The Extra Work that goes into
Building a Manufacturing Facility
when it is FDA-Regulated
Jorge Ferreira
Director of Aseptic Processing and
Fill/ Finish Technologies
Our Questions…
Extra Work???…
what extra
work?…
“The Extra Work that goes into
Building a Manufacturing Facility
when it is FDA-Regulated…”
Who is
this?…
Boston PDA ASQ 042005
Why do they
regulate
facilities?…
2
How do they
regulate
facilities?…
©2005
1
U. S. Food and Drug Administration
Excerpt from the FDA Mission Statement…
“…the FDA is responsible for
protecting the public health
by assuring the safety,
efficacy, and security of
human and veterinary drugs,
biological product, medical
devices…”
emphasis added…
Who is
the FDA?
3
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U. S. Food and Drug Administration
Some little known FDA factoids…
‹
FDA monitors the manufacture, import, transport, storage,
and sale of about $1 trillion worth of products annually
‹
FDA regulates more than 150,000 medical products
‹
Regulated products account for 25 cents of every dollar
spent by consumers
‹
9,000 employees/ conduct 16,000 facility visits
‹
Cost to taxpayers less than $0.02 per day per person
For more information go to
www.fda.gov
4
Who is
the FDA?
©2005
2
Historical milestones of the FDA
‹
1862- PRESIDENT LINCOLN appoints a chemist to serve in the
Bureau of Chemistry, the predecessor of the Food and Drug
Administration.
‹
1820- Eleven physicians establish U.S. PHARMACOPEIA, the first
compendium of standard drugs for the United States.
‹
1906- The original FOOD AND DRUGS ACT is passed by Congress
‹
1938- The FEDERAL FOOD, DRUG, AND COSMETIC (FDC) ACT
is passed by Congress
‹
1949- FDA publishes GUIDANCE TO INDUSTRY for the first time.
Who is
the FDA?
5
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FDA Regulation
The purpose of FDA regulation…
‹
Safety- ensure products are safe to
use…
• Product Review and Approvals
• Products are monitored for continued
safety after they are in use
‹
Efficacy- ensure products work in the
manner they claim…
• Accurate labels and product information
• Demonstrated effectiveness
‹
FDA evaluates “Benefit vs. Risk”
6
Why do they
regulate
facilities?…
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3
FDA Regulation
Compliance is not optional…
‹
Federal Regulation
‹
All products (prescription and over-the-counter) that
are available for use in the U.S. must be produced
according to the FDA's cGMP regulations.
cGMP Regulations
‹
“current Good Manufacturing Practice”
‹
Dynamic set of requirements intended to protect product:
• Identity
Why do they
regulate
facilities?…
• Strength
• Quality
• Purity
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FDA Regulation
How are FDA regulations enforced…
‹
Federal Regulations establish cGMPs…
• To ensure Product Quality
• To ensure Consistent Production
‹
FDA enforces cGMPs…
• Inspection
• Enforcement
How do they
regulate
facilities?…
For more information go to
www.fda.gov/ora
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4
FDA Regulation
Code of Federal Regulations
Title 21- Food and Drugs- Parts 1 to 1405
Regulations applicable to the pharmaceutical
industry:
• 21 CFR Parts 210 and 211- Human Pharmaceutical Products and
Veterinary Products
• 21 CFR Part 600 and 620- Biologically Derived Products
• 21 CFR Part 820- Quality System Regulation for Medical Devices
• 21 CFR Part 11- Electronic Records
What regulations
does the FDA
enforce?…
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Quality Control
cGMP Regulations establish Quality Control
requirements for all operations including:
‹ Approval and rejection of product
‹
Audits
How do we establish Quality?
‹
‹
PDA/ ISPE- Validation
ASQ- Quality Audit
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5
Quality Control
ValidationEstablishing documented evidence which
provides a high degree of assurance that a
specific process will consistently produce
a product which meets it’s pre-determined
specifications and quality attributes.
ISPE Definition…
For more information go to
www.ispe.org
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Quality Control
Quality AuditA quality audit is a systematic, independent
inspection and examination of a process or
quality system to ensure compliance to
requirements.
ASQ Definition…
For more information go to
www.asq.org
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FDA Inspection/ Enforcement
GMP Compliance requires documented evidence…
‹
Must demonstrate that all operations comply with requirements and
specifications…
• Product
• Process
• Facility
‹
Quality Control- ensure products are produced in a manner that
demonstrates that they meet all requirements
• Maintain “state of control”
• Maintain “unadulterated” status…
‹
This “quality effort” is unique to FDA regulated facilities
• Hence, the “Extra Work”…
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GMP Compliance - Extra Work…
A great deal of “Extra Work” can be required
throughout the life of a project…
‹
‹
‹
‹
‹
Design and Engineering
Construction
Commissioning
Validation
Operation
The goal is GMP Compliance…
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WFI
CS
CA
Design and Engineering Phase…
A
A
CIPS
GMP Compliance - Extra Work…
A
A
CA
A
A A A A A A
A
Filter
CA
Filter
Filter
Filter
Filter
GMP Design Reviews
CA
500/1000 L
Fixed
Formulation
Tank
250/500 L
Portable
Formulation
Hold
Tank
AA
A
A
A
A A
A
A
TE
CIPR/PD
A
A
TE
PD
PD
CS
CA
A
A
PF
A
• Establish design criteria to be verified
during Qualification efforts…
• Identify “Direct Impact” Systems/
components to be validated
• FDA Pre-Reviews
‹
Filter
Filter
‹
PR
A
PR
Filter
A
PR
A Filter
250/500 L
Portable
Formulation
Hold
Tank
A
PF
PF
PF
A A
PF
PF
A
PD
PF
TE
Vendor Data Requirements
• Establish documentation requirements
up front which will support downstream
efforts…
‹
User Requirement Specifications
• Establish documentation of project
specific performance requirements
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GMP Compliance - Extra Work…
Construction Phase…
‹
cGMP Training for Trades/ Craft workers
• Training records
‹
Construction Quality
• Weld Records
• Witnessing and documentation of test results
• Engineering Turn-over Packages
‹
Clean Construction Techniques
• Ductwork
• Piping
• Installation Sequence for Facility and Equipment
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GMP Compliance - Extra Work…
Commissioning and Start-up Phase…
‹
Integrated C & Q Approach
• Record of commissioning activities become part of
qualification record
• Need to be properly documented
‹
Testing and Documentation
• Capacity
‹
Cleaning and Passivation
• Clean Piping
‹
Testing and Balancing
• HVAC Systems
‹
Start-up Sequence
• Major Utilities/ Clean Utilities/ Equipment
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GMP Compliance - Extra Work…
Validation Phase…
‹
Installation/ Operational Qualification
• P+ID system walk-down
• Loop Checks
• Temperature Mapping
FAT/ SAT
‹ Performance Qualification
‹
• Environmental Monitoring
• HEPA Filter Aerosol Challenge (DOP)
• Clean Utility USP Testing
‹
Process Validation
• Product testing
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GMP Compliance - Extra Work…
Operation Phase…
‹
cGMP Training for Production Personnel
• Training Records
‹
Batch Records
•
•
•
•
•
‹
Documentation of each significant production step
Equipment used
Samples
Label Control
Other requirements
QC Release
• In-process testing
• QC Release
• Other requirements
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Future Trends in Regulation…
Pharmaceutical cGMPs for 21st CenturyA Risk Based Approach
‹
FDA Strategic Initiative currently underway
• Science-based, efficient risk management
• Existing GMPs have not been updated in 25 years…
‹
Final Report issued September 2004
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Answers…
GMP Compliance is…
not “Extra Work”…
‹ It is a mandatory level of Quality…
‹ A diligent response to industry
requirements to do our part to help ensure
public health and safety; which impacts:
‹
•
•
•
•
Design
Construction
Qualification
Operation
Did we get
our
Answers?…
©2005
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START Transition
Coordination
Basic Engineering
(By Others)
Project Approach
Washington Group Team Integration Plan
O
M
Q
OE
O
M
Q
D
P
C
S
D
P
C
S
V
CP
OP
I
V
CP
OP
I
• P&IDs - AFD
• General Arrangements
• Budgetary Vendor Prices
• Budgetary Subcontractor Prices
• Validation Master Plan
• Constructibility
• Design Development
• Construction Execution Plan
- Safety, QC, etc.
• Refined Cost and Schedule (Risk
Analysis) Definition (Value Engineering)
• Permit Preparation/Local Meetings
Procurement
&
Contracting
OE
D
P
C
V
OP
Constructi
on
S
• Long Lead Equipment
• Subcontractors
• Expediting
• Vendor Prints
• Project Controls
• Document Control
a
O
P
M
OE
O
M
Q
OE
O
M
Q
B
F
D
C
S
D
P
C
S
D
P
C
S
Q
I
V
OP
I
V
OP
I
V
OP
I
a
• Site Mobilization
• Owner/Contractor/Subcontractor Coordinations
• Safety
• Quality Control
• Project Controls
• Turnover/Mechanical Completion
• Labor Relations
• Punchlists
• Document Control
O
Operations
Maintenance
Q
Quality/Regulatory/Control
Monitoring
OS
OP
I
Safety
a
• Pre-Commissioning
• Startup Systems
• Spare Parts
• Vendor Coordination
• Project Controls
• Document Control
a
™
a
• Drawings and Specifications
• P&IDs – AFC
• Equipment Arrangements – AFC
• Tie-In Line Schedule
• Validation Protocols/Integration
• Construction Integration
• Review/Approvals
• Project Controls
• Document Control
• Subcontract Packages
Operatio
ns
Q
Custom
er
O
M
• Staffing
• Fit-Out
• Project Turnover/Transition
• OQ, PQ
• Project Controls
• Document Control
• PRODUCE FLU
VACCINE
PROJECT
SUCCESS
COST INPUTS
B Business
OE Engineering
F Finance
M
a
OE
RESPONSIBILITY LEGEND
OWNER
Field
Execution
Validation
IQ/Commissioni
ng
Detailed Design
OE
CONTRACTOR
D
Design
P
Procurement
C
Construction
S
Commissioning
V
Validation
CP Procurement
CS Safety
Order of Magnitude Estimate
Capital Appropriation
Design Development (WBS)
™
a
Construction
Change Control Audits
PROJECT TEAM
INTEGRATION FLOWCHART
NOVEMBER, 2004
Procurement
Industrialization
11
Questions/ Discussions
‹
Thanks to our Hosts!!!
• New England Chapter of the PDA
• Boston Chapter of the ASQ
‹
Thanks to our Sponsors!!!
• Commissioning Agents, Inc
• Masy Systems, Inc.
• Washington Group International
‹
Thank You for your attention!!!…
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