Statistical Approaches to Addressing the Requirements of the New FDA
Process Validation Guidance for Small Molecules
Jason Marlin, MS/T Statistics, Eli Lilly & Co.
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Key Takeaways from The FDA Guidance for Industry, “Process Validation:
General Principles and Practices,” January 2011
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the level of sampling and testing in validation must be sufficient to confirm
uniform product quality throughout the batch during processing
the level of sampling and testing in validation must provide statistical
assurance that the process is reproducible and consistently delivers quality
products
Considerations:
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A statistician’s review is required for approval of a Process Validation protocol to
ensure the testing achieves the above requirements
Statistical assurance statements
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FDA Guidance (footnote reference 1) recommends this in Stage 3: “We recommend that a statistician or person with adequate training in statistical
process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and
process capability.”
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Reality…
Limited statistical resources
Many PV protocols
World-wide sites
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Need for general PV requirements.
What we did, in general…
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Readily Pass and Marginally Pass terminology are employed
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The terms Readily Pass and Marginally Pass were introduced in the
FDA draft Guidance for Industry “Powder Blends and Finished
Dosage Units -- Stratified In-Process Dosage Unit Sampling and
Assessment,” published October 2003.
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Attributes addressed by this work
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UDU
Potency
Purity
Water Content
Release Profile
Appearance
UDU
Unit Dose Uniformity is confirmed by two types of data in a
PV.
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Blend Uniformity
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Drug Product Dosage Form Uniformity
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Potency samples are obtained to demonstrate uniformity of the blend for
tablet and powder-filled capsules.
Dosage unit samples are collected using an appropriate stratified
sampling method.
Blend Uniformity Weight-Corrected Potencies
Used to demonstrate blend uniformity
Follow PQRI guidance (readily & marginally pass)
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UDU Sample Collection and Testing
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n = 60 Dosage Units
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3 dosage units from each of 20 stratified locations (pull at
least 7 per location)
Unit dose samples are tested for potency with
corresponding individual weights recorded.
 Weight corrected potency recorded
 Non-weight corrected potency recorded
UDU Criteria
Readily Pass - meet Bergum’s criteria
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Will be ASTM standard soon (E2709)
Test provides criteria for the Mean and Maximum Allowable Standard
Deviation of the 60 Dosage Units (reported in % of Label Claim)
If criteria met, we have 95% confidence that the UDU <905> criteria
would be met at least 95% of the time for the batch in question
Marginally pass:
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|100 - Mean| + 2.4 * s < 15.0 , RSD (wt-corrected)≤6.0%.
Output from Bergum’s CuDAL Simulation
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Potency
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Release Limits accounting for change on stability and
assay variability must be established
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To Readily Pass potency
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Must meet the Marginally Pass criteria (see below),
Using potency data from Non-Weight Corrected Potency UDU results, assess
within-batch and between-batch capability.
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Combine all the mean non weight-corrected potency results from each location within
and across validation batches (NLT 20 location means per batch for CU products).
For 3-batch validations of standard CU products, this should be 60 or more location
means.
Compute the Cpk for the location means, compared to the shelf-life registered criteria
and the Cpk of the location means must be NLT 1.0
To Marginally Pass potency
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the composite test result must meet the corresponding Release Limits
Purity and Water
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Release Limits accounting for change on stability and assay
variability must be established
To Pass (no distinction between Readily and Marginally Pass)
 test results must meet the corresponding Release Limits
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Dissolution
Three Dissolution runs (B/M/E) of at least n=6 Dosage
Units per location are performed for each validation batch.
 Readily pass
 Pass the marginally pass criteria
 Pass Bergum’s 95/95 criteria for dissolution mean and SD
 Marginally pass
 All dissolution runs at each location pass Dissolution
Specification by Stage 2
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Appearance
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Select a random sample from the batch or subsection, per the
corresponding plan: medium risk (n=800) or high risk
(n=1250). The acceptance criteria (for both medium and high risk
plans) are provided in the following table:
Defect classification
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Accept/reject
Critical
0/1
Major
7/8
Minor
21/22
We specify and control consumer risk , LQL
Individual sample plans are selected from ANSI/ASQ Z1.4-2003,
indexed by the AQL, with LQL implied.
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Additional Challenges
• Statistical reviews of all PV documents?
• Stage 2 to Stage 3 Transition—what constitutes sufficient postvalidation monitoring?
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Conclusions
• Increased scrutiny of validation protocols and of
validation data
• Still some uncertainty on post-Stage II monitoring
• Three validation batches are the standard
o Within batch variation is well understood
o Between batch variation requires time element
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PQRI Guidance
Marginally Pass Criteria
All results within 75.0-125.0% of target mg/mg
All location averages are within 90.0-110.0% of target mg/mg
RSD of weight-corrected potencies not more than 6.0%
Readily Pass Criteria
All results within 75.0-125.0% of target mg/mg
All location averages are within 90.0-110.0% of target mg/mg
RSD of weight-corrected potencies not more than 4.0%
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