1. Statistical Approaches to Addressing the Requirements of the New FDA Process Validation Guidance for Small Molecules 1 Jason Marlin, MS/T Statistics, Eli Lilly & Co.

2. Key Takeaways from The FDA Guidance for Industry, “Process Validation: General Principles and Practices,” January 2011  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:  1 A statistician’s review is required for approval of a Process Validation protocol to ensure the testing achieves the above requirements  Statistical assurance statements  1 The 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.” 2

3. Reality…  Limited statistical resources  Many PV protocols  World-wide sites  Need for general PV requirements. 3

4. What we did, in general…  Readily Pass and Marginally Pass terminology are employed  The terms Readily Pass and Marginally Pass were introduced in the FDA draft Guidance for Industry “Powder Blends and Finished Dosage Units -- Stratified In-Process Dosage Unit Sampling and Assessment,” published October 2003. 4

5. Attributes addressed by this work  UDU  Potency  Purity  Water Content  Release Profile  Appearance 5

6. UDU  Unit Dose Uniformity is confirmed by two types of data in a PV.  Blend Uniformity  Potency samples are obtained to demonstrate uniformity of the blend for tablet and powder-filled capsules.  Drug Product Dosage Form Uniformity  Dosage unit samples are collected using an appropriate stratified sampling method. 6

7. Blend Uniformity Weight-Corrected Potencies 7  Used to demonstrate blend uniformity  Follow PQRI guidance (readily & marginally pass)

8. UDU Sample Collection and Testing  n = 60 Dosage Units  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 8

9. UDU Criteria  Readily Pass - meet Bergum’s criteria  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 criteria would be met at least 95% of the time for the batch in question  Marginally pass:  |100 - Mean| + 2.4 * s < 15.0, RSD (wt-corrected)≤6.0%. 9

10. 10 Output from Bergum’s CuDAL Simulation

11. Potency  Release Limits accounting for change on stability and assay variability must be established  To Readily Pass potency  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.  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  the composite test result must meet the corresponding Release Limits 11

12. Purity and Water  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 12

13. Dissolution 13  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

14. Appearance  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:  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. 14 Defect classificationAccept/reject Critical0/1 Major7/8 Minor21/22

15. Additional Challenges Statistical reviews of all PV documents? Stage 2 to Stage 3 Transition—what constitutes sufficient post- validation monitoring? 15

16. Conclusions 16 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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18. PQRI Guidance 18 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%