1. VALIDATION What is the new guidance?

2. What is a Compliance Policy Guide? Explain FDA policy on regulatory issues CGMP regulations and application commitments. Advise the field staff on FDA’s standards and procedures to be applied when determining industry compliance CPGs may come from a request for an advisory opinion, from a petition from outside the Agency, or from a perceived need for a policy clarification by FDA personnel.

3. The Big Disclaimer It represents the FDA's current thinking on the topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations.

4. Process Validation Requirements for Drug Products and APIs Subject to Pre-Market Approval CPG 490.100

5. Background The CPG covers CDER/CBER/CVM products Sterile and Nonsterile processes The CPG does not address methods and controls designed to ensure product sterility (e.g. aseptic fill validation) Does not cover BLAs or recombinant protein drug products

6. Areas of interest Conformance batch Validation before PAI Validation before commercial distribution Process analytical technology API process validation

7. When is process validation expected? Not necessary before an NDA is approved Although many prefer to validate the manufacturing process prior to the preapproval inspection. Reduce time to market Gain additional process information It is necessary before commercial distribution

8. Why Validate? Quality by design, built in Can’t inspect quality in Demonstrate control of process Good science Good business It’s the law

9. Process Validation and the Law Dosage Forms Required by CGMPRs (211.100; 211.110) Enforced as GMP under the FD&C Act (501(a)(2)(b)) APIs Enforced as GMP under the FD&C Act (501(a)(2)(b))

10. Validated Process Provides a high level of scientific assurance to reliably produce acceptable product Using rational experimental design Evaluation of data From development to commercial phase

11. What is expected? Before commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support post- approval product distribution.

12. There is a new term!! Conformance Batch Prepared to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make acceptable product.

13. Conformance Batches Formerly known as validation batches NDAs may be approved prior to completion of the initial conformance batch phase of process validation The manufacture of the initial conformance batches should be successfully completed prior to commercial distribution

14. Inspection of validation activities during a PAI PAI team will assess any validation activities whether completed or not A withhold recommendation will be made if: Questionable integrity Demonstrate that the process is not under control Firm has not committed to making appropriate changes If deficiencies found in already approved product validations

15. Inspection of validation activities - - post-approval Cover within 1 st year of manufacture at commercial scale if It is the first drug produced at the site There were previous problems validating a similar process for another product Equipment/process is substantially different from existing equipment/processes Inherently variable/complex operations

16. Inspection of validation activities - - post-approval If a firm has a good validation history with similar products/processes Process validation protocol & report may be sent to District office for evaluation

17. Inspection of validation activities - - post-approval If significant deficiencies in validation efforts are found… Initial conformance batch phase not completed Protocol not followed or inadequate Data shows process not in control And product has been distributed… Recommend regulatory action

18. Completion of conformance batches prior to distribution It is expected for most products May not be needed for certain products Orphan drugs Radiopharmaceuticals

19. Completion of conformance batches prior to distribution If product distribution is to be concurrent with release of conformance batches, FDA will assess: Basis for justification Protocol/plan & available data to verify controls prior to release; eventual process validation Post distribution monitoring for problems

20. Process analytical technology For manufacturing processes that use PAT, it may not be necessary for a firm to manufacture multiple conformance batches prior to initial distribution. This will be decided on a case by case basis by FDA depending on how and the extent PAT is used.

21. API’s used in other already approved drug products Process validation is expected prior to approval of the application if the API is already being used in another drug product and is made by essentially the same process/scale Conformance batches will be reviewed

22. API’s: NMEs or new process Not having completed process validation and initial conformance batches will not delay approval of the NDA FDA will audit and assess any available process validation protocols, activities, data, and information whether or not completed A withhold recommendation will be made if any completed API validation efforts include data of questionable integrity or demonstrate that the API process is not under control and the firm has not committed to making appropriate changes.

23. APIs & Biotech Some biotech NDAs require validation information to be submitted as part of the CMC section.

24. Deficiencies in other validated API processes If process validation activities are deficient for an API process similar to that of the API under inspection and for which a warning letter or other regulatory action will be proposed, a withhold recommendation for the dosage form will be made. A withhold recommendation will be made if the API firm has not established or is not following an adequate initial conformance batch validation plan/protocol or when the process is not under control as demonstrated by repeated batch failures due to manufacturing process variability.

25. So What Is New? (nothing really…… Wink, wink Nudge, nudge!!)

26. So What Is Missing?