this particular
manufacturing step is not captured in the master batch record or in
any regulatory filing(s) as part of the normal manufacturing process.
• Zmab is manufactured at a contract manufacturing company –
Bigtime Biotech (BB) - that has a platform process for the
manufacture of monoclonals. One of the standard operating
procedures in place at BB for their platform processes allows for
reprocessing for this kind of situation and it is referenced in the
master batch record.
Case Study 2 - Questions
1.
2.
3.
Is the described scenario a reprocessing step? Why or Why not?
What, if any information needs to be filed to global health
authorities?
If Zmab were a licensed product, would this change anything with
regard to classification and reporting categories?
4.
What do you consider the true definition of reprocessing to be?
5.
Likewise what is not considered reprocessing?
6.
What would be examples of each?
7.
What are current industry practices with regard to reprocessing?
8.
What systems and requirements are needed for reprocessing to be
acceptable in:
- Clinical products?
- Commercial products?
9.
To what extent is reprocessing applied by industry?
Back-up
ICH Q7 - Reprocessing
• Introducing an intermediate or API, including one that does not conform
to standards or specifications, back into the process and reprocessing by
repeating a crystallization step or other appropriate chemical or physical
manipulation steps (e.g., distillation, filtration, chromatography, milling)
that are part of the established manufacturing process is generally
considered acceptable. However, if such reprocessing is used for a
majority of batches, such reprocessing should be included as part of the
standard manufacturing process.
• Continuation of a process step after an in-process control test has shown
that the step is incomplete is considered to be part of the normal process.
This is not considered to be reprocessing.
• Introducing unreacted material back into a process and repeating a
chemical reaction is considered to be reprocessing unless it is part of the
established process. Such reprocessing should be preceded by careful
evaluation to ensure that the quality of the intermediate or API is not
adversely impacted due to the potential formation of by-products and
over-reacted materials.
ICH Q7 - Reworking
• 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. 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 a report can be
written and the batch released once it is found to be acceptable.
• Procedures should provide for comparing the impurity profile of each
reworked batch against batches manufactured by the established process.
Where routine analytical methods are inadequate to characterize the
reworked batch, additional methods should be used.
WHO Annex 4
The reworking or recovery of rejected products should be
exceptional. It is permitted only if the quality of the final product is
not affected, if the specifications are met, and if it is done in
accordance with a defined and authorized procedure after
evaluation of the risks involved. A record should be kept of the
reworking or recovery. A reworked batch should be given a new
batch number.
The introduction of all or part of earlier batches, conforming to the
required quality, into a batch of the same product at a defined
stage of manufacture should be authorized beforehand. This
recovery should be carried out in accordance with a defined
procedure after evaluation of the risks involved, including any
possible effect on shelflife. The recovery should be recorded.
The need for additional testing of any finished product that has
been reprocessed, reworked or into which a recovered product has
been incorporated, should be considered by the quality control
department.