Current Good Manufacturing Practice:Vaccines

Current Good Manufacturing Practice:Vaccines

Mary MalarkeyMary Malarkey

Director, Office of Compliance and Biologics QualityDirector, Office of Compliance and Biologics Quality

Center for Biologics Evaluation and ResearchCenter for Biologics Evaluation and Research

FDA Science Board; April 15, 2005FDA Science Board; April 15, 2005

Summary:Vaccine CGMPSummary:Vaccine CGMP

Statutes and regulationsStatutes and regulations Unique challenges with VaccinesUnique challenges with Vaccines

Problems observed in the industryProblems observed in the industry Pharmaceutical GMPs for the 21Pharmaceutical GMPs for the 21stst Century: Century:

a Risk-Based Approacha Risk-Based Approach Programs already in place at CBERPrograms already in place at CBER Additional impact of initiative on vaccinesAdditional impact of initiative on vaccines

Recent Lessons – other initiativesRecent Lessons – other initiatives

StatutesStatutes

Vaccines are biological products as defined in Vaccines are biological products as defined in section 351(i) of the Public Health Service Act section 351(i) of the Public Health Service Act (PHSA)(PHSA)

Vaccines are drugs as defined in section 201(g) of Vaccines are drugs as defined in section 201(g) of the Federal Food, Drug and Cosmetic Act (FDCA)the Federal Food, Drug and Cosmetic Act (FDCA)

Vaccines are licensed after submission, review Vaccines are licensed after submission, review and approval of a biologics license application and approval of a biologics license application (BLA) in accordance with section 351(a) of the (BLA) in accordance with section 351(a) of the PHSAPHSA

Vaccines are licensed biological drugsVaccines are licensed biological drugs

RegulationsRegulations

Like other pharmaceutical human drugs:Like other pharmaceutical human drugs: Vaccines are investigated clinically (IND) in Vaccines are investigated clinically (IND) in

accordance with 21 CFR Parts 50 and 312;accordance with 21 CFR Parts 50 and 312; Preparation of vaccine drug products is held to Preparation of vaccine drug products is held to

21 CFR Parts 210-211, ie the same CGMP21 CFR Parts 210-211, ie the same CGMP Vaccines are also held to the licensing and Vaccines are also held to the licensing and

biologics standards, as applicable, in 21 biologics standards, as applicable, in 21 CFR Parts 600-680CFR Parts 600-680

Unique challenges with VaccinesUnique challenges with Vaccines

Unlike a substantial number of injectable Unlike a substantial number of injectable pharmaceuticals, vaccines are administered to a large pharmaceuticals, vaccines are administered to a large population of patients that are most often young and population of patients that are most often young and healthy.healthy.

Starting materials may have inherent bioburden, e.g. Starting materials may have inherent bioburden, e.g. egg-based vaccines or may be infectious until egg-based vaccines or may be infectious until inactivated e.g. bacterial vaccines.inactivated e.g. bacterial vaccines.

From beginning to end, the manufacturing process for From beginning to end, the manufacturing process for a vaccine can take several months to a year.a vaccine can take several months to a year.

In some cases, older products, licensed many years In some cases, older products, licensed many years ago. ago.

Unique challenges with VaccinesUnique challenges with Vaccines

As with other biological products, vaccines:As with other biological products, vaccines: Must be processed under defined Must be processed under defined

conditions/controls throughout production to conditions/controls throughout production to consistently produce a safe, pure and potent consistently produce a safe, pure and potent product and preclude the introduction of product and preclude the introduction of environmental contaminationenvironmental contamination

Cannot withstand heat sterilization without Cannot withstand heat sterilization without affecting product qualityaffecting product quality

Must be “aseptically” processedMust be “aseptically” processed

Unique challenges with VaccinesUnique challenges with Vaccines

The defined conditions/controls for vaccines would The defined conditions/controls for vaccines would include but not be limited to, where applicable:include but not be limited to, where applicable: Bioburden testing of the product at various points in the Bioburden testing of the product at various points in the

manufacturing process.manufacturing process. Segregation of pre- and post-inactivation steps and Segregation of pre- and post-inactivation steps and

appropriate methods for inactivation testingappropriate methods for inactivation testing Cleaning of facilities and equipment using procedures Cleaning of facilities and equipment using procedures

shown to be effective for removal of residual product shown to be effective for removal of residual product and bioburdenand bioburden

Monitoring of the manufacturing environment to Monitoring of the manufacturing environment to continuously assess conditionscontinuously assess conditions

Unique challenges with VaccinesUnique challenges with Vaccines

Aseptic processing?Aseptic processing? Product is filter sterilized at some point during the Product is filter sterilized at some point during the

manufacturing process manufacturing process For vaccines, this may be earlier in the process than many For vaccines, this may be earlier in the process than many

products.products. Once conjugated to an adjuvant, sterile filtration no longer Once conjugated to an adjuvant, sterile filtration no longer

possible.possible. Subsequent steps must be carefully controlled to avoid Subsequent steps must be carefully controlled to avoid

introduction of contaminants.introduction of contaminants. All materials that contact the product are sterilized.All materials that contact the product are sterilized. Careful adherence to aseptic technique/practice by Careful adherence to aseptic technique/practice by

personnelpersonnel

Problems ObservedProblems Observed

What problems have we observed in the vaccine What problems have we observed in the vaccine industry?industry? Defined conditions/controls not in place throughout the Defined conditions/controls not in place throughout the

manufacturing process, has resulted in failures at the manufacturing process, has resulted in failures at the end of production that cannot be adequately end of production that cannot be adequately investigated due to lack of datainvestigated due to lack of data

Issues with segregation of pre- and post-inactivation Issues with segregation of pre- and post-inactivation stepssteps

Inadequate cleaning procedures that result in cross-Inadequate cleaning procedures that result in cross-contaminationcontamination

Problems ObservedProblems Observed

Environmental monitoring data collected but Environmental monitoring data collected but not adequately evaluated or investigated when not adequately evaluated or investigated when levels exceeded or same organisms identified in levels exceeded or same organisms identified in the in-process or final product.the in-process or final product.

Inadequacies in aseptic processing:Inadequacies in aseptic processing: Validation doesn’t simulate actual manufacturing Validation doesn’t simulate actual manufacturing

conditionsconditions Poor aseptic technique observed during aseptic Poor aseptic technique observed during aseptic

operationsoperations

Problems ObservedProblems Observed

Many of these observed problems represent Many of these observed problems represent deficiencies in the manufacturer’s deficiencies in the manufacturer’s Quality Quality Systems.Systems.

Many of these observed problems are not atypical Many of these observed problems are not atypical to the pharmaceutical industry, as a whole.to the pharmaceutical industry, as a whole.

Many of these observed problems were discussed Many of these observed problems were discussed at length and assessed under the GMP Initiative.at length and assessed under the GMP Initiative.

What do we mean by Quality Systems?

What do we mean by Quality Systems?

Key points:Key points: Management involvement and responsibility at Management involvement and responsibility at

all levelsall levels Adequate systems for identifying and Adequate systems for identifying and

correcting problems to prevent recurrence and correcting problems to prevent recurrence and proactively identifying trends to prevent proactively identifying trends to prevent problems for occurringproblems for occurring

Pharmaceutical CGMP for the 21st Century: A Risk-Based ApproachPharmaceutical CGMP for the 21st Century: A Risk-Based Approach

CBER membership on the CGMP Steering CBER membership on the CGMP Steering Committee and working groups established under Committee and working groups established under the initiative the initiative

A risk and A risk and sciencescience-based approach to CGMP -based approach to CGMP Many working group charges already in place for Many working group charges already in place for

CBER regulated biological drug products, CBER regulated biological drug products, including vaccinesincluding vaccines

CBER membership on the Council on CBER membership on the Council on Pharmaceutical Quality, the body charged with Pharmaceutical Quality, the body charged with implementation of the working group productsimplementation of the working group products

Programs in Place:Prior to Approval

Programs in Place:Prior to Approval

What was already in place at CBER?What was already in place at CBER? Integrated review and inspection processIntegrated review and inspection process

Biologics License Application review committee Biologics License Application review committee consists of members from the Office of Vaccines consists of members from the Office of Vaccines Research and Review, the Division of Manufacturing Research and Review, the Division of Manufacturing and Product Quality, OCBQ, the Office of Biostatistics and Product Quality, OCBQ, the Office of Biostatistics and Epidemiology, and other CBER componentsand Epidemiology, and other CBER components

The same components participate in pre-IND, IND, pre-The same components participate in pre-IND, IND, pre-BLA and, as necessary, BLA meetings with sponsors. BLA and, as necessary, BLA meetings with sponsors. Provide advice and guidance on all aspects, including Provide advice and guidance on all aspects, including facility design and CGMP compliancefacility design and CGMP compliance

Programs in Place:Prior to Approval

Programs in Place:Prior to Approval

Pre-license inspection conducted by review Pre-license inspection conducted by review committee:committee: DMPQ lead inspector – covers facilities and CGMPDMPQ lead inspector – covers facilities and CGMP Product reviewer(s)/scientist(s) participateProduct reviewer(s)/scientist(s) participate ORA invited to participateORA invited to participate

Resolution of issues prior to approvalResolution of issues prior to approval Same paradigm for pre-approval inspections for Same paradigm for pre-approval inspections for

significant changes to the application (21 CFR significant changes to the application (21 CFR 601.12) e.g. new or renovated facility601.12) e.g. new or renovated facility

Programs in Place:Post Approval

Programs in Place:Post Approval

Team Biologics Program – established 1997 and Team Biologics Program – established 1997 and began vaccine inspections in 1999began vaccine inspections in 1999 Highly specialized team of ORA investigatorsHighly specialized team of ORA investigators Product specialist participation in inspections extremely Product specialist participation in inspections extremely

important for complex vaccine manufacturing processesimportant for complex vaccine manufacturing processes Improvements being made to program based on Improvements being made to program based on

evaluation, e.g.evaluation, e.g. Implementation of a Quality Management System to Implementation of a Quality Management System to

ensure continuous feedbackensure continuous feedback Regular communications between investigators and Regular communications between investigators and

product specialists; continuous training.product specialists; continuous training.

Programs in Place:Post-Approval

Programs in Place:Post-Approval

All Team Biologics findings are reviewed All Team Biologics findings are reviewed at CBER.at CBER.

If action is recommended by Team If action is recommended by Team Biologics, a complete evidentiary and Biologics, a complete evidentiary and scientific review is undertaken at CBER scientific review is undertaken at CBER and, if CBER concurs, sent to the Office of and, if CBER concurs, sent to the Office of General Counsel for review and General Counsel for review and concurrence.concurrence.

Impact of the Initiative on Vaccines

Impact of the Initiative on Vaccines

GMP Steering Committee recognized issues GMP Steering Committee recognized issues related to Quality Systems, in addition to related to Quality Systems, in addition to other issues, and working groups were other issues, and working groups were formed to addressformed to address

Several working group products directly Several working group products directly impact the vaccine industryimpact the vaccine industry

Guidance to IndustryGuidance to Industry

Issuance of Final Guidance on Sterile Drug Products Issuance of Final Guidance on Sterile Drug Products Produced by Aseptic Processing; September 2004.Produced by Aseptic Processing; September 2004.

Includes recommendations on aseptic processing that Includes recommendations on aseptic processing that begins earlier in the process, such as the case with begins earlier in the process, such as the case with vaccines.vaccines.

Issuance of Draft Guidance for Industry on Quality Issuance of Draft Guidance for Industry on Quality System Approaches to Pharmaceutical CGMP; System Approaches to Pharmaceutical CGMP; September 2004. September 2004.

Provides the agency’s current thinking on Quality Provides the agency’s current thinking on Quality System principlesSystem principles

Comments to the docket under review by the working Comments to the docket under review by the working group. group.

GMP Harmonization Analysis Working Group

GMP Harmonization Analysis Working Group

What was our charge?What was our charge? ““..to perform a formal analysis of 21 CFR 210 ..to perform a formal analysis of 21 CFR 210

and 211 against EU GMPs, PIC/S and other and 211 against EU GMPs, PIC/S and other GMP regulations across the Agency.”GMP regulations across the Agency.”

The intent of the analysis was to highlight the The intent of the analysis was to highlight the differences in these various regulations and differences in these various regulations and report back possible recommendations for report back possible recommendations for modifications to the CGMP regulations.modifications to the CGMP regulations.

Working Group RepresentationWorking Group Representation

CBERCBER CDERCDER CDRHCDRH CFSANCFSAN CVMCVM OCPOCP ORAORA

What did we compare?What did we compare?

21 CFR 210 and 211 – Drug GMPs21 CFR 210 and 211 – Drug GMPs

vs.vs. EU GMP EU GMP 21 CFR 110 –Food GMPs21 CFR 110 –Food GMPs 21 CFR 120 – Juice HACCP21 CFR 120 – Juice HACCP 21 CFR 820 – Device GMPs (QSR)21 CFR 820 – Device GMPs (QSR) 21 CFR 226 – Type A Medicated Articles21 CFR 226 – Type A Medicated Articles

(CVM)(CVM)

What did we conclude?What did we conclude?

More similarities than differences between More similarities than differences between the various regulationsthe various regulations

Differences often commodity related, e.g. Differences often commodity related, e.g. sanitation and personnel practices for foodssanitation and personnel practices for foods

Presented to GMP Steering Committee; Presented to GMP Steering Committee; June 25, 2004.June 25, 2004.

What are the next steps?What are the next steps?

Modifications to Parts 210/211 will be Modifications to Parts 210/211 will be undertaken using an incremental approachundertaken using an incremental approach

Continued pursuit of International Continued pursuit of International Harmonization through ICH and PIC/SHarmonization through ICH and PIC/S

What are the goals of the modifications?

What are the goals of the modifications?

to encourage timely detection and response to encourage timely detection and response to emerging defects or indications that to emerging defects or indications that product quality has been compromisedproduct quality has been compromised

to provide further clarity and modernize the to provide further clarity and modernize the regulationsregulations

to harmonize various aspects of parts 210 to harmonize various aspects of parts 210 and 211 both internationally and with other and 211 both internationally and with other Agency regulations.  Agency regulations. 

HarmonizationHarmonization

In September 2004, FDA announced it will apply In September 2004, FDA announced it will apply to Pharmaceutical Inspection Cooperation Scheme to Pharmaceutical Inspection Cooperation Scheme (PIC/S)(PIC/S) Membership consists of inspectors/investigators from Membership consists of inspectors/investigators from

countries around the worldcountries around the world Opportunity to discuss approaches, obtain information, Opportunity to discuss approaches, obtain information,

and harmonize, where possible.and harmonize, where possible. CBER has been active in this area with respect to blood CBER has been active in this area with respect to blood

and blood products for many years.and blood products for many years. Seek to expand to vaccinesSeek to expand to vaccines

Recent Lessons:Additional Vaccine Initiatives

Recent Lessons:Additional Vaccine Initiatives

Biological drug manufacturers, including vaccine Biological drug manufacturers, including vaccine manufacturers, have been subject to routine GMP manufacturers, have been subject to routine GMP inspections every two years.inspections every two years. Starting in FY05, influenza vaccine manufacturers will Starting in FY05, influenza vaccine manufacturers will

be inspected annually due to complex issues associated be inspected annually due to complex issues associated with this product (e.g. “new” product each year)with this product (e.g. “new” product each year)

Analysis of other manufacturers being performed to Analysis of other manufacturers being performed to consider increased coverage for other medically consider increased coverage for other medically necessary products, particularly those produced off-necessary products, particularly those produced off-shoreshore

Partnering with Foreign Regulators

Partnering with Foreign Regulators

Chiron experience made clear the need for Chiron experience made clear the need for information sharing with our foreign regulatory information sharing with our foreign regulatory counterparts.counterparts.

Had established an agreement with Chiron and the Had established an agreement with Chiron and the British Medicines and Healthcare Products British Medicines and Healthcare Products Regulatory Agency (MHRA) that allowed sharing Regulatory Agency (MHRA) that allowed sharing in that casein that case

On February 14, 2005, signed a general, formal On February 14, 2005, signed a general, formal confidentiality agreement with MHRA allowing confidentiality agreement with MHRA allowing sharing in all casessharing in all cases

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

Actively pursuing other agreements to Actively pursuing other agreements to facilitate sharing of information on facilitate sharing of information on vaccines.vaccines.

Outreach to the Vaccine IndustryOutreach to the Vaccine Industry

Recognition of the need for increased Recognition of the need for increased communication pre- and post- approvalcommunication pre- and post- approval

Workshop or possible “roundtable” under Workshop or possible “roundtable” under discussiondiscussion

Sessions on vaccines planned or being planned at Sessions on vaccines planned or being planned at several conferences in FY05 and FY06, e.g.:several conferences in FY05 and FY06, e.g.: GMP by the Sea in August 2005GMP by the Sea in August 2005 European conference on vaccines October 2005European conference on vaccines October 2005

Outreach to Vaccine IndustryOutreach to Vaccine Industry

Meetings with individual vaccine Meetings with individual vaccine manufacturers:manufacturers: to discuss new technologies and other changes to discuss new technologies and other changes

to increase capacity and manufacturing control.to increase capacity and manufacturing control. to provide advice on potential pathways to to provide advice on potential pathways to

approval and facilitate approval of new approval and facilitate approval of new vaccines, whenever possible.vaccines, whenever possible.

ConclusionConclusion

Manufacturers of vaccines are required to follow Manufacturers of vaccines are required to follow the CGMP regulations in Parts 210-211, and the CGMP regulations in Parts 210-211, and additional standards in Parts 600-680, as additional standards in Parts 600-680, as applicable.applicable.

Vaccines pose a unique challenge to industry and Vaccines pose a unique challenge to industry and FDA.FDA.

The agency has issued useful guidance for this The agency has issued useful guidance for this industry and is pursuing an incremental approach industry and is pursuing an incremental approach to modifications to Parts 210-211to modifications to Parts 210-211

ConclusionConclusion

Our approach to regulation of vaccines has been Our approach to regulation of vaccines has been reviewed and is being modified based on recent reviewed and is being modified based on recent lessonslessons

Partnering with our foreign regulatory Partnering with our foreign regulatory counterparts is key to ensuring communication in counterparts is key to ensuring communication in this global industrythis global industry

Increased outreach to the vaccine industry to Increased outreach to the vaccine industry to increase communication and facilitate increase communication and facilitate improvements; approvals of new vaccines.improvements; approvals of new vaccines.