Current Good Manufacturing Practice: Vaccines Mary Malarkey Director, Office of Compliance and Biologics Quality Center for Biologics Evaluation and Research FDA Science Board; April 15, 2005

Summary:Vaccine CGMP Statutes and regulations Unique challenges with Vaccines Problems observed in the industry Pharmaceutical GMPs for the 21st Century: a Risk-Based Approach Programs already in place at CBER Additional impact of initiative on vaccines Recent Lessons – other initiatives

Statutes Vaccines are biological products as defined in section 351(i) of the Public Health Service Act (PHSA) Vaccines are drugs as defined in section 201(g) of the Federal Food, Drug and Cosmetic Act (FDCA) Vaccines are licensed after submission, review and approval of a biologics license application (BLA) in accordance with section 351(a) of the PHSA Vaccines are licensed biological drugs

Regulations Like other pharmaceutical human drugs: Vaccines are investigated clinically (IND) in accordance with 21 CFR Parts 50 and 312; Preparation of vaccine drug products is held to 21 CFR Parts 210-211, ie the same CGMP Vaccines are also held to the licensing and biologics standards, as applicable, in 21 CFR Parts 600-680

Unique challenges with Vaccines Unlike a substantial number of injectable pharmaceuticals, vaccines are administered to a large population of patients that are most often young and healthy. Starting materials may have inherent bioburden, e.g. egg-based vaccines or may be infectious until inactivated e.g. bacterial vaccines. From beginning to end, the manufacturing process for a vaccine can take several months to a year. In some cases, older products, licensed many years ago.

Unique challenges with Vaccines As with other biological products, vaccines: Must be processed under defined conditions/controls throughout production to consistently produce a safe, pure and potent product and preclude the introduction of environmental contamination Cannot withstand heat sterilization without affecting product quality Must be “aseptically” processed

Unique challenges with Vaccines The defined conditions/controls for vaccines would include but not be limited to, where applicable: Bioburden testing of the product at various points in the manufacturing process. Segregation of pre- and post-inactivation steps and appropriate methods for inactivation testing Cleaning of facilities and equipment using procedures shown to be effective for removal of residual product and bioburden Monitoring of the manufacturing environment to continuously assess conditions

Unique challenges with Vaccines Aseptic processing? Product is filter sterilized at some point during the manufacturing process For vaccines, this may be earlier in the process than many products. Once conjugated to an adjuvant, sterile filtration no longer possible. Subsequent steps must be carefully controlled to avoid introduction of contaminants. All materials that contact the product are sterilized. Careful adherence to aseptic technique/practice by personnel

Problems Observed What problems have we observed in the vaccine industry? Defined conditions/controls not in place throughout the manufacturing process, has resulted in failures at the end of production that cannot be adequately investigated due to lack of data Issues with segregation of pre- and post-inactivation steps Inadequate cleaning procedures that result in cross-contamination

Problems Observed Environmental monitoring data collected but not adequately evaluated or investigated when levels exceeded or same organisms identified in the in-process or final product. Inadequacies in aseptic processing: Validation doesn’t simulate actual manufacturing conditions Poor aseptic technique observed during aseptic operations

Problems Observed Many of these observed problems represent deficiencies in the manufacturer’s Quality Systems. Many of these observed problems are not atypical to the pharmaceutical industry, as a whole. Many of these observed problems were discussed at length and assessed under the GMP Initiative.

What do we mean by Quality Systems? Key points: Management involvement and responsibility at all levels Adequate systems for identifying and correcting problems to prevent recurrence and proactively identifying trends to prevent problems for occurring

Pharmaceutical CGMP for the 21st Century: A Risk-Based Approach CBER membership on the CGMP Steering Committee and working groups established under the initiative A risk and science-based approach to CGMP Many working group charges already in place for CBER regulated biological drug products, including vaccines CBER membership on the Council on Pharmaceutical Quality, the body charged with implementation of the working group products

Programs in Place: Prior to Approval What was already in place at CBER? Integrated review and inspection process Biologics License Application review committee consists of members from the Office of Vaccines Research and Review, the Division of Manufacturing and Product Quality, OCBQ, the Office of Biostatistics and Epidemiology, and other CBER components The same components participate in pre-IND, IND, pre-BLA and, as necessary, BLA meetings with sponsors. Provide advice and guidance on all aspects, including facility design and CGMP compliance

Programs in Place: Prior to Approval Pre-license inspection conducted by review committee: DMPQ lead inspector – covers facilities and CGMP Product reviewer(s)/scientist(s) participate ORA invited to participate Resolution of issues prior to approval Same paradigm for pre-approval inspections for significant changes to the application (21 CFR 601.12) e.g. new or renovated facility

Programs in Place: Post Approval Team Biologics Program – established 1997 and began vaccine inspections in 1999 Highly specialized team of ORA investigators Product specialist participation in inspections extremely important for complex vaccine manufacturing processes Improvements being made to program based on evaluation, e.g. Implementation of a Quality Management System to ensure continuous feedback Regular communications between investigators and product specialists; continuous training.

Programs in Place: Post-Approval All Team Biologics findings are reviewed at CBER. If action is recommended by Team Biologics, a complete evidentiary and scientific review is undertaken at CBER and, if CBER concurs, sent to the Office of General Counsel for review and concurrence.

Impact of the Initiative on Vaccines GMP Steering Committee recognized issues related to Quality Systems, in addition to other issues, and working groups were formed to address Several working group products directly impact the vaccine industry

Guidance to Industry Issuance of Final Guidance on Sterile Drug Products Produced by Aseptic Processing; September 2004. Includes recommendations on aseptic processing that begins earlier in the process, such as the case with vaccines. Issuance of Draft Guidance for Industry on Quality System Approaches to Pharmaceutical CGMP; September 2004. Provides the agency’s current thinking on Quality System principles Comments to the docket under review by the working group.

GMP Harmonization Analysis Working Group What was our charge? “..to perform a formal analysis of 21 CFR 210 and 211 against EU GMPs, PIC/S and other GMP regulations across the Agency.” The intent of the analysis was to highlight the differences in these various regulations and report back possible recommendations for modifications to the CGMP regulations.

Working Group Representation CBER CDER CDRH CFSAN CVM OCP ORA

What did we compare? 21 CFR 210 and 211 – Drug GMPs vs. EU GMP 21 CFR 110 –Food GMPs 21 CFR 120 – Juice HACCP 21 CFR 820 – Device GMPs (QSR) 21 CFR 226 – Type A Medicated Articles (CVM)

What did we conclude? More similarities than differences between the various regulations Differences often commodity related, e.g. sanitation and personnel practices for foods Presented to GMP Steering Committee; June 25, 2004.

What are the next steps? Modifications to Parts 210/211 will be undertaken using an incremental approach Continued pursuit of International Harmonization through ICH and PIC/S

What are the goals of the modifications? to encourage timely detection and response to emerging defects or indications that product quality has been compromised to provide further clarity and modernize the regulations to harmonize various aspects of parts 210 and 211 both internationally and with other Agency regulations. 

Harmonization In September 2004, FDA announced it will apply to Pharmaceutical Inspection Cooperation Scheme (PIC/S) Membership consists of inspectors/investigators from countries around the world Opportunity to discuss approaches, obtain information, and harmonize, where possible. CBER has been active in this area with respect to blood and blood products for many years. Seek to expand to vaccines

Recent Lessons: Additional Vaccine Initiatives Biological drug manufacturers, including vaccine manufacturers, have been subject to routine GMP inspections every two years. Starting in FY05, influenza vaccine manufacturers will be inspected annually due to complex issues associated with this product (e.g. “new” product each year) Analysis of other manufacturers being performed to consider increased coverage for other medically necessary products, particularly those produced off-shore

Partnering with Foreign Regulators Chiron experience made clear the need for information sharing with our foreign regulatory counterparts. Had established an agreement with Chiron and the British Medicines and Healthcare Products Regulatory Agency (MHRA) that allowed sharing in that case On February 14, 2005, signed a general, formal confidentiality agreement with MHRA allowing sharing in all cases

Have agreements in place with other regulatory counterparts of countries where vaccines are or may be manufactured for U.S. use (e.g. Health Canada, EMEA) Actively pursuing other agreements to facilitate sharing of information on vaccines.

Outreach to the Vaccine Industry Recognition of the need for increased communication pre- and post- approval Workshop or possible “roundtable” under discussion Sessions on vaccines planned or being planned at several conferences in FY05 and FY06, e.g.: GMP by the Sea in August 2005 European conference on vaccines October 2005

Outreach to Vaccine Industry Meetings with individual vaccine manufacturers: to discuss new technologies and other changes to increase capacity and manufacturing control. to provide advice on potential pathways to approval and facilitate approval of new vaccines, whenever possible.

Conclusion Manufacturers of vaccines are required to follow the CGMP regulations in Parts 210-211, and additional standards in Parts 600-680, as applicable. Vaccines pose a unique challenge to industry and FDA. The agency has issued useful guidance for this industry and is pursuing an incremental approach to modifications to Parts 210-211

Conclusion Our approach to regulation of vaccines has been reviewed and is being modified based on recent lessons Partnering with our foreign regulatory counterparts is key to ensuring communication in this global industry Increased outreach to the vaccine industry to increase communication and facilitate improvements; approvals of new vaccines.