1. Best Practices and Application of GMPs for Small Molecule Drugs in Early Development Best Practices and Application of GMPs for Small Molecule Drugs in Early Development IQ Workshop, Feb 4-5, 2014, Washington, D.C. Manufacturing Breakout Session 1

2. Survey Results: Drug Product Manufacturing in Early Development A total of 10 IQ member companies responded

3. Survey Results: Drug Product Manufacturing in Early Development A total of 10 IQ member companies responded

4. 4 Topic 1: Batch Documentation – IQ proposal to design batch records that accommodate manufacturing flexibility  Raw materials or API do not necessarily need to be fully released at start of manufacture  Room/line clearance does not necessarily need to be performed by Quality  Process parameters do not need to be pre-determined in all cases  Executed BR must serve as a record to allow replication of a process DISCUSSION – What approaches have you successfully implemented  What are typical lead-times before the start of a early development campaign?  What is the role of Quality?  Describe your early development manufacturing control strategy  Defined process parameters versus in process control limits.  Which process parameters should be pre-defined, which should be left undefined? – What obstacles have you encountered

5. 5 Topic 2: Change Control – IQ proposal to design manufacturing practices that accommodate changes  Process changes during manufacture should be documented as operations notes or modifications  These would not require prior approval from Quality  Changes should not trigger a formal CAPA unless the deviation is systemic and could apply across projects  Product specific changes do not require CAPA  Changes from Batch-to-Batch are expected and should be documented to capture development history DISCUSSION – What change control approaches have you successfully implemented  What is the role of Quality in approving planned and unplanned manufacturing deviations?  How are manufacturing deviations handled in your quality management system?  What are some examples of manufacturing changes that should require a CAPA? – What obstacles have you encountered

6. Bonus Slides

7. GMPs in Early Development Part 3: Drug Product Manufacturing Published in August 2012 issue of Pharmaceutical Technology Volume 36, Issue 8, pp. 56-61 7

8. 8 IQ DP Mfg Paper: Batch documentation –Batch documentation preparation and execution  Minimum requirements are given in available guidance. Must serve as a record to allow for replication of the process.  are expected due to limited product and process knowledge  Flexibility in specifying process parameters In the batch record; should record and document during batch execution, do not require prior approval by Quality in every case. –Change control  Changes from batch to batch are expected and should be documented to capture development history, and communicated to affected areas  system should capture documented appropriately (Quality pre-approval not required before implementation but adequately justified, change control system is not required)  Formal sampling plan not required when collecting data “for development purposes”

9. 9 IQ DP Manufacturing Paper: Raw Materials –Excipient specifications  Should be based upon compendial specifications if available in at least one of the pharmacopeia (USP, EP, JP)  Materials meeting specifications of at least one of the pharmacopeia are acceptable for use in early phase clinical studies in US, Europe and Japan  If no compendial specifications are available, vendor specifications and/or alternative compendial specifications (e.g. USP Food Chemical Codex) should guide specification setting –Approval for use  Manufacturing can be initiated prior to final release of excipients & API –Risk-based vendor qualification  Vendors must be qualified, but extent of qualification can vary with phase of development and should include internal risk assessment  Qualification can proceed in parallel to batch manufacture, but must be completed prior to final batch disposition.