Transcript FPP assessment: common deficiencies

2-2 FPP assessment: common
deficiencies
Wondiyfraw Worku
4th Assessment training
January 2012
Copenhagen
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Talk structure
• Types of deficiencies
• Common deficiencies
– By CTD section
– Specific examples and assessment concerns
– Tips
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Types of dossier deficiencies
• Missing information or data
– ex : Dissolution profile data for biobatch, missing blank record,
• Inadequate discussion
– ex : Development of formulation & mfg process
• Wide limits with out adequate justification
– ex: Limits for impurities, assay
• Undefined parameters
– ex: Granulation & compression parameters
• Unsolicited changes (additional data)
– ex: Widening of shelf life limits for impurities
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•
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Number of deficiencies per dossier (mean)
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4.0
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5.0
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Where common deficiencies are
located (FPP part)
6.0
HIV n=74
TB, n=42
Malaria, n=18
RH, n=13
3.0
2.0
1.0
0.0
Note: Most of our dossiers are solid orals
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Section 3.2.S
• Submission of LOA & open part representing superseded APIMF
version
• Submission of Superseded CEP
– Changes that may impact the FPP may not be known to the FPP
applicant
• ex: if there are changes in the mfg process including last purification step
– May affect polymorph form and PSD
– May need additional analytical validation and stability studies on the FPP (if there are
new impurities)
– Consider whether the API is water soluble or not
– Consider asking for updated LOA & open part as well as summary of
changes. Next assessors to consider the impact on the FPP
– In case of CEP request for a copy of the current version and all annexes
as well as a summary of changes
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Section 3.2.S
• Failure to discuss polymorphism and PSD when relevant
– Future API batches may have different properties than the
batches used in the biobatch
• ex: missing info on polymorph screening and absence of data on the biolot
API batch
• ex: missing PSD data on the biolot API batch and absence of appropriate
limits
– As usual, check dose solubility and presence of known
polymorphs
– Look for results for the biolot API batch (COA and XRD or DSC
plots)
– Consider the need for inclusion of polymorph ID in the spec (one
may use the ICH decision tree)
– Set acceptable limits for PSD and check if proposed limits are ok
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Why are we so worried about
Polymorphism and PSD?
• Both affect intrinsic solubility
– Crystal structure could be closely compacted or loosely
compacted
• Determines water penetration and wettability of the cyrstals
– This affects release rate of drug molecules from the crystal structure to the
release media
– PSD determines available surface area for solute-water
molecule interaction
• Note:
– Wet granulation at the FPP mfg stage normally does not change
the crystal nature nor the size of crystals (except in some cases
formation of solvates)
– Where as, crystal structure and particle size of the API may
affect the granule characteristics (porosity/density and size)
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3.2.S
• Other deficiencies and considerations:
– Failure to provide signed and dated spec used by the
FPP manufacturer
– Failure to provide info on the source and qualification
of RS used at the FPP site
– Failure to provide COAs for Exhibit API batches
(including biolot API batch) as tested by the FPP site
– Use of different analytical methods than those used
by the API manufacturer (i.e. with out supporting
validation data)
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Section 3.2.P.2
• Failure to provide adequate discussion on:
– Development of prototype formulation (ex: APIexcipient compatibility)
• Stability studies may not be sufficient in detecting potential
interactions (binary mixtures are better in detecting potential
interactions)
– Check also conditions used vs FPP process conditions
– Check if specific excipients are included in the comparator formulation
– In case of incompatibility, consider the step at which the excipient is
introduced
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Section 3.2.P.2
• Failure to provide adequate discussion on:
– Optimization of formulation and mfg process parameters at lab or
pilot scale and observations made from scale up activities
• Issues may arise later on when the process is scaled up to production
scale (usually after PQ)
– Check if common optimization activities such as determining levels of
disintegrant and lubricant amounts were discussed.
– Check if common process optimization activities such as mixing time, and
water uptake were discussed
– Take the absence in to consideration when you review BMR and Validation
protocol
– On case by case basis, demand improved development summary
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Section 3.2.P.2
• Failure to provide adequate discussion on
– Development/selection of dissolution methods and
limits
• Method or limits may not be reliable for future variations
–
–
–
–
Challenge use of surfactants
Consult the FDA dissolution database
Consult methods approved for other PQD dossiers
For biowaiver based applications, consider the biowaiver conditions
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Section 3.2.P.2
• Failure to provide full dissolution profile data on
the biobatch
– We need a reference profile to adequately assess
variations later on
• Check presence of data in the usual three pH media without
surfactant
– If there is a need for surfactant, then with surfactant
• If biobatch has already expired, demand data on the next
valid batch manufactured with same formulation, process and
scale
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Section 3.2.P.2
• Failure to provide adequate discussion on
development/selection of container closure
systems
– For initial shelf life assessment we have limited
stability data that should be supplemented with other
considerations.
• For certain products one time performance tests (such as
moisture permeation data) that must be seen in conjunction
with the overall shelf life assessment
– Data may be obtained from the container supplier
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Section 3.2.P.2
• Other deficiencies:
– Missing justification and supporting data for tablet
scoring
– Missing or incomplete dilution compatibility data for
sterile products
– Missing data on filter compatibility for filter sterilized
products
– Missing discussion on leachables/extractables for
containers for liquid preparations
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Section 3.2.P.3
• Failure to submit filled and/or blank records for
all proposed batch sizes
– The mfg process for production batches should be
representative of those used for the bio/biowaiver
batch
• Check availability of blank records for all proposed batch
sizes and clearly state which size is the highest proposed
batch size in the assessment report.
• Compare (page by page) each of the blank records with the
filled biobatch record
• We need to be aware of differences so that we can evaluate
their impact on future batches of the FPP
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Section 3.2.P.3
• Failure to specify critical equipments and process
parameters in batch records
– ex: Granulation process, Drying, Compression, Sterile filtration
parameters
– Unspecified or widely open parameter leads to batch to batch
variation
• Try to understand each specific steps at least for critical processing steps
• Identify missing parameters and check the values used for the primary
(biobatch).
• Discuss the primary (biobatch) observed values in the assessment report
and specify them in your question
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Impact of variation in mfg process:
wet granulation
• Granulation can be characterized by a set of parameters (mixing
mechanism, mixing time, mixing speed, fluid and its addition rate).
– Each set of parameters may yield granules of different shape, size and
porosity
• Porosity but also shape and size affect penetration and wettability of the granules
in vivo
– This may determine the release of drug particles from the granular matrix and further
solubility of the drug molecules in the release medium.
– Variations in shape and size of granules also affect processability (flowability and
compressibility) and may lead to high wt and content variation, hardness and friability
problems
– Wet granulation may also change morphology of some APIs (from
Anhydrous to hydrated form), there by changing the dissolution
characteristics.
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High shear mixing
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Section 3.2.P.3
• Other common deficiencies:
– Failure to include appropriate limits (as a range) for moisture
content of final blend
– Failure to provide supporting hold time data
– Failure to include in PV the need for dissolution profile testing of
process validation batches and similarity determination to the
biobatch profile
– Failure to include key SOPs referenced in BMRs for sterile
products
– Failure to provide adequate media fill data or protocol which
matrixes the proposed product and process features
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Section 3.2.P.4 (Excipients)
• Failure to provide qualitative compositions and
approval declaration for flavours
– Flavours contain several constituents forming the
flavour
– Each substance in the flavour should have been
approved for use in foods
• Demand for full listing of flavour forming substances
– Confidential information can be sent directly from the supplier to WHO
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Section 2.3.P.5 (Control)
• Wider acceptance limits (impurities, moisture
content, dissolution, etc)
– Usually for shelf life spec in an anticipation of
potential OOS/OOT stability results
• Make sure you also assess the shelf life/stability/regulatory
specification
– Impurities, except, metabolite impurities should be controlled with
same qualified release limit
– Dissolution- no change allowed
– Moisture content- check stability trends vis à vis impacts on the other
parameters (appearance, dissolution, assay and related substances)
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Section 3.2.P.5
• Other common deficiencies
– Failure to include specific identity test (or combination of tests)
– Failure to provide adequate qualification data when observed
limits are already above the qualification limit
– Premature skip testing proposals
– Assuming that monograph limits for impurities are adequate in all
cases
– Failure to provide analytical method validation results w.r.t all
specified degradation products
– Failure to demonstrate equivalence with claimed monograph
method when in-house method is used.
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Section 3.2.P.7 (Containers)
• In case of oral liquids, failure to include dose
measuring device and missing supporting data
– Doses as low as 0.6ml may be withdrawn
• Missing ID tests from specifications for primary
containers
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Section 3.2.P.8 (stability)
• Failure to provide full data corresponding to
current acceptable protocol
– Example: Testing limited to monograph tests
(common in TB, Malaria & RH dossiers)
– Studies not inline with ICH recommendations
• Should we ask fresh stability data as tested with current
acceptable specifications before PQ?
• Ensure that stability results meet current acceptable
specifications and not merely the limits specified in the
stability sheet
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Section 3.2.P.8 (stability contd)
• Other common deficiencies
– Failure to discuss results (variabilities, trend, OOS,
OOT results)
– Failure to provide photostability data or supporting
data thereof
– Failure to submit updated stability data unless
requested
– Failure to provide stability protocol and commitments
for future stability programmes
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Deficiencies related to additional
data
• Failure to submit quality related updates when
new BE/biowiaver data is submitted
– If there is a change in the bio/biowaiver batch, this
means we lost our reference batch for Q assessment
• Always check the status of the BE assessment
• Check if the new study was made on new or same batch
• If on a new batch, consider additional requirements as Q part
of the dossier
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QIS related deficiencies
• Indicating erroneous information
• Failure to include adequate summary
• Failure to update sections on submission of
additional data
– We need to carefully check the data in QIS as it will
be the basis of prequalification.
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• Thank you
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