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API Starting Materials Co-Leaders: Nina Cauchon (Amgen); Megan McMahon (Pfizer) Co-Speakers/Moderators: John Lepore (Merck); Barbara Scott (FDA); Kasturi Srinivasachar (FDA); Tim Watson (Pfizer) Speaker comments and provided slides are not intended to represent the official views of the speakers’ organizations or AAPS API Starting Materials • Represent the start of full GMP manufacturing controls • Represent the start of the manufacturing process description for the API process • Defined properties and quality – Well-understood impurity profile and impact on overall control strategy – The sponsor is accountable for SM quality • Differentiated from other reagents/solvents (significant structural fragment of API) • Custom vs. Commercial Regulatory Guidance and Papers • ICH Q7 – GMP for Active Pharmaceutical Ingredients • ICH Q11: Development and Manufacture of Drug Substances • EMA Reflection paper on the Requirements for Selection and Justification of Starting Materials for the Manufacture of Chemical Active Substances – Sept 2014 • *ICH Q11 IWG Q&A Document – in progress Issues for Starting Material Selection • Transparency – Clarity of selection rationale, justification and connections to control strategy in marketing application • Impurity profile and purge – How do stereochemistry, mutagenic impurities, metals impact? • Significant structural fragment Issues for Starting Material Selection • Proximity (number of chemical transformations (CTs) from drug substance) – CTs should be sufficient to robustly control impurities and stereochemistry – Salt formation steps and deprotection steps are not considered chemical transformations, though these often offer significant purification opportunities and reduce risk. – Critical steps for safety and efficacy should be included in the regulatory synthesis • Role of GMP Issues for Starting Material Selection • Lifecycle change management – Changes in SMs synthesis/ suppliers may impact API quality – Supplier availability and dependability – Multiple supplier impact on API quality • Stability and storage requirements What’s next? • ICH Q11 Implementation Working Group (IWG) is preparing a Q&A document on the Selection and Justification of Starting Materials for the Manufacture of Drug Substances • Tentative Timing for Q&A Document: – – – – Approval of Topic/Rapporteur & IWG Defined (complete) First IWG Meeting (complete) Step 2 Sign-off November 2015 Step 4 Sign-off TBD Discussion Groups Case Study #1 (Linear Synthesis)* R1 Step 1 A Step 2 R2 R3 C Step 3 D (B) Step 4 R1 R3 R1 Purification R4 Final Drug Substance R3 Step 6 R4 Step 5 F E “Crude” Drug Substance *Example taken from ICH Q11 Case Study 1, Scenario 1 • Assume a significant structural fragment is introduced in Step 5. It is a commercially available chemical. – How is this represented in the dossier (raw material or starting material)? – How does the company manage quality of a significant structural fragment that is not custom made? • Unknown route of synthesis? • Unknown impurities? • Variable impurity profiles? Case Study 1, Scenario 2 • Why might a reviewer challenge the proposal to use compound D as an API starting material? – Stereochemistry control (reactions setting or purifications) • What discussion/data could be provided in the dossier to support the stereochemistry being set prior to the regulatory commitment? – Assume a known mutagenic impurity is generated in Step 2. • What data/discussion/commitments might support having this step outside of the regulatory synthesis? • Lifecycle management for changes to starting material manufacturing processes or suppliers? Case Study #2 (Convergent Synthesis) A Chiral center introduction Step 1 [B] Step 3 Non-isolated intermediates E Step 2 C D Step 4 Non-isolated intermediates Step 5 Final Drug Substance [F] Case Study 2, General Considerations • Which are the appropriate starting materials? Always A and D? • How to determine the number of steps? If “step 4” is comprised of three separate chemical transformations how does this change the SM designation? • Options for purification? • Other discussion? Case Study 2, Scenario 1 • Starting material D is sourced from 2 companies and is prepared using two routes of synthesis. – How is this presented in the dossier? – Is material from the two suppliers managed under a common specification, even if impurity profile is different? – How are companies managing vendor change control in general? – Other considerations? More Topics for Discussion • Is isolation of intermediates the only way to reduce impurities? • How are companies managing risk of non-acceptance of proposed starting materials? – Are any risk mitigation steps implemented prior to filing (such as Agency consultation, process validation of steps prior to the proposed regulatory synthesis) • Are companies observing inconsistent feedback from different regulatory agencies? Please provide examples. • Can reviewers point to/discuss any common deficiencies observed in starting material justification? – Examples from generic perspective and innovator perspective? More Topics for Discussion • What are the current company practices for the following: – Level of detail provided for API SM synthesis? – Level of detail for impurity fate and purge studies? • Differences for standard organic PRIs vs. mutagenic impurities? – Specifications for raw materials or intermediates used in API SM synthesis? – Use of validated methods for API SM testing/in-process testing? Summary/Output Change Control • Supplier management – Q10 – Qualification of new routes, new vendors – Complex supply chain – Risk assessment – Quality agreements • Drivers for change: – Site changes, scale change, cost, new technology Global Acceptability • Inconsistent feedback/expectations from different regulatory agencies. – Management of different regulatory commitments • Manufacture to tightest regulatory commitments • Lifecycle management manages separately for different regulatory commitments – Managing risk of regulatory rejection to launch Pre-Registration Regulatory Advice • Timing – Driven by availability of supportive data for justification and not phase of development – Challenging for accelerated programs (break-through therapies) • Who to receive feedback from? – All major markets or most conservative? • Communication of diverging opinions between agencies Risk Mitigation • Ensuring use of launch supplies – Full GMPs for pre-starting material steps – Validation of pre-starting material steps • Transparency around company change control within dossier • Seeking regulatory feedback prior to submission • Detailed knowledge/understanding of starting material synthesis Convergent vs. Linear Synthesis • Number of steps – Isolated intermediates vs. bond forming steps – Opportunities for purification (other than isolation) • Not preferred to have all purification at API isolation and purification • ICH Q11 on drug substance CQAs • More justification and dialogue may be needed for convergent synthesis Managing Unknown Impurities • Risk based assessments • Purge of structurally dis-similar impurities vs. structurally similar impurities • Understanding potential impurities Q11 Principles • All principles should be considered, not one or two principles in isolation • Significant structural fragment (clarification of what this means) • Science based justifications Critical Steps • Criticality of steps that introduce chirality or mutagenic impurities – Introduction of stereocenter or mutagenic impurity may occur prior to designated starting materials with appropriate control strategy • Critical steps are those that impact drug substance CQAs