Beruflich Dokumente
Kultur Dokumente
GPhA 2007 Fall Technical Conference October 10, 2007 Deborah M. Autor, Esq. Director CDER Office of Compliance
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Overview
CDER OC Mission and Vision FDA Modernization: Drug Quality for the 21st Century Trends: Recalls, Manufacturing Sites and Inspections Foreign Inspections Raw Material Control FDAs Pharmaceutical Ingredient Safety Task Force Bioequivalence Inspections Postmarketing Adverse Drug Experience (ADE) Reporting Marketed Unapproved Drugs Initiative 2
Mission
Mission (purpose) of the CDER Office of Compliance: To promote and protect public health through strategies and actions that minimize consumer exposure to unsafe, ineffective, and poor quality drugs.
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Vision
Vision (ambition) of the CDER Office of Compliance: Through excellence in risk- and sciencebased policy, surveillance, and enforcement, we prevent consumer exposure to unnecessary risk from drugs throughout their lifecycle.
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PQS
How did we get here? Are there challenges ahead?
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A new vision for ensuring product quality (Brussels, July 2003) A harmonized pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality
New ICH guidelines (high level guidelines, more visionary, less prescriptive, flexible regulatory approaches)
Pharmaceutical Development (Q8) Quality Risk Management (Q9) Pharmaceutical Quality Systems (PQS) (Q10)
For companies with : 1. Good design and control strategies 2. Good Risk Management strategies 3. Good Quality Systems
Quality Systems
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Management Responsibilities
PQS
Process Performance & Product Quality monitoring CAPA Change Management elements Management review
Enablers
GMP
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Trends
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Drug Recalls
977 Recalls in FY 2007 (through 9/21)
Drug Recalls
14 1000 750 Number 17 20 154 168 2003 16 138 130 2004 316 169 2005 45 188 128 2006 103 2007 250 0 860 500
Fiscal Year
Class III Class II Class I
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Drug Recalls
Adjusted to account for multiple-recall incidents
Drug Recalls
1000 750 Number 500 16 4 100 178 1997 246 162 1999 15 179 145 2001 15 236 187 2002 20 154 168 2003 16 138 130 2004 9 217 169 2005 22 188 128 2006 14 189 103 2007 250 0
Fiscal Year
Class III Class II Class I
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EERs Submitted for NDAs and ANDAs (Originals and Supplements) October 1, 2002 September 31, 2006
4000 3500 3000 2500
2552 2622 2746 3569 3606 3447
2585
Domestic
Foreign
19
Foreign Inspections
20
Switzerland 5%
21
Others 1%
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70
15 6 4
Preapproval/ Surveillance
Preapproval
Surveillance
For Cause
Therapeutic Drug
FY 07
24
CHINA INDIA
20 10 0 FY 04
13
16 11
FY 05
FY 06
FY 07
25
FY 06
16
FY 05
13
FY 04 0
*FY 2007 data current as of 9/25/07
18 5 10 15 20
26
FY 04
17 1 0 18
FY 05
13 0 0 13
FY 06
15 0 1 16
FY 07*
10 1 0 11
27
Lab Controls 9%
2 2 2 2 3
0
*FY 2007 data current as of 9/25/07
4
30
FY 05
30
FY06
32
FY 07 0 10 20 30 40 50 60
62 70
31
FY 04
25 2 6 3 36
FY 05
21 2 7 3 33
FY 06
16 6 11 1 34
FY 07
41 8 14 6 62
32
API 66%
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Lack/Inadequate SOPs 9%
Lab Controls 9%
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8 9 10 11 14
0
*FY 2007 data current as of 9/25/07
10
15
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DEG Contamination
Scope of the Problem: Recurrent DEG poisoning worldwide (resulting in hundreds of deaths) 2006Panama 1995-1996Haiti 1990-1998Argentina, Bangladesh, India, and Nigeria 1937United States (Elixir Sulfanilamide) FDA issued guidance in May 2007 to recommend testing and other controls to avoid DEG contamination: Guidance for Industry: Testing of Glycerin for Diethylene Glycol
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What can drug manufacturers do to prevent similar occurrence with any pharmaceutical ingredient?
Apply quality systems approach to monitor ingredient supply chain integrity
Establish a robust supplier qualification program (e.g. audits, quality agreements, appropriate ongoing QC of incoming lots) Only do business with trustworthy sources Verify each ingredient shipment comes from approved suppliers/manufacturers Verify shipments came through expected routes and were not diverted or tampered with Isolate ingredients that are suspected of being non-genuine or mishandled or perhaps adulterated
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in vitro studies
e.g., study nasal spray drug products for local action
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BE Program Focus
Audit studies pivotal to approval decisions
generic and innovator drug products PEPFAR applications
expedited review process many studies conducted outside U.S.
Address CDER reviewer concerns about data integrity and study conduct Investigate complaints
allegations of improper study conduct, fraud
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Inspectional Oversight
BE program monitors studies from multiple sources
contract research organizations (CROs) sponsor facilities clinical investigators academic laboratories sites within and outside the U.S. inspections in India increasing
FY02, no BE inspections in India Since FY05, ~50 BE inspections in India
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Consequences
FDA rejection of unreliable data unfavorable application outcome
can affect multiple applications
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Inspectional Findings
Examples of deficiencies for generic BE studies include
failure to follow protocols and SOPs dosing and reserve sample issues method not adequately validated inappropriate analytical run acceptance inadequate record keeping
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26 22
7 2 2004
VAI
5 0
2005
OAI
2006
30 30
19 18 19 9
16 16
5 5 4
4 4 3
5 2
Incomplete Inaccurate
Other
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Quality Improvement
Development and Implementation of Corporate Quality Assurance and Corrective Action can prevent noncompliance. Development and Implementation of Quality Assurance and Corrective Actions can avert subsequent regulatory action.
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Regulatory Meetings
A meeting requested by FDA management to inform responsible individuals or firms about how products, practices, processes, or other activities violate the law A tool to obtain prompt voluntary compliance
As a follow-up to a Warning Letter (WL) when firms have not corrected all significant violations To achieve voluntary correction more quickly than through written communication or legal remedies In conjunction with a WL to emphasize the significance of violations
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Summary
Risk-Based Strategic Maximizing our impact on the public health
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