Integrated Process and Facility Assessment for NDAs/ANDAs

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1 Integrated Process and Facility Assessment for NDAs/ANDAs Zhigang Sun, Ph.D. Acting Branch Chief Office of Process and Facilities FDA/CDER/OPQ AAPS - CPDG Seminar Chicago, IL / April 6, 2017 Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of the FDA

2 Background Office of Pharmaceutical Quality (OPQ) Integrated Quality Assessment (IQA) Office of Process and Facilities (OPF) Integration of Process & Facility Reviews Integration of Review and Facility Inspection Summary Outline 2

3 Challenges to Pharmaceutical Quality Product recall and defect reporting data indicating inherent flaws in product and process design Alarming drug shortages of critical drugs due to quality issues & ineffective quality management systems Inconsistency in applying the same quality standards to both brand and generic drugs Limited information about the current state of pharmaceutical quality 3

Office of Pharmaceutical Quality (OPQ) Single super-office in CDER dedicated to product quality Across all drug products (new, generic, OTC) Across all manufacturing sites (domestic and

4 Office of Pharmaceutical Quality (OPQ) Single super-office in CDER dedicated to product quality Across all drug products (new, generic, OTC) Across all manufacturing sites (domestic and foreign) One Quality Voice oversight throughout the drug product lifecycle Integration of review, inspection, surveillance, research, and policy All quality related issues for NDAs, ANDAs, and BLAs 4

5 OPQ Organization 5

6 Background Office of Pharmaceutical Quality (OPQ) Integrated Quality Assessment (IQA) Office of Process and Facilities (OPF) Integration of Process & Facility Reviews Integration of Review and Facility Inspection Summary Outline 6

Team-based Integrated Quality Assessment (IQA) IQA team provides aligned, patient-focused, and risk-based drug product quality recommendations for NDAs, ANDAs, & BLAs, inclusive of drug substance,

7 Team-based Integrated Quality Assessment (IQA) IQA team provides aligned, patient-focused, and risk-based drug product quality recommendations for NDAs, ANDAs, & BLAs, inclusive of drug substance, drug product, manufacturing, and facilities. A team of subject-matter experts (SME) performing a quality assessment of an application OPQ IQA Team consists of: Application Technical Lead (ATL) Regulatory Business Process Manager (RBPM) Discipline Reviewers (includes ORA) 7

team meetings Integrate PAI with quality review Non-IQA process: One application,

8 How is the IQA different from previous process? IQA process: Expert teams Concurrent assessment Single review template Scheduled team meetings Integrate PAI with quality review Non-IQA process: One application, one reviewer Independent assessment Separate templates Inconsistent communication between disciplines Disconnect from PAI 8

9 OPQ s IQA Team Roles Role / Task Scientific Content / Initial Risk Assessment Process and Timeline IQA Executive Summary Assessment of Drug Substance / DMF Assessment of Drug Product Assessment of the Manufacturing Process Assessment of Facilities Assessment of Biopharmaceutics Assessment of Microbiology Assessment of Environmental Analysis Labeling & Package Insert Pre-approval Inspections (PAI) Lifecycle Knowledge Management Responsible* ATL / IQA Team RBPM ATL / IQA Team DS/DP Reviewer DP Reviewer Process Reviewer Facility Reviewer Bio pharm Reviewer Micro Reviewer EA reviewer DP Reviewer ORA Lead / SMEs participate ATL/ IQA Team * general cases 9

10 Background Office of Pharmaceutical Quality (OPQ) Integrated Quality Assessment (IQA) Office of Process and Facilities (OPF) Integration of Process & Facility Reviews Integration of Review and Facility Inspection Summary Outline 10

11 Why OPF? OPF was designed to utilize necessary specialization and expertise to provide oversight on assessment of pharmaceutical manufacturing (process, facility and micro) Traditionally, manufacturing process review was isolated from pre-approval inspection (PAI) A higher degree of integration between the review and inspection is needed to deal with current challenges (e.g., emerging technologies, prioritization of medically necessary products, etc.), and to make better decisions to assure drug product quality 11

Office of Process and Facilities (OPF) A large, diverse organization (chemists, chemical engineers, pharmaceutical scientists, microbiologists, biologists, etc.

12 Office of Process and Facilities (OPF) A large, diverse organization (chemists, chemical engineers, pharmaceutical scientists, microbiologists, biologists, etc.) Responsible for a wide range of process related review and inspection aspects Process review Microbiology review Facility review Involved in nearly all application types All original NDAs, ANDAs and BLAs All site change snda, sanda and sbla Certain complex drug substances Some INDs, meeting packages, process change supplements Holistic Assessment through Riskbased Review and Inspection 12

OPF Organization Immediate Office Bob Iser (Director) Dave Doleski (Acting Deputy Director) VACANT (Sr. Scientific Advisor) Norman Schmuff (Associate Dir.

Affairs) Albinus D Sa Senior Advisor / Special Assistant Division of Process Assessment I Rapti Madurawe Division of Process Assessment II Sharmista Chatterjee Division of Process Assessment III

13 OPF Organization Immediate Office Bob Iser (Director) Dave Doleski (Acting Deputy Director) VACANT (Sr. Scientific Advisor) Norman Schmuff (Associate Dir. for Science) Bernetta Lane (Acting Associate Director for Reg. Affairs) Albinus D Sa Senior Advisor / Special Assistant Division of Process Assessment I Rapti Madurawe Division of Process Assessment II Sharmista Chatterjee Division of Process Assessment III Naiqi Ya Division of Microbiology Assessment Lynne Ensor Division of Inspectional Assessment Mahesh Ramanadham (acting) Process Assessment Divisions I, II, III: 8 branches for solid & liquid drug products 1 branch for complex drug substances (ANDAs) Microbiology Division: 3 branches for sterile, small molecule drug product and substance 1 branch for biotech drug substance and product Inspectional Assessment Division: 3 branches Mixed product and application types 13

14 Background Office of Pharmaceutical Quality (OPQ) Integrated Quality Assessment (IQA) Office of Process and Facilities (OPF) Integration of Process & Facility Reviews Integration of Review and Facility Inspection Summary Outline 14

Process Review Begin with the End in Mind Evaluate adequacy of proposed final commercial scale manufacturing process Focus on review of drug product (DP) manufacturability Adequacy of DP

15 Process Review Begin with the End in Mind Evaluate adequacy of proposed final commercial scale manufacturing process Focus on review of drug product (DP) manufacturability Adequacy of DP manufacturing at exhibit batch scale Batch formula, process flow diagram, batch records & reconciliation, etc. Risk assessment for process, in-process controls, etc. Adequacy of scale up to commercial scale Comparison of exhibit & commercial batches (e.g., batch sizes & key equipment, process parameters, in-process control etc. ) Scale up experience (e.g., lab scale pilot scale commercial scale) Process robustness (e.g., formulation and process optimization studies) Batch-to-batch consistency at commercial scale Control strategy & process monitoring 15

16 Risk Based Review for Process Process Assessment Tool Includes a risk based approach to process assessment Developed by OPF and consistent with OPQ efforts A tool to standardize process reviews Identify high risk unit operations Identify appropriate risk mitigation steps Perform structured risk-based assessment Document residual risks Goal is to expedite process review with consistent quality Evaluation of proposed risk mitigation approaches In-process controls Setting of process parameter targets/ranges 16

17 Example: Process Review for NDAs/ANDAs (typical oral solid dosage form) 17

18 Facility Review Identify manufacturing risks from a CGMP perspective Evaluate the compliance history of each facility related to the proposed operations Determine the need for an on-site pre-approval inspection (PAI) in collaboration with OPQ review team Assess PAI establishment inspection reports (EIRs) Ensure continuity in the review of the application and the assessment of operations on-site Recommend final status (Approval or Withholding) for each facility named in the application 18

19 Risk Based Review for Facility Facility Risk: Are there manufacturing risks associated with the inspectional history and current operations at this facility that impact my application? Process Risk: What are the manufacturing risks associated with the proposed unit operations in this application? Product Risk: Is there limited knowledge about the manufacture of this product? What s the connection between manufacturing and clinical efficacy and patient safety? Facility Reviewers assess these three risks to make Pre-approval inspection (PAI) recommendation Product Process Facility 19 19

20 Facility Evaluation for NDAs/ANDAs Determine acceptability of each facility for its proposed operation. Final recommendation based on: Relevant application facts (process development, control strategy, master batch records, etc.) Manufacturing capability Inspectoral history (EIR review, quality defect data, etc.) Collective analysis of factors listed above 20

21 When is PAI needed for NDAs/ANDAs? PAI decision is made based on product, process and/or facility specific issues Considering areas of potential risk Based on evaluation of: facility history inspectional outcomes from most recent inspections; NOT time since last inspection information that was provided in the submission PAIs may also be recommended during review of an application (e.g., critical concern raised by IQA team) or when an amendment is received (e.g., new facility proposed) LOOK AT THE PAI TRIGGERS and KNOW YOUR FACILITIES 21 21

22 Manufacturing Assessment Design Implementation Control Process Review Facility Review 22

23 Integration of Process & Facility Review Role / Task Scientific Content / Initial Risk Assessment Process and Timeline IQA Executive Summary Assessment of Drug Substance / DMF Assessment of Drug Product Assessment of the Manufacturing Process Assessment of Facilities Assessment of Biopharmaceutics Assessment of Microbiology Assessment of Environmental Analysis Labeling & Package Insert Pre-approval Inspections (PAI) Lifecycle Knowledge Management Responsible* ATL / IQA Team RBPM ATL / IQA Team DS/DP Reviewer DP Reviewer Process Reviewer Facility Reviewer Bio pharm Reviewer Micro Reviewer EA reviewer DP Reviewer ORA Lead / SMEs participate ATL/ IQA Team * general cases Product Process Facility Facility review is part of the overall quality recommendation Facility assessment should not be considered as having a separate status (as occurred pre-opq) Efficient communication between process & facility reviewers Consultation regarding of PAI request & 483 responses 23

24 Benefits of Integration of Process & Facility Review Process reviewer benefits from taking the associated facility risk (history of recall, OOS results, experience) into consideration while performing process review If a novel/high risk process is identified, process reviewer should evaluate the firm s previous experience in that particular process by communicating with the facility reviewer and looking into the relevant facility evaluation Facility reviewer benefits from better understanding of process risk and saving review time related to evaluation of process risk More focus on performing appropriate risk analysis based on evaluation of the facility record (approved ANDA, EIR, FAR, experience at the process/technology/dosage form) that are relevant to product and process risks OOS: Out Of Specification EIR: Establishment Inspection Report FAR: Field Alert Report 24

25 Integration of Process & Facility Review Role / Task Scientific Content / Initial Risk Assessment Process and Timeline IQA Executive Summary Assessment of Drug Substance / DMF Assessment of Drug Product Assessment of the Manufacturing Process Assessment of Facilities Assessment of Biopharmaceutics Assessment of Microbiology Assessment of Environmental Analysis Labeling & Package Insert Pre-approval Inspections (PAI) Lifecycle Knowledge Management Responsible* ATL / IQA Team RBPM ATL / IQA Team DS/DP Reviewer DP Reviewer Process Reviewer One person Facility Reviewer Bio pharm Reviewer Micro Reviewer EA reviewer DP Reviewer ORA Lead / SMEs participate ATL/ IQA Team * general cases More efficient & effective In-depth understanding of risks associated with both process and facility. Earlier final decision for onsite PAI request Not fully implemented yet Evolving process: Cross-training of Both Reviewers Process/Facility Role Swap Process/Facility Single Reviewer 25

26 Background Office of Pharmaceutical Quality (OPQ) Integrated Quality Assessment (IQA) Office of Process and Facilities (OPF) Integration of Process & Facility Reviews Integration of Review and Facility Inspection Summary Outline 26

Team-based Integrated Quality Assessment Previous Review Process No formal risk assessment process to define scope and extent Discipline reviewers worked in silos and wrote independent assessments

27 Team-based Integrated Quality Assessment Previous Review Process No formal risk assessment process to define scope and extent Discipline reviewers worked in silos and wrote independent assessments Separate review templates for each discipline Rare communications between application reviewers and facility investigators Team-based Integrated Quality Assessment Formal risk assessment of product, process, and facility to enhance efficiency and effectiveness of review and inspection Team of discipline reviewers in constant communication A single collaborative assessment in a consolidated review template Integration of review and inspection for more informed decisions on facility acceptability and application approvability 27

28 Inspections & Application Decisions Application Acceptability by Review? PAI* Needed? * Pre-approval Inspection Is SSI* Needed/ Occurring? * Site Surveillance Inspection PAI decision driven by application specifics Surveillance decision driven by Site Selection Model Application/Facility is acceptable for approval from surveillance perspective - unless facility is classified as OAI A recent positive surveillance inspection (NAI/VAI) does not mean a PAI will not be needed. NAI - No Action Indicated VAI - Voluntary Action Indicated OAI - Official Action Indicated 28

29 Pre-Approval Inspection (PAI) Contributes to FDA s assurance that the manufacturing establishment(s) supporting an application are: Capable of manufacturing a drug Submitted data are accurate & complete Compliance Program Guidance Manual (CPGM) tionsandanswersoncurrentgoodmanufacturingpracticescgmpfordrugs/ucm pdf CPGM establishes Criteria for deciding if a PAI may be needed On-site coverage Guidance for inspection outcome These criteria are distinct and separate from any potential surveillance inspection decision 29

* As found in current CPGM 7346.832 Priority PAI Criteria* Why remove time since last inspection trigger for PAI?

30 * As found in current CPGM Priority PAI Criteria* Why remove time since last inspection trigger for PAI? PAI triggers focus on those aspects most relevant to the specific application under review Surveillance program provides ongoing facility assessment, includes pharmaceutical quality system Time since the last surveillance inspection relevant to the surveillance program and is a risk factor in determining when a surveillance inspection should be conducted 30

PAI Objectives & Outcomes Objective 1: Readiness for Commercial Manufacturing Determine whether the establishment(s) has a quality system that is designed to achieve sufficient control over the

31 PAI Objectives & Outcomes Objective 1: Readiness for Commercial Manufacturing Determine whether the establishment(s) has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operations. Objective 2: Conformance to Application Verify that the formulation, manufacturing or processing methods, and analytical (or examination) methods are consistent with descriptions contained in the CMC section of the application for the biobatch (and other pivotal clinical batches, when applicable), the proposed commercial scale batch, and the API(s). Objective 3: Data Integrity Audit Audit the raw data, hardcopy or electronic, to authenticate the data submitted in the CMC section of the application. Verify that all relevant data (e.g., stability, biobatch data) were submitted in the CMC section such that CDER product reviewers can rely on the submitted data as complete and accurate Lead investigator from ORA will make an initial recommendation at the conclusion of the inspection Recommend Approval Recommend Withholding Approval OPF makes the final recommendation on status of the Facilities 31

PAI Process Workflow Overview Pre-Requisite:

the last surveillance inspection to support an

(E) Inspection Review and Final Recommenda tion

Approval Inspection may be recommended (B)

Inspection/ Field Recommendat ion & Report (C)

32 PAI Process Workflow Overview Pre-Requisite: Sites must be cgmp compliant as indicated by the last surveillance inspection to support an approval recommendation. (E) Inspection Review and Final Recommenda tion (A) Submission Routine Surveillance Post Approval Inspection may be recommended (B) Initial Risk Assessment to support PAI (D) Inspection/ Field Recommendat ion & Report (C) PAI Request communicated along with risks (KTM)* to Field *KTM: Knowledge Transfer Memo 32

33 Integration of Review and Facility Inspection Role / Task Scientific Content / Initial Risk Assessment Process and Timeline IQA Executive Summary Assessment of Drug Substance / DMF Assessment of Drug Product Assessment of the Manufacturing Process Assessment of Facilities Assessment of Biopharmaceutics Assessment of Microbiology Assessment of Environmental Analysis Labeling & Package Insert Pre-approval Inspections (PAI) Lifecycle Knowledge Management Responsible* ATL / IQA Team RBPM ATL / IQA Team DS/DP Reviewer DP Reviewer Process Reviewer Facility Reviewer Bio pharm Reviewer Micro Reviewer EA reviewer DP Reviewer ORA Lead / SMEs participate ATL/ IQA Team * general cases As part of PUDFA & GUDFA commitments, the PAI needs to be complete during the review time frames for NDAs/ANDAs PAI is part of the overall quality assessment and should not be considered as having a separate status (as occurred pre-opq) IQA team members (ORA, OPF, others) share knowledge and participate on PAI PAI findings are fed back into IQA team & OPF makes the final recommendation on status of the facilities listed in a pending original applications and supplements 33

34 Reviewers Participate on PAI Subject Matter Experts (SMEs) conduct application reviews AND participate on PAI In general SMEs are process and/or facility reviewers Reviewer is extremely familiar with the submission (design), and applies that knowledge to inspection (implementation) Better assessment of issues that can affect quality Conformance to Application Commitments & Data Integrity Benefits of integrated review and facility inspection Fully informed risk-based quality decisions Unified voice from PAI and review functions of the IQA team Benefit to review: Reviewer can better understand the implementation of the process and controls, in support of a more comprehensive application assessment Benefit to inspection: ORA investigators can have real-time discussion with a reviewer and immediate access to review team's knowledge and expertise specific to the application 34

Post Approval Audit Inspections (PoAI) Situations Exhibit batch to be significantly scaled up for commercial operation. Limited development data provided.

35 Post Approval Audit Inspections (PoAI) Situations Exhibit batch to be significantly scaled up for commercial operation. Limited development data provided. Firm commits to collect critical test results (e.g. BU for low API loading product) during validation and commercial operation Related Risks Limited assurance of relevance of selected process parameters & controls Limited data on outcomes of results on attributes critical to product quality. Reviewers may participate on post approval audit inspection following approval actions (CPGM ) Focuses include on-site review of: Completed validation activities (PD, PPQ and CPV) Execution against application commitments Confirm intended equipment, operations and controls are consistent with submission; changes if any are being managed under quality oversight and being appropriately reported No significant quality issues impacting product have arisen (e.g. that completed and on-going stability studies are successful) 35

36 Pre-Operational Review/Visit In some circumstances, CDER reviewers and ORA investigator may participate on a Pre-Operational Review/Visit (POR/POV)* POR/POVs provide CDER and ORA an opportunity to visit the manufacturing facility prior to a pre-approval inspection. FDA can evaluate and discuss any manufacturing facility, equipment and process issues Valuable feedback to the manufacturer prior to submission, IQA process and PAI Provides FDA the opportunity to become aware of future manufacturing operations and new technologies Early involvement with new technology will increase efficiency and timely quality evaluation of manufacturing operations & associated facilities * 36

Integrated Examples & Success Stories Joint evaluation of PAI request & 483 responses Facility and/or process reviewers participate on PAI with ORA Investigator

37 Integrated Examples & Success Stories Joint evaluation of PAI request & 483 responses Facility and/or process reviewers participate on PAI with ORA Investigator Single OPF reviewer performs process & facility reviews and patriciates on PAI with ORA investigator OPF/ORA Inspection team with routine briefings with IQA team.. 37

38 Summary Traditionally, facility review and pre-approval inspection (PAI) were separate from manufacturing process review. With the launch of Office of Pharmaceutical Quality (OPQ), facility review and PAI become parts of the holistic quality assessment by using a team-based integrated quality assessment (IQA) approach Facility review considers risks from both a CGMP perspective and a review perspective, incorporating the OPQ review team s findings to ensure a holistic assessment Process review is integrated with facility review to fully evaluate pharmaceutical manufacturing process as well as the facility and its capability to be successfully implemented at a commercial scale Reviewers may participate on PAIs/PoAIs to help assure that the entire control strategy is appropriately implemented to potentially mitigate manufacturing and scale-up risks that may occur after approval 38

39 Acknowledgements Joanne Wang Vidya Pai Derek Smith Sharmista Chatterjee David Doleski Robert Iser 39

40 For general Surveillance inspection inquiries - CDEROSIAB@fda.hhs.gov Additional Questions: CDER-OPQ-Inquiries@fda.hhs.gov 40

Pre-Approval Inspection Program Update

Pre-Approval Inspection Program Update David Doleski Acting Deputy Director, OPF FDA/CDER/OPQ 2015 GPhA CMC Workshop June 10, 2015 1 Objectives of Office of Pharmaceutical Quality (OPQ) A single unit in