Quality Workshop
Copenhagen – January 2012
Biobatch
Considerations
for
Quality
Assessment
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Lynda Paleshnuik | January 2012
Overview
Biobatch basics (biowaiver vs bioequivalence study, size)
Biowaivers and their considerations for quality (Q) assessors
Formulation of the proposed product
Dissolution
API lot, formulation and method of manufacture
Biobatch uniformity
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Lynda Paleshnuik | January 2012
Biobatch basics
 The biobatch is a key component of the quality assessment,
regardless of whether there is:
 a biowaiver (BW) supported by dissolution studies and a formulation
comparison, or
 A bioequivalence (BE) study
 When there is a BW, this does not mean there is no biobatch, or
that its importance is lessened. The biobatch (BW or BE batch)
is of prime importance to support the dossier.
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Lynda Paleshnuik | January 2012
Biobatch basics
 The size of the biobatch must be adequate to represent the
production batch size, i.e. no scale up beyond ten times.
 This applies throughout the life of the product, not just
before PQ/approval. Scale up beyond ten times should be
supported with a new biobatch/BW data to support the new
size (possible exception for low-risk cases if well-defined).
 A biobatch should be the greater of 100,000 units, or not less
than 1/10th the proposed production size.
 A biobatch of < 100,000 units may be accepted, but then no
scale-up is allowed. This should be clearly indicated in
reports for the product, as it affects allowable variations.
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Lynda Paleshnuik | January 2012
Biowaivers
 Familiarity with the BW policies is useful for Q assessors.
 BE/BW is done by bio assessors; quality assessors in PQP
should not comment on the BE studies. But an awareness of
the quality-related issues is helpful.
 There are two general quality considerations for BWs:
1) formulation, and 2) dissolution considerations
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Lynda Paleshnuik | January 2012
BCS-based biowaivers
Currently the dossiers with the following APIs are eligible
for BCS-based biowaiver:
ARV’s: lamivudine, stavudine, zidovudine (+
abacavir
sulfate, emtricitabine added November 2011)
TB’s: ethambutol, isoniazid, levofloxacin,
ofloxacin and
pyrazinamide
The new BCS-based BW doc now also makes reference to
FDCs. (Difficult to envision due to formulation
restrictions and lack of FDC comparators).
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Lynda Paleshnuik | January 2012
Biowaiver considerations for Q assessors
Formulation
Formulation considerations for BCS-based BWs:
BCS Class 1 APIs
Similar amounts (to comparator) of the same excipients are
encouraged.
“Well-established excipients in usual amounts should be
employed” (generally required in PQP, not just for BWs)
Excipients that may affect bioavailability of the API (e.g.
mannitol, sorbitol, surfactants) should be Q&Q with the
comparator (qualitatively and quantitatively the same)
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Lynda Paleshnuik | January 2012
Biowaiver considerations for Q assessors
Formulation
Formulation considerations for BCS-based BWs:
BCS Class 3 APIs
 Excipients must be qualitatively the same and quantitatively
very similar to the comparator. Very similar defined as level 1
SUPAC changes.
 Excipients that may affect bioavailability of the API (e.g.
mannitol, sorbitol, surfactants) should be Q&Q with the
comparator (qualitatively and quantitatively the same)
 For isoniazid-containing products, lactose and other reducing
sugars should be Q&Q with the comparator.
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Lynda Paleshnuik | January 2012
Biowaiver considerations for Q assessors
Formulation
Other formulation considerations:
Bioequivalence studies are not considered necessary for certain
categories of products, e.g. aqueous parenterals, solutions for oral
use (e.g. syrups, elixirs, tinctures), powders for oral solution,
gases, aqueous otic/ophthalmic products, aqueous topicals or
aqueous inhaler products when the products meet certain
formulation conditions (see TRS 937 Section 4).
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Lynda Paleshnuik | January 2012
Consider the form
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Lynda Paleshnuik | January 2012
Biowaiver considerations for Q assessors
Formulation
 Proportional strength biowaivers: formulations are either
exactly proportional (e.g. common granulation) or same total
weight with the difference in API made up with diluent (see
TRS 937 Section 9.3)
 Very minor quantitative differences may be accepted (e.g.
SUPAC level 1). Be cautious with regard to the limitations of
the SUPAC guides (multi-functional excipients not considered,
and some combined groups, e.g. simple and super-disintegrants,
missing groups e.g. surfactants)
 Ensure diluent is used to make up API amount in second
scenario (not stated in TRS 937)
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Lynda Paleshnuik | January 2012
Biowaiver considerations for Q assessors
Dissolution
BCS Class 1:
 The test and comparator products
must be at least rapidly dissolving.
(NLT 85% in 30 minutes)
BCS Class 3:
 The test and comparator products must be very rapidly
dissolving (NLT 85% in 15 minutes).
Criteria in both cases applies to behaviour in all 3 media.
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Lynda Paleshnuik | January 2012
Dissolution Considerations
The dissolution of the biobatch (test product) should always be
fully characterized in the dossier (both for when BE and BW).
Dissolution should be run on the tablets as they are required for
the BE study: e.g. whole chewable tablets when they “may be
swallowed whole”…. Dissolution testing of chewable tablets
should normally be the same as non-chewables (including
using whole tablets) even when they should always be chewed.
If the dossier is supported by a biowaiver, there are specific
requirements regarding dissolution. Dissolution limits in
specifications should meet the requirements on the previous
page, i.e. 85% in 15 or 30min.
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Lynda Paleshnuik | January 2012
Dissolution Considerations
 Process validation protocol for production batches should
include comparative dissolution (single medium, i.e. proposed
medium) against biobatch data.
 The comparison can be against biobatch data, as the batch may be
expired.
 Yet another reason why the data on the dissolution profile of
the biobatch is so important to be provided and reviewed in
the original report. If the absence is noted in the first review,
the data is usually available before the biobatch expires.
Time points are also important, as future comparative
studies must use the same time points for the test products.
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Lynda Paleshnuik | January 2012
Biolot dissolution comment
Biolot dissolution data was not requested in the first report. Now the
biolot is expired:
We note that the biobatch has expired and that dissolution profile data for this
batch in the other media (other than the release) is not available. Please note
that the biobatch should always be fully characterized for its dissolution
characteristics in multiple media, and this is an expected part of every dossier.
The multimedia dissolution profiles established for the biobatch in this regard
will be used as reference profiles for any future variation applications that
may require submission of comparative dissolution profile data. As a result,
you are requested to take note and confirm that for future applications, the
biobatch dissolution profile will be established in at least the three usual pH
buffer media (pH 1.2, pH 4.5 and pH 6.8) including the release medium.
Continues next slide…
15 |
Lynda Paleshnuik | January 2012
Biolot dissolution comment
 For the current application, you are requested to submit the
required multimedia multipoint dissolution study on the
remaining process validation batch of the proposed batch size
of 120,000 tablets.
[If the data is unavailable on the biolot, data should be provided
for a lot which is the same as the biolot (as much as possible).]
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Lynda Paleshnuik | January 2012
Dissolution Considerations
 Q: The process validation protocol for a solid oral product
normally must include comparative dissolution profiles against
the biolot. For a product containing only BCS class 3 API(s)
with acceptable biowaiver, the process validation protocol does
not need to include this requirement for comparative dissolution
profiles against the biolot. What is the reason for this
exception?
 A: Because the FPP specifications must include dissolution
with limits of at least NLT 85% in 15 minutes (don’t assume,
make sure). The criteria is met by meeting the release
specifications, which are part of process validation.
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Lynda Paleshnuik | January 2012
Quality assessment
API lot used in the biobatch
The API lot used in the biobatch is of critical importance in the
quality review.
 API specs should be based on the results of primary lots,
especially the lot used in the biobatch.
 All subsequent lots of the API should be representative of the lot
used in the biobatch.
 For a BCS low solubility API, particle size (PDS) and
polymorphism specifications should reflect the results of the API
lot used in the biostudy
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Lynda Paleshnuik | January 2012
Quality assessment
API lot used in the biobatch
What does this mean for multiple API suppliers, or a change in
API supplier?
 The FPP manufacturer should have a single set of API specs
that applies to API from each proposed supplier (there may be
different requirements for a single parameter, e.g. residual
solvents.)
 It is not a requirement to have FPP batches manufactured with
API from each supplier, prior to PQ
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Lynda Paleshnuik | January 2012
Quality assessment
API lot used in the biobatch
Demonstrated similar quality of API from each supplier:
 COAs from each supplier showing equivalent or superior
quality to the API lot used in the biolot
 The purity profile need not be identical for suppliers, but
the impurities must be adequately controlled for each
(qualified limits).
 For BSC low solubility APIs, API from each supplier
should have the same polymorphic form*/similar PSD to
that of the API used in the biolot. *unless equivalent
stability/solubility of the alternate form is demonstrated
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Lynda Paleshnuik | January 2012
Quality assessment
Fundamental importance of the biobatch
There was one biobatch, demonstrated to be bioequivalent
(BE) or similar (BW) to the comparator product.
The biolot should be representative of all future
production batches.
=
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Lynda Paleshnuik | January 2012
…
Quality assessment
Biobatch formulation and method of manufacture
 A key aspect of the Q assessment: comparison of the
biobatch records to the master production records for
the largest intended production size
 Ensure first that the biolot is within 10x the largest
proposed production size.
If not, this is unacceptable.
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Lynda Paleshnuik | January 2012
Biobatch formulation and method of manufacture
Elements of the comparison:
● Formulation (including excipients, their grades
and amounts)
• Generally no differences allowed but minor
quantitative differences may be justified
● Manufacturing process (equipment, processing
parameters and controls)
• Some provision made for changes to equipment
due to scale-up
• Differences should be justified
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Lynda Paleshnuik | January 2012
Biobatch uniformity
 Why is uniformity of the biobatch necessary?
 Biobatch size 100,000 tablets
 Tablets used in the average study: ≈ 100
 Previously part of the process validation of
primary lots.
If not part of above, need uniformity demonstration:
 Either an in-process demonstration of the uniformity of the final
blend, or equivalent sampling during compression or (more
likely) after packaging, e.g. at least 100 total units sampled
from at least 5 points or containers.
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Lynda Paleshnuik | January 2012
Biostudy acceptability
 When dossier review is near completion (few issues
remain, or ready for QA), the assessor should check
that:
 A) the biostudy was accepted, (check final BE report)
and
 B) if the biostudy report was completed long after the
initial quality review, check whether the biolot batch #
has changed.
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Lynda Paleshnuik | January 2012
Biostudy acceptability
 Situation: the quality assessment is almost complete (most
issues have been resolved). The above check was done and it
was noted that the original BE study was rejected/failed, and at
some point in the assessment process a new biostudy was
submitted. Need to know:
 Did the new study include a new biolot?
 Was this ever communicated to the quality assessors? Were
biobatch records and other relevant data submitted/assessed?
NOTE: This change may also be observed when the SOQR is sent
for confirmation or the QIS is updated (correction to biobatch
#)
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Lynda Paleshnuik | January 2012
New biolot question (1)
Due to the new biostudy submitted for product X, (new
biobatch Y), the following information is required to be
submitted for quality review.
 The current blank master production records for the
largest proposed production size, if more recent than the
previously submitted version. Your response should
include the change history since the previous version
submitted.
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Lynda Paleshnuik | January 2012
New biolot question (2)
 The executed records of the biobatch, with a tabulated
comparison of the formulation and manufacturing process
compared to the proposed production batches, including
formulation, equipment, process parameters and controls
as outlined in current master production documents.
 The COA of the biobatch, and the COA of the API lot
used to manufacture the Biobatch.
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Lynda Paleshnuik | January 2012
New biolot question (3)
 Data to demonstrate the dissolution profile of the
Biobatch in three media across the physiological pH
range.
 Data to demonstrate the uniformity of the biobatch.
Note that when the response is received, the report
should include a discussion of all points above.
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Lynda Paleshnuik | January 2012
Examples
 Ofloxacin solubility: a dossier indicates it may not be soluble
over the physiological pH range. It’s listed as one of the BW
APIs as BCS class 1.
 What to do?
 Solubility data is always important. If it is contradictory, at
minimum this should be discussed, including a BE consult.
 Note that the BCS classifications for solubility in TRS 937 are
error-prone (based on limited data). Data on solubility should
always be discussed and highlighted in the Q report.
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Lynda Paleshnuik | January 2012
Example
 No blank production records provided. How best to ask the
question?
 You are requested to provide blank master production records
for the largest proposed production batch size. With your
response you should provide a detailed comparison of
differences in formulation and manufacture (equipment,
processing parameters and controls) between the production
batch manufacture and the biobatch.
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Lynda Paleshnuik | January 2012
Example
There are two important elements to the above question:
The largest proposed size is important.
The reference to comparison to the biolot may save the
assessors work and serves as reminder to those reviewing the
response. Example where this was not included in the question,
the assessment of the response was: “The applicant provided the
blank master production records and it is ok.”
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Lynda Paleshnuik | January 2012
Biolot as reference
Example questions
The biolot serves as the primary reference whenever possible.
Example: the granulation was not fully characterized in master
documents. IF there is little or no scale-up to production size, the
actual parameters (rather than instructions) used to make the biolot
should be the basis of the granulation details in production
records.
1. “Granulation should be characterized by addition of defined
amount(s) of water, with mixing over specified period(s) of time at
defined speed, based on the actual processing of the batch used in
biostudies.”
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Lynda Paleshnuik | January 2012
Example questions
2. “You are requested to revise the master production records to
include a range for the ampere reading used to determine the endpoint of the granulation of each sublot. Based on the results
observed for the batches used in biowaiver studies, a limit of 005009 amperes would be considered acceptable.”
3. [proposed limit  25 amp] “The added limit on amperage for
the granulation steps should be revised to include an upper limit.
The highest value observed for the Biobatch was 27.4 amp,
therefore a limit of 25-30 amp would be acceptable at this
time. It is understood that this limit may be further optimized
with additional manufacturing experience.”
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Lynda Paleshnuik | January 2012
Example questions
4. “You are requested to submit a revised MPD and a process
validation protocol for the 400,000 tablet commercial batch size
that include full characterization of the granulation process or a
tentative granulation endpoint established based on your
available pharmaceutical development/scale up data and
manufacturing experience from the biolot, since the latter must
be representative of the proposed commercial product. It is
understood that this endpoint will be further optimized during the
production of the first three production scale validation batches. ”
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Lynda Paleshnuik | January 2012
Conclusion
The assessment of the biobatch is a key component of the
quality assessment, whether there is a BW or BE study.
If the dossier is supported by a biowaiver, there are
considerations for quality assessors regarding formulation
and dissolution.
The API lot, formulation and method of manufacture of
the biolot require careful consideration and should be the
primary reference for the assessor regarding the proposed
production product.
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Lynda Paleshnuik | January 2012
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Lynda Paleshnuik | January 2012