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
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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_002/7356002FINAL.pdf
Compliance Program
Facilities 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 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 Design
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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
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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
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Request by industry for “reviewing plans for
construction of new or modifications of facilities
prior to commercial production.”
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Does NOT replace existing inspectional activities
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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
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Review
Conceptual drawings
Proposed plant layouts
Flow diagrams for facility
Critical systems and areas
FMD 135 Review Types
 Pre-construction
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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
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On-site review of specific portions of the plant while
construction is in progress
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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
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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
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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 postdevelopment 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:
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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
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