Bruce Ross, M.A. M.P.H.
Director, India Office
FDA Foreign Priorities,
Inspections and
Compliance
Agenda
• Priorities
• Challenges of globalization
• cGMP deficiencies
• Comparison
• Post inspection regulatory actions
2
FDA Strategic Priorities
2011-2015
 Advance Regulatory Science: the science of
developing new tools, standards and
approaches to assess the safety and
effectiveness, quality and performance of
FDA-regulated products
 Strengthen the safety and integrity of the
global supply chain
• A paradigm shift is required to meet this
•
•
challenge: focus on prevention of threats
Innovative analytical tools
International capacity building
3
Advancing Regulatory Science
1. Modernize Toxicology
2. Stimulate Innovation in Clinical Evaluations
3. Support New Approaches to Improve
Product Manufacturing and Quality
4. Ensure FDA Readiness to Evaluate
Innovative Emerging Technologies
5. Harness Diverse Data through Information
Sciences
6. Implement a New Prevention-Focused Food
Safety System to Protect Public Health
7. Facilitate Development of Medical
Countermeasures
8. Strengthen Social and Behavioral Science Make Informed Decisions about Regulated
Products
4
Pathway to Global Product
Safety and Quality
 Global economic forces are
having a dramatic effect on
food and drug supply
chains.
 Cross border flows of
goods, information and
capital are increasing much
faster than global GDP.
 U.S. Imports in 2009:
•
•
•
•
•
10-15% of food consumed
30% of drugs by value
80% of API used in US
50% of medical devices
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalReg
ulatoryOperationsandPolicy/GlobalProductPathway/default.htm
Expected annual growth 5-15%
5
Four Pillars of the Strategy
1. Create global coalitions of regulators
2. Build global data-information systems and
networks and proactively share data with
peers
3. Expand intelligence-gathering, with an
increased focus on risk analytics
4. Effectively allocate agency resources based
on risk, and leveraging government,
industry and public and private third parties
6
Globalization Challenges
 Explosion of production of FDA-regulated goods
 Distinction between domestic and imported
products is obsolete
 Supply chain more complex, oversight much more
difficult
 FDA-regulated products originate from more than
150 countries and pass through 300 ports of entry
• 130,000 importers
• 300,000 foreign facilities
 Increase in variety and complexity of imported
medical products
 Growing demand, yet constrained supply
7
Understanding FDA’s
Approach and Expectations
Communicate
Leverage Resources
Establish and use new “tools”
Secure supply chain
Become a global agency
• Stop distinguishing between
foreign and domestic procedures,
policies, and expectations
8
FDA Foreign Offices
London
Brussels
Headquarters
Silver Spring, MD
Mexico City
Beijing
Amman
New Delhi
Mumbai
San Jose
Santiago
Pretoria
9
Shanghai
Guangzhou
Objectives of FDA’s Foreign Offices
 Gain improved knowledge about product manufacturing
and transport to the United States;
 Leverage knowledge and resources and strengthen
capacity to better assure product safety;
 Work with regulated industry so they will better
understand FDA regulations, standards and guidance;
 Coordinate with USG colleagues in-country (e.g.,
USDA/FAS, DOC/CBP, USAID, USTR,) on approaches to
enhance product safety; and
 Increase capacity to perform more timely FDA overseas
inspections, especially of high risk products.
10
FDA’s Enforcement Priorities
 Drug quality in OTCs
 Assure investigations (complaints, rejects)
are prompt and root causes corrected
 Data integrity and quality systems
 Supply chain security
• Contract manufacturers
• Raw material/excipient vendor qualification programs
11
FDA’s Enforcement Priorities
 Combating economically motivated
adulterated products/ingredients
 Field alert reporting (defect reports)
 Contaminated, sub- or super-potent, high-
risk compounded drugs
 Post-market adverse event reporting
12
Major Inspection Types
1. Pre-approval
2. “For-cause” or directed
3. Post-marketing adverse drug event
4. CGMP surveillance (routine)
13
Foreign establishments
routinely inspected
 Manufacturers of drugs, including
• API and dosage form
• human and animal
• biotech, vaccine, etc. (biologicals)
 Re-packagers/re-labelers
 Independent sterilizers
 Independent laboratories
14
FDA’s Inspectorate
 1,700 investigators in our field offices
conducting domestic inspections
 About 400 investigators and 150 analysts
qualified to conduct foreign inspections (all
commodities)
 Dedicated Foreign Cadres
– Drugs
– Foods
– Medical devices
15
FDA Foreign Inspections
since 2008
2500
2000
2217
1500
1422
1000
1220
945
500
0
2008
2009
2010
Fiscal Year
16
2011
FDA’s Foreign Inspection
Accomplishments
1600
1422
1400
1220
1200
933
1000
800
600
400
1006
767
148
845
790
96
132
125
329
153
350
270
354
945
153
259
277
325
687
686
2009
2010
262
287
264
200
213
374
370
342
2004
2005
2006
499
491
2007
2008
0
2003
17
Other
Foods
Devices
Drugs
FDA Foreign Inspections
types & numbers
 Factors which result
in inspections
• Pre-Approval
Submissions
(PEPFAR)
• Routine surveillance
• Follow - up
• Food assessments
• MOUs/international
agreements
• Import issues
• Emergencies
1400
1200
1000
Foods
800
Drugs
Devices
600
Vet
Biologics
400
200
0
2006
18
2008
2011
FDA Foreign GMP Inspections
600
500
400
PAI GMP
300
GMP
200
100
0
2002
2003
2004
2005
2006
2007
19
2008
2009
2010
2011
FDA’s Foreign Inspections
by country, FY 2010
Canada, 94
Germany, 132
Italy, 66
Switzerland, 42
Spain, 40
France, 59
Japan, 71
Others, 66
China, 133
India, 138
20
FY 11 International inspection
obligation per program area
 Drugs – 1249
1400
 Devices - 472
1200
 Foods - 994
1000
 CVM - 88
800
 Biologics - 42
600
400
 TOTAL – 2825*
200
0
21
Drugs
Devices
Foods
CVM
Biologics
India inspections
(FY 2008-2012)
120
100
80
Devices
Drugs
60
BIMO
40
Foods
20
0
2008
2009
2010
2011
22
2012*
* Partial year
Drug Inspections in India
Breakdown by inspection category
160
140
120
100
BIMO
80
3
60
3
40
20
0
1
1
10 18
9
10
42 43
4
0
3 63
52 63 56 59
46
34 33 31
23
GMP
PAI-GMP
FDA inspection process
24
Inspections…
 Are fact finding
 Require evidence
 Require organization
and time management
 Are regulatory
25
Purpose of GMP Audits
 To ensure that adequate quality systems are
maintained.
 To assess compliance with the cGMP’s and
firm’s standard operating procedures.
 To identify problems that can impact
product quality.
 To assure there is a procedure for
investigating non-compliance with the
quality system and for prescribing and
verifying corrective action. The procedures
should include a description of how records
of corrective actions are maintained.
System Based Inspections
GMP Inspections will follow a system based
inspectional approach. The Quality System
will always be covered while coverage of the
other 5 systems will be rotated.
•
•
•
•
•
•
Quality System
Facilities and Equipment System
Materials System
Production System
Laboratory System
Packaging and Labeling System
Product Risk Analysis
Common Elements
• Difficulty associated with manufacturing
process, products with most critical
manufacturing steps (sterile/non-sterile, wet
granulation/dry blends,
suspensions/solutions Hazard identification
• Severity ranking
• Probability ranking (with cause identification)
• Assessment of risk level for each identified
hazard (risk matrix)
Inspection objectives
 Conduct inspection in accordance with FDA law and
regulations
Current Good Manufacturing Practice
 Accomplish what is necessary per established
inspection procedures
(“Compliance Programs”)
 Follow-up on additional questions/ concerns in
inspection assignment
29
CGMP Inspection Programs
(Compliance Program Guidance Manuals)
Pre-approval:

7346.832/7352.832, Pre-Approval Inspections/Investigations
Post-Approval/Surveillance:

7356.002, Drug Process Inspections
 Sterile Drug Process Inspections
 Drug Repackers and relabelers
 Radioactive Drugs
 Compressed Medical Gases
 Active Pharmaceutical Ingredients Process Inspections
 Inspections of Licensed Biological Therapeutic Drug Products
Refer to: http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/default.htm
30
Inspection Participation
 Investigators (inspectors)
 Analysts (lab experts)
 GMP Assessors/Evaluators
 Product Reviewers/Assessors
 Other Specialists
31
Systems-Based Approach
 Quality Systems
 Materials
Management
 Production
 Facilities &
Equipment
 Packaging &
Labeling
 Laboratory Control
32
Conduct of an inspection
 Quality
• Annual Product Reviews
• List of non-conformance reports
• Out-of-specification results
• Complaints
• Rejected/Aborted/Destroyed batches
• Field Alerts (defect reports)
• Corrective actions since previous inspection
33
Conduct of an inspection
 Materials Management
(ingredients & packaging)
• Separation and control of materials
• Identification of materials
• Labeling practices
• Sampling of incoming materials
• Inventory control systems
34
Conduct of an inspection
 Production
• Personnel practices
• Contemporaneous completion of
documents
• Written procedures
• Calibration stickers for critical
equipment
• Condition of equipment
35
Conduct of an inspection
 Facilities & Equipment
• Equipment design
• Heating/Ventilation/Cooling systems
• Water systems
36
Conduct of an inspection
 Packaging and Labeling
• Appropriate controls
• Line clearance procedures
• Visual inspection procedures (sterile products)
• Label issuance and reconciliation documents
37
Conduct of an inspection
 Laboratory control
• Raw data practices
• Sample flow
• Sample/standard identification
• Status of the instruments
• Stability
• Methods in use
38
Conclusion of an inspection
Formal close out
May include:
• Sample collections
• Issuance of FDA 483,
Inspectional Observations
39
FY 2009 cGMP deficiencies
systems cited
Laboratory System
29%
Packaging & Labeling
5%
Production System
10%
Material System
4%
QA System
39%
Facility & Equipment
13%
40
FY 2011 cGMP deficiencies
systems cited
Lababoratory
System
27%
Packaging &
Labeling
5%
Material System
6%
QA System
29%
Production System
24%
Facility &
Equipment
9%
41
Top 10 deficiencies cited
2011 international inspections
 Inadequate Quality Systems
 Lack of investigations of batches that fail to meet
specifications
 Lack of written procedures or inadequate SOPs
 Inadequate laboratory controls
 Un-validated test methods
 Inadequate stability program
 Inadequate process validation or no process validation
 Lack of process controls that validate the performance of
manufacturing process
 Inadequate validation of equipment cleaning and maintenance
cleaning
 Inadequate controls of components, intermediates, and raw
materials
42
cGMP deficiency observations
for international inspections
Packaging & Labeling
Laboratory System
Production System
2011
2009
Material System
Facility & Equipment
QA System
0
10
20
43
30
40
50
FY 2010 cGMP deficiencies
cited in India
Production System
21%
Material System
4%
Packaging & Labeling
1%
Facilities/Equipment
20%
QA Systems
37%
Laboratory System
17%
44
Top 10 deficiencies
cited in 2011 in India
 Inadequate Quality Systems
 Lack of investigations of batches that fail to meet
specifications
 Deficient records and reports
 Inadequate process validation or no process validation
 Lack of process controls that validate the performance of
manufacturing process
 Inadequate laboratory controls
 Inadequate stability program
 Lack of written procedures or inadequate SOPs
 Inadequate controls of components, intermediates, and raw
materials
 Inadequate validation of equipment cleaning and
maintenance cleaning
45
Comparing cGMP deficiencies
(Europe, China & India)
40
37
35
30
29
29
25
25
20
15
10
23
20
24
20
17
13
Europe
China
India
15
7
5
5
7
4
5 5
1
0
QA System Facility & Production
Equipment System
Material
System
46
Laboratory Packaging
System & Labeling
After the inspection
 Write the Establishment Inspection Report (EIR)
• Must be done in a timely manner
 Submit recommendation
 EIR reviewed by GMP product experts
 Final classification of inspection (acceptable,
unacceptable: Warning Letter, Untitled Letter,
Import Alert etc.)
47
Warning and Untitled Letters
drug sites - 2005 to 2010
20
18
16
14
12
10
Warning Letters
Untitled Letters
8
6
4
2
0
2005
2006
2007
2008
48
2009
2010
Source CDER ICB
International Warning Letters
issued 2009 & 2010
49
Global marketplace
Ensuring safe,
effective and
quality foods
and drugs for
the citizens of
India, the
United States
and the world
50
Key Initiatives
1. Set post-inspection deadlines
2. Take responsible steps to speed the
warning letter process
3. Work more closely with FDA’s
regulatory partners.
51
Key Initiatives
4. Swift, appropriate enforcement action
with prioritizing on follow-up.
5. Be prepared to take immediate action
in response to public health risks
6. Develop and implement a formal
warning letter “close-out” process
52
Questions?
NDBoxFDAIndiaOffice@state.gov
Bruce.Ross@fda.hhs.gov
54
Bruce Ross, M.A., M.P.H.
Country Director, India
Bruce.Ross@fda.hhs.gov