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FDA’s Role in Plant FDA’s Role in Plant Design ReviewsDesign Reviews
Erin D. McCaffery, InvestigatorErin D. McCaffery, Investigator
New Jersey District OfficeNew Jersey District Office
May 19, 2009May 19, 2009
OverviewOverview
cGMP RequirementscGMP Requirements cGMP and Pre-approval Coverage of cGMP and Pre-approval Coverage of
Plant DesignPlant Design FMD 135FMD 135 ConsultantsConsultants FDA ResourcesFDA Resources Current Compliance IssuesCurrent Compliance Issues
cGMP RequirementscGMP Requirementsfor Facility Designfor Facility Design
21 CFR 211 subpart C--Buildings and Facilities21 CFR 211 subpart C--Buildings and Facilities 211.42 Design and construction features211.42 Design and construction features 211.44 Lighting211.44 Lighting 211.46 Ventilation, air filtration, air heating and 211.46 Ventilation, air filtration, air heating and
coolingcooling 211.48 Plumbing211.48 Plumbing 211.50 Sewage and refuse211.50 Sewage and refuse 211.52 Washing and toilet facilities211.52 Washing and toilet facilities 211.56 Sanitation211.56 Sanitation 211.58 Maintenance211.58 Maintenance
cGMP Coverage of DesigncGMP Coverage of Design
CPGM 7356.002, Drug Manufacturing Inspections CPGM 7356.002, Drug Manufacturing Inspections http://www.fda.gov/ora/cpgm/7356_002/7356-002FINAL.pdf
Compliance ProgramCompliance Program
Facilities and Equipment SystemsFacilities and Equipment Systems
Facilities Cleaning and maintenance Facility layout and air handling systems for
prevention of cross-contamination (e.g. Penicillin, beta-lactams, steroids, hormones, cytotoxics, etc.)
Specifically designed areas for the manufacturing operations performed by the firm to prevent contamination or mix-ups
Facilities and Equipment SystemsFacilities and Equipment Systems
Facilities General air handling systems Control system for implementing changes in the
building Lighting, potable water, washing and toilet
facilities, sewage and refuse disposal Sanitation of the building, use of rodenticides,
fungicides, insecticides, cleaning and Sanitizing agents
Pre-approval Coverage of DesignPre-approval Coverage of Design
CPGM 7346.832, Pre-approval Inspections/ CPGM 7346.832, Pre-approval Inspections/ Investigations Investigations
http://www.fda.gov/cder/gmp/PAI-7346832.pdfhttp://www.fda.gov/cder/gmp/PAI-7346832.pdf
CP 7346.832, Pre-approval CP 7346.832, Pre-approval Inspections/InvestigationsInspections/Investigations
CP 7346.832, Pre-Approval CP 7346.832, Pre-Approval Inspection/InvestigationsInspection/Investigations
Facility DesignFacility Design
5. Building and Facilities: The addition of any new drug to a production environment must be carefully evaluated as to its impact on other productsimpact on other products already under production and changes that will be necessary to the building and facility. Construction of new walls, installation of new equipment, and other significant changes must be evaluated for their impact on the overall compliance with GMP impact on the overall compliance with GMP requirements. requirements.
Compliance ProgramCompliance Program7346.832, Pre-Approval 7346.832, Pre-Approval Inspection/InvestigationsInspection/Investigations
5. Building and Facilities For example, new products, such as cephalosporins, would require that the firm demonstrate through appropriate separation and controls that cross-contamination can not occur with regard to other products being made in the same facility. Also, facilities that may already be operating at full capacity may not have adequate space for additional products.
Field Management Directive 135Field Management Directive 135Pre-operational Reviews of Pre-operational Reviews of
Manufacturing FacilitiesManufacturing Facilities
Request by industry for “reviewing plans for Request by industry for “reviewing plans for construction of new or modifications of facilities construction of new or modifications of facilities prior to commercial production.”prior to commercial production.”
Does NOT replace existing inspectional activitiesDoes NOT replace existing inspectional activities
Must serve objective of FDA’s overall Must serve objective of FDA’s overall compliance and regulatory policiescompliance and regulatory policies
FMD 135 Review TypesFMD 135 Review Types
Design ReviewDesign Review Pre-construction ReviewPre-construction Review Construction/Equipment Installation and Construction/Equipment Installation and
Qualification ReviewQualification Review Pre-Production ReviewPre-Production Review
FMD 135 Review TypesFMD 135 Review Types
Design ReviewDesign Review Conceptual drawingsConceptual drawings Proposed plant layoutsProposed plant layouts Flow diagrams for facilityFlow diagrams for facility Critical systems and areas Critical systems and areas
FMD 135 Review TypesFMD 135 Review Types
Pre-construction reviewPre-construction review Plan, elevation and isometric drawings for all Plan, elevation and isometric drawings for all
manufacturing areas and utility and process manufacturing areas and utility and process systems for the plant i.e.systems for the plant i.e.• drainage and water systemsdrainage and water systems• HVACHVAC• Equipment, layout and piping in manufacturing and Equipment, layout and piping in manufacturing and
lab areaslab areas
FMD 135 Review TypesFMD 135 Review Types
Construction/Equipment Installation and Construction/Equipment Installation and Qualification ReviewQualification Review On-site review of specific portions of the plant while On-site review of specific portions of the plant while
construction is in progressconstruction is in progress• Piping systemsPiping systems• Methods of constructionMethods of construction• Reviewed before they are concealedReviewed before they are concealed• May be done in phases at District discretionMay be done in phases at District discretion• Depth/frequency variesDepth/frequency varies
FMD 135 Review TypesFMD 135 Review Types
Pre-Production ReviewPre-Production Review
““At the pre-production stage, the review At the pre-production stage, the review will normally be an inspection and should will normally be an inspection and should follow the guidance in the applicable follow the guidance in the applicable Compliance Program and the IOM.”Compliance Program and the IOM.”
FMD 135 Review TypesFMD 135 Review Types
Pre-Production ReviewPre-Production Review Follow CPGM 7346.832 for a new productFollow CPGM 7346.832 for a new product AND follow CPGM 7356.002 if other approved AND follow CPGM 7356.002 if other approved
products/processes exist at the siteproducts/processes exist at the site
What to expect on a Pre-opWhat to expect on a Pre-op
No FDA 482, Notice of InspectionNo FDA 482, Notice of Inspection No Establishment Inspection Report (EIR)No Establishment Inspection Report (EIR) No FDA 483, Inspectional Observations!!!!No FDA 483, Inspectional Observations!!!! Candid dialogue regarding potential issues Candid dialogue regarding potential issues
(“Red Flags”)(“Red Flags”) Questions regarding the design strategy Questions regarding the design strategy Discussions of risk if other products Discussions of risk if other products
already existalready exist
What to expect on a Pre-opWhat to expect on a Pre-op
All facility diagrams, site plans, personnel All facility diagrams, site plans, personnel flow diagrams, etc. will be required well in flow diagrams, etc. will be required well in advance of the meeting or on-siteadvance of the meeting or on-site
Pre-op reviews do NOT guarantee Pre-op reviews do NOT guarantee compliancecompliance
Less than 50 have been requested and Less than 50 have been requested and conducted in New Jersey District since conducted in New Jersey District since 19971997
Bubble DiagramsBubble Diagrams(reproduced with permission from BTEC compliments of ISPE)(reproduced with permission from BTEC compliments of ISPE)
Block Flow Diagram of a Block Flow Diagram of a Biomanufacturing FacilityBiomanufacturing Facility
(Reproduced with permission from BTEC compliments of ISPE)(Reproduced with permission from BTEC compliments of ISPE)
Quality Systems Approach to Quality Systems Approach to Pharmaceutical cGMP Regulations Pharmaceutical cGMP Regulations B. Quality by Design and Product DevelopmentB. Quality by Design and Product Development
Quality by designQuality by design means designing and developing a means designing and developing a product and associated manufacturing processes that product and associated manufacturing processes that will be used during product development to ensure that will be used during product development to ensure that the product consistently attains a predefined quality at the product consistently attains a predefined quality at the end of the manufacturing process. the end of the manufacturing process. 5. Quality by Quality by design, in conjunction with a quality system, provides a design, in conjunction with a quality system, provides a sound framework for the transfer of product knowledge sound framework for the transfer of product knowledge and process understanding from drug development to and process understanding from drug development to the commercial manufacturing processes and for post-the commercial manufacturing processes and for post-development changes and optimization. The CGMP development changes and optimization. The CGMP regulations, when viewed in their entirety, incorporate regulations, when viewed in their entirety, incorporate the concept of quality by design. This guidance the concept of quality by design. This guidance describes how these elements fit together.describes how these elements fit together.
QbD Design Review QbD Design Review
Pre-op can be requested Pre-op can be requested Pre-approval CPGM 7346.832Pre-approval CPGM 7346.832 Anticipated that greater process Anticipated that greater process
knowledge may lead to greater design knowledge may lead to greater design considerationsconsiderations
ConsultantsConsultants
FDA’s Role as a Regulatory AuthorityFDA’s Role as a Regulatory Authority Consultants can provide:Consultants can provide:
Meaningful reviewsMeaningful reviews Bring broader experience to a siteBring broader experience to a site Provide objective evaluationsProvide objective evaluations
ConsultantsConsultants
Decisions made by consultants still require Decisions made by consultants still require Quality Unit review and approval if cGMP Quality Unit review and approval if cGMP relevantrelevant
Qualifications should be deemed adequate Qualifications should be deemed adequate prior to hiringprior to hiring
Work should be routinely evaluated by Work should be routinely evaluated by management to assure it meets needsmanagement to assure it meets needs
Pre-op Review Request in NJPre-op Review Request in NJ
U.S. Food and Drug AdministrationU.S. Food and Drug Administration
New Jersey District OfficeNew Jersey District Office
ATTN: Mimi Roa Remache, ADDATTN: Mimi Roa Remache, ADD
10 Waterview Blvd.10 Waterview Blvd.
Parsippany, NJ 07054Parsippany, NJ 07054
Pre-op Review RequestPre-op Review Requestin Another District or Outside U.S. with U.S. in Another District or Outside U.S. with U.S.
Corporate HeadquartersCorporate Headquarters
U.S. Food and Drug AdministrationU.S. Food and Drug Administration
District Office Mailing addressDistrict Office Mailing address
Re: Pre-op Review RequestRe: Pre-op Review Request
Pre-op Review RequestPre-op Review RequestOutside the U.S.Outside the U.S.
U.S. Food and Drug AdministrationU.S. Food and Drug AdministrationOffice of Compliance Office of Compliance
Drug Manufacturing and Product QualityDrug Manufacturing and Product QualityBldg. 51Bldg. 51
10903 New Hampshire Avenue10903 New Hampshire AvenueSilver Spring, MD 20993Silver Spring, MD 20993
RE: Pre-op Review RequestRE: Pre-op Review Request
