fda foreign priorities, inspections and compliance

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

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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

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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Distinction between domestic and imported products is obsolete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

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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

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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

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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

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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

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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

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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

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India inspections (FY 2008-2012)

2008 2009 2010 2011 2012*0

20

40

60

80

100

120

Devices

Drugs

BIMO

Foods

* Partial year

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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

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FDA inspection process

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Inspections…

Are fact finding Require evidence Require organization

and time management Are regulatory

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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

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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

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http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/default.htm

Inspection Participation

Investigators (inspectors)

Analysts (lab experts)

GMP Assessors/Evaluators

Product Reviewers/Assessors

Other Specialists

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Systems-Based Approach

Quality Systems

Materials Management

Production

Facilities & Equipment

Packaging & Labeling

Laboratory Control

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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

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Materials Management (ingredients & packaging)

• Separation and control of materials

• Identification of materials

• Labeling practices

• Sampling of incoming materials

• Inventory control systems

34


Production

• Personnel practices

• Contemporaneous completion of documents

• Written procedures

• Calibration stickers for critical equipment

• Condition of equipment

35


Facilities & Equipment

• Equipment design

• Heating/Ventilation/Cooling systems

• Water systems

36


Packaging and Labeling

• Appropriate controls

• Line clearance procedures

• Visual inspection procedures (sterile products)

• Label issuance and reconciliation documents

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Laboratory control• Raw data practices

• Sample flow

• Sample/standard identification

• Status of the instruments

• Stability

• Methods in use

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Conclusion of an inspection

Formal close out

May include:• Sample collections

• Issuance of FDA 483, Inspectional Observations

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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%


5%

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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

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cGMP deficiency observationsfor international inspections

QA System

Facility & Equipment

Material System

Production System

Laboratory System


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


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

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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.)

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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

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Ensuring safe, effective and quality foods and drugs for the citizens of India, the United States and the world

Global marketplace

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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.

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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

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Questions?

[email protected]

[email protected]

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Bruce Ross, M.A., M.P.H.

Country Director, India [email protected]

fda foreign priorities, inspections and compliance

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