FDA Perspective on Process Validation for Biotech Products

1 ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. FDA Perspective on Process Validation for Biotech Products Zhihao Peter Qiu, Chief, Division of Inspectional Assessment Office of Process and Facilities Office of Pharmaceutical Quality FDA, Center for Drug Evaluation and Research Outline Overview of the 2011 Guidance for Industry Process Validation : General Principles and Practices Regulatory Requirements for specified biological Products submitted under Biologics License Applications (BLAs). An integrated CMC review and inspection for BLAs Overview of pre-license and pre-approval inspections Examples of 483 Observations/Case Studies 2. 1. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. Statutory and Regulatory Requirements for Process Validation Section 501(a)(2)(B) of the Act (21 351(a)(2)(B)). A drug .. shall be deemed to be adulterated .. if .. the methods .. used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.

2 21 CFR (a): There shall be written procedures for production and Process control designed to assure that the drug Products have the identity, strength, quality, and purity they purport or are represented to possess . 3. Drug Quality Principles Quality, safety, and efficacy are designed or built into the product . Each manufacturing step should be adequately controlled to assure final product meets all quality attributes. Testing of in- Process and final product cannot adequately assure drug quality. 4. 2. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. 2011 Process Validation Guidance For purposes of this guidance, Process Validation is defined as the collection and evaluation of data, from the Process design stage through commercial production, which establishes scientific evidence that a Process is capable of consistently delivering quality product . Process Validation involves a series of activities taking place over the lifecycle of the product and Process .

3 This guidance describes the Process Validation activities in three stages. 5. Three Stages Process Validation Stage 1 Process Design: The commercial Process is defined during this stage based on knowledge gained through development and scale-up activities. Stage 2 Process Qualification: During this stage, the Process design is evaluated to determine if the Process is capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the Process remains in a state of control. 6. 3. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. Stage 1: Process Design Objective: Design a Process suitable for routine commercial manufacturing that can consistently deliver quality product : 1. Building and capturing Process knowledge and understanding, which can include: Early Process development and small scale experiments Development of laboratory or pilot-scale models Design of Experiment (DOE) studies Risk analysis tools Computer simulations 2.

4 Establishing a strategy for Process control, which can include: Process controls to reduce input variability and/or adjust for variability during the manufacturing Process Appropriate in- Process monitoring and operational limits, especially for attributes that are not readily measured or characterized 7. Stage 2: Process Performance Qualification (PPQ). Objective: Evaluate the Process design and determine if it is capable of reproducible commercial manufacture: a. Design of facilities and qualification of equipment and utilities to assure proper facility design and qualification prior to PPQ. b. Process Performance Qualification (PPQ). combines actual facility, utilities, qualified equipment, and trained personnel with the manufacturing Process , control procedures and components to produce commercial batches 8. 4. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. Stage 3 - Continued Process Verification Objective: Provide continual assurance that the Process remains in a validated state for commercial manufacturing.

5 Some related activities: System in place to detect and characterize variability, and determine root cause Monitoring, assessing, and adjusting variability as needed Gathering data to improve/optimize manufacturing Process Facility and equipment maintenance 9. PPQ: NDA/ANDA vs BLA. NDA/ANDA: PPQ must be successfully completed before commercial distribution of a drug product Facilities must be ready for inspection at the time of submission BLA: Complete commercial scale PPQ studies prior to submission submit PPQ data in an application Facilities must be ready for inspection at the time of submission and manufacture the complete product during PLI/PAI within the review cycle 10. 5. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. What is a Biological product ? Section 351 PHS Act, as amended by FDAMA. Biological product a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product , or analogous product , applicable to the prevention, treatment, or cure of a disease or condition of human beings.

6 *Biological Products are regulated by CBER and CDER. 11. What is a specified biological product ? Specified (definition from 21 CFR ): Therapeutic recombinant DNA-derived Products Monoclonal antibody Products for in vivo use Therapeutic synthetic peptide Products of 40 amino acids or less Therapeutic DNA plasmid Products Specified biological Products are regulated by CDER. Include biosimilar Products regulated under BsUFA. 12. 6. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. Unique Requirements for BLAs product and facility must meet standards prior to license issuance (21. CFR ). Complete commercial scale Process Validation studies and submit data in an application (2011 PV Guidance). Facility ready for inspection and is manufacturing the BLA. product Provide production schedules for the complete product 2-4 months after the submission No Type II DMFs for DS sites Note: BLA combination Products are regulated under 21 CFR 600s, 210/211, and 820.

7 13. Integration of Functions for Biotech Products CMC review and inspection responsibilities are shared between Office of Biotechnology Products (OBP) and Office of Process and Facilities (OPF). A team approach to review and inspection Enables a continuous Process in regulatory review and inspection Allows for a better assessment of the firm's Process understanding and quality oversight 14. 7. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. Integrated Review and Inspection Office of Biotech Products (OBP). Leads in the overall assessment for product quality: Approves manufacturing Process and final specifications (except microbiology). Active participants on inspections product specific elements, data verification, conformance to standards and commitments in the BLA or supplement Office of Process and Facilities (OPF). Leads in the overall assessment for CGMP compliance Leads the pre-license inspection team Responsible for evaluating CGMP compliance status of a firm and conformance and commitments in the BLA or supplement Leads in microbiology and facilities assessments of drug substance and drug product sections of applications and supplements Assess cross contamination controls 15.

8 Process Validation for Biotech Products Data for commercial scale PPQ batches Equipment cleaning Validation Columns and membrane lifetime Validation Sterilization Validation In- Process hold time Validation Media fill for aseptic processing Filter Validation Shipping Validation Test method Validation 16. 8. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. Assessment of Manufacturing Facility during a Pre-License Inspection 17. Inspection Types Pre-License Inspection (PLI) - announced, generally required for approval of an original BLA. DS and DP Manufacturing and critical testing sites are subject to inspection by CDER. Other associated establishments listed in the BLA are covered by ORA investigators Pre-Approval Inspection (PAI) announced, could be waived Triggered by major changes as described in Prior Approval Supplements involving changes that have a substantial potential to have an adverse effect on the identity, strength, quality and purity or potency of the product (21 CFR ).

9 Surveillance and Post-Approval Inspection announced or unannounced ORA with CDER product reviewer participation For Cause Inspection 18. 9. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. Purposes of Pre-License/Pre-approval Inspections To meet statutory obligation in the FD&C and PHS Acts To assess compliance with CGMPs and applicable sections of the 21 CFR 600, 21 CFR 210 and 211, and 21 CFR 820, if applicable To verify compliance with commitments made in the BLA or Supplement Evaluate Process consistency for safe, pure and potent Products 19. Regulatory Authority 21 CFR Inspectors Inspections by an officer of the FDA with special knowledge of the manufacturing methods and controls 21 CFR Time of Inspection Inspection conducted while the establishment is in operation and is manufacturing the complete product for which a biologics license is desired 21 CFR Biologics licenses; issuance and conditions product examination - compliance with requirements Availability of product for examination and inspection during all phases of manufacture Inspection - compliance with requirements (establishment).

10 One biologics license to cover all locations; each location subject to inspection by FDA. Note: FDA enforces laws enacted by Congress and issues regulations as authorized by Congress to implement its statutory authority. The regulations can create binding obligations and have the force of law. 20. 10. ISPE Process Validation Conference 12 14 September 2017. Bethesda, MD. Objectives of Pre-Approval Inspection Program Compliance Program Readiness for Commercial Manufacturing Verify that the applicant has demonstrated ability to operate with integrity and in compliance with CGMPs Conformance to Application Assure adherence to application commitments Data Integrity Audit Assure the authenticity and accuracy of data submitted in applications 21. Assessment of PV during PLIs Stage 2. Design and qualification of facilities, equipment and utilities Conduct facility walkthrough Verify data for equipment qualification and PM. Verify monitoring data for facilities and utilities Process Performance Qualification (PPQ).