FDA’s Role in Plant Design Reviews Erin D. McCaffery, Investigator New Jersey District Office erin.mccaffery@fda.hhs.gov May 19, 2009

Overview cGMP Requirements cGMP and Pre-approval Coverage of Plant Design FMD 135 Consultants FDA Resources Current Compliance Issues

cGMP Requirements for Facility Design 21 CFR 211 subpart C--Buildings and Facilities 211.42 Design and construction features 211.44 Lighting 211.46 Ventilation, air filtration, air heating and cooling 211.48 Plumbing 211.50 Sewage and refuse 211.52 Washing and toilet facilities 211.56 Sanitation 211.58 Maintenance

cGMP Coverage of Design CPGM 7356.002, Drug Manufacturing Inspections http://www.fda.gov/ora/cpgm/7356_002/7356-002FINAL.pdf

Compliance Program

Facilities and Equipment Systems 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 Systems 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 Design CPGM 7346.832, Pre-approval Inspections/ Investigations http://www.fda.gov/cder/gmp/PAI-7346832.pdf

CP 7346.832, Pre-approval Inspections/Investigations

CP 7346.832, Pre-Approval Inspection/Investigations Facility 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 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 requirements.

Compliance Program 7346.832, Pre-Approval Inspection/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 135 Pre-operational Reviews of Manufacturing Facilities Request by industry for “reviewing plans for construction of new or modifications of facilities prior to commercial production.” Does NOT replace existing inspectional activities Must serve objective of FDA’s overall compliance and regulatory policies

FMD 135 Review Types Design Review Pre-construction Review Construction/Equipment Installation and Qualification Review Pre-Production Review

FMD 135 Review Types Design Review Conceptual drawings Proposed plant layouts Flow diagrams for facility Critical systems and areas

FMD 135 Review Types Pre-construction review Plan, elevation and isometric drawings for all manufacturing areas and utility and process systems for the plant i.e. drainage and water systems HVAC Equipment, layout and piping in manufacturing and lab areas

FMD 135 Review Types Construction/Equipment Installation and Qualification Review On-site review of specific portions of the plant while construction is in progress Piping systems Methods of construction Reviewed before they are concealed May be done in phases at District discretion Depth/frequency varies

FMD 135 Review Types Pre-Production Review “At the pre-production stage, the review will normally be an inspection and should follow the guidance in the applicable Compliance Program and the IOM.”

FMD 135 Review Types Pre-Production Review Follow CPGM 7346.832 for a new product AND follow CPGM 7356.002 if other approved products/processes exist at the site

What to expect on a Pre-op No FDA 482, Notice of Inspection No Establishment Inspection Report (EIR) No FDA 483, Inspectional Observations!!!! Candid dialogue regarding potential issues (“Red Flags”) Questions regarding the design strategy Discussions of risk if other products already exist

What to expect on a Pre-op All facility diagrams, site plans, personnel flow diagrams, etc. will be required well in advance of the meeting or on-site Pre-op reviews do NOT guarantee compliance Less than 50 have been requested and conducted in New Jersey District since 1997

Bubble Diagrams (reproduced with permission from BTEC compliments of ISPE)

Block Flow Diagram of a Biomanufacturing Facility (Reproduced with permission from BTEC compliments of ISPE)

Quality Systems Approach to Pharmaceutical cGMP Regulations B.        Quality by Design and Product Development Quality by design means designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process. 5.   Quality by design, in conjunction with a quality system, provides a sound framework for the transfer of product knowledge and process understanding from drug development to the commercial manufacturing processes and for post-development changes and optimization.  The CGMP regulations, when viewed in their entirety, incorporate the concept of quality by design.  This guidance describes how these elements fit together.

QbD Design Review Pre-op can be requested Pre-approval CPGM 7346.832 Anticipated that greater process knowledge may lead to greater design considerations

Consultants FDA’s Role as a Regulatory Authority Consultants can provide: Meaningful reviews Bring broader experience to a site Provide objective evaluations

Consultants Decisions made by consultants still require Quality Unit review and approval if cGMP relevant Qualifications should be deemed adequate prior to hiring Work should be routinely evaluated by management to assure it meets needs

Pre-op Review Request in NJ U.S. Food and Drug Administration New Jersey District Office ATTN: Mimi Roa Remache, ADD 10 Waterview Blvd. Parsippany, NJ 07054

U.S. Food and Drug Administration District Office Mailing address Pre-op Review Request in Another District or Outside U.S. with U.S. Corporate Headquarters U.S. Food and Drug Administration District Office Mailing address Re: Pre-op Review Request

Pre-op Review Request Outside the U.S. U.S. Food and Drug Administration Office of Compliance Drug Manufacturing and Product Quality Bldg. 51 10903 New Hampshire Avenue Silver Spring, MD 20993 RE: Pre-op Review Request