fda foreign priorities, inspections and compliance
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FDA Foreign Priorities, Inspections and Compliance. Bruce Ross , M.A. M.P.H. Director, India Office. Agenda. Priorities Challenges of globalization cGMP deficiencies Comparison Post inspection regulatory actions. - PowerPoint PPT PresentationTRANSCRIPT
FDA Foreign Priorities, Inspections
and ComplianceBruce Ross, M.A. M.P.H.
Director, India Office
Agenda
• Priorities
• Challenges of globalization
• cGMP deficiencies
• Comparison
• Post inspection regulatory actions
2
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
FDA Strategic Priorities 2011-2015
3
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
Advancing Regulatory Science
4
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
• Expected annual growth 5-15%
Pathway to Global Product Safety and Quality
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/GlobalProductPathway/default.htm
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 supply7
Understanding FDA’s Approach and Expectations
CommunicateLeverage ResourcesEstablish and use new “tools”Secure supply chainBecome a global agency
• Stop distinguishing between foreign and domestic procedures, policies, and expectations
8
FDA Foreign Offices
PretoriaSantiago
San Jose
Mexico City
HeadquartersSilver Spring, MD
London
Brussels
AmmanNew Delhi
MumbaiGuangzhou
Shanghai
Beijing
9
10
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.
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
16
9451220
1422
2217
0
500
1000
1500
2000
2500
2008 2009 2010 2011Fiscal Year
FDA Foreign Inspections
since 2008
135%
FDA’s Foreign Inspection
Accomplishments
2003 2004 2005 2006 2007 2008 2009 20100
200
400
600
800
1000
1200
1400
1600
259374 370 342
499 491687 686
264
350270 287
329 262
277 325
148
153132 125
96153
213
354
OtherFoodsDevicesDrugs
1422
1220
9451006
790845933
767
17
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 2006 2007 2008 2009 2011
0
200
400
600
800
1000
1200
1400
Foods
Drugs
Devices
Vet
Biologics
Drugs
- 63 %
Food
s - 8
4%
18
19
FDA Foreign GMP Inspections
2002 2003 2004 2005 2006 2007 2008 2009 2010 20110
100
200
300
400
500
600
PAI GMPGMP
FDA’s Foreign Inspections
by country, FY 2010
India, 138
China, 133
France, 59
Germany, 132
Canada, 94Italy, 66
Switzerland, 42
Spain, 40
Japan, 71
Others, 66
20
FY 11 International inspection obligation per
program area
Drugs – 1249 Devices - 472 Foods - 994 CVM - 88 Biologics - 42 TOTAL – 2825*
Series10
200
400
600
800
1000
1200
1400
Drugs
Devices
Foods
CVM
Biologics
21
India inspections (FY 2008-2012)
2008 2009 2010 2011 2012*0
20
40
60
80
100
120
Devices
Drugs
BIMO
Foods
* Partial year
22
Drug Inspections in India
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
0
20
40
60
80
100
120
140
160
10 1834 33 31
6346 52 63 56 59
11
4 0 3
33
910
42 43
01
2 7 11
25
2023
5438
46
Breakdown by inspection category
BIMO
GMP
PAI-GMP
23
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
QA System39%
Facility & Equipment13%
Material System4%
Production System10%
Laboratory System29%
Packaging & Labeling5%
40
FY 2011 cGMP deficiencies systems cited
Lababoratory System
27%
Facility & Equipment9%
Production Sys-tem24%
Material System6%
QA System29%
Packaging & Labeling
5%
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 observationsfor international inspections
QA System
Facility & Equipment
Material System
Production System
Laboratory System
Packaging & Labeling
0 5 10 15 20 25 30 35 40 45
20112009
43
FY 2010 cGMP deficiencies cited in India
QA Systems 37%
Laboratory System 17%
Facilities/Equipment20%
Material System4%
Production System21% Packaging & Labeling
1%
44
Top 10 deficiencies cited in 2011 in India
Inadequate Quality SystemsLack of investigations of batches that fail to meet
specificationsDeficient records and reportsInadequate process validation or no process validationLack of process controls that validate the performance of
manufacturing processInadequate laboratory controlsInadequate stability programLack of written procedures or inadequate SOPsInadequate controls of components, intermediates, and raw
materialsInadequate validation of equipment cleaning and
maintenance cleaning45
Comparing cGMP deficiencies (Europe, China &
India)
QA Sys-tem
Facility & Equipment
Production System
Material System
Laboratory System
Packaging & Labeling
0
5
10
15
20
25
30
35
40
29
13
25
5
23
5
20
7
15
7
29
5
37
1720
4
24
1
EuropeChinaIndia
46
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
2005 2006 2007 2008 2009 20100
2
4
6
8
10
12
14
16
18
20
Warning LettersUntitled Letters
Source CDER ICB
48
International Warning Letters
issued 2009 & 2010
49
Ensuring safe, effective and quality foods and drugs for the citizens of India, the United States and the world
Global marketplace
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
Bruce Ross, M.A., M.P.H.
Country Director, India [email protected]