1. FDA’s Role in Plant Design Reviews
Erin D. McCaffery, Investigator
New Jersey District Office
May 19, 2009

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

3. cGMP Requirements for Facility Design
21 CFR 211 subpart C--Buildings and Facilities
Design and construction features
Lighting
Ventilation, air filtration, air heating and cooling
Plumbing
Sewage and refuse
Washing and toilet facilities
Sanitation
Maintenance

4. cGMP Coverage of Design
CPGM , Drug Manufacturing Inspections

5. Compliance Program

6. 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

7. 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

8. Pre-approval Coverage of Design
CPGM , Pre-approval Inspections/ Investigations

9. CP 7346.832, Pre-approval Inspections/Investigations

10. 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.

11. 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.

12. 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

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

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

15. 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

16. 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

17. 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.”

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

19. 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

20. 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

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

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

25. 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.

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

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

28. 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

29. 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

30. 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

31. 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
RE: Pre-op Review Request