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Presentation:
Indian Pharmaceutical Association - Industrial Pharmacy Division
Hyderabad, Mumbai, Ahmedabad - India
March 24th, 26th, and 28th 2007
Angela Moy
SGS - Life Science Services
Outline
FDAs Mission
Background of FDAs 21st Century Initiatives
Types of FDA Inspections
Risk Based and Systems Based Approach
CGMPs and Modern Quality Systems
Quality Systems Model
Six Quality Systems
Outcomes of FDA Inspections
Conclusion
References
2
FDAs Mission
Preventable
adverse
events
Remaining
uncertainties
Unexpected side effects
Injury Unstudied uses
or death Unstudied populations
4
Reported Drug Quality Defects
Product defect,
14% Formulation/
substitution,
Delivery 22%
system, 10%
Packaging, 6%
Adverse drug
Fill problem, reports, 18%
4%
Contamination/
sterility, 3%
Labeling, 14%
Other, 9%
Fiscal year 2005
5
Background of FDAs 21st Century Initiatives
6
Background of FDAs 21st Centurys Initiatives
(cont.)
8
Background of Risk-Based Approach
9
Scope of Quality Systems Approach
10
Foreign Inspection by Firm Type in 2004
Intermediates
10%
API
51%
Dosage
27%
11
Foreign Inspections by Country in 2004
India
Others 14%
19%
Germany
Ireland 14%
4%
Spain
4%
Switzerland
4% Italy
10%
Japan
5%
China
France 7%
5%
Canada
United Kingdom
7%
7%
12
Most Common GMP Deficiencies by Systems
- FDA Inspections in 2004 & 2005
Materials
6%
Packaging and Labeling Laboratory
1% 19%
Quality
46%
13
2005 Foreign inspections
14
Types of FDA Inspections
1. CGMP Biennial (every two years)
2. Pre-Approval Inspection (PAI)
Targets - Manufacturers
Objectives:
Assure correlation between manufacturing process for:
Clinical trial
Bioavailability study
Stability studies
Submission information
NDAs = New Drug Applications
BLAs = Biologic Licence Applications
NMEs = New Molecular Entity Drugs
New BLAs = New Biologics
Assure scientific evidence that supports full scale production
procedures and controls
Assure validation of the manufacturing process
3. For cause Inspection, e.g. Field Alert filing, other health risks brought
to FDAs attention
Inspection may involve more than one assignment and will certify
corrections to previous inspections
15
Traditional vs Systems Based Inspection
16
Concepts of Modern Quality Systems
17
Change Control
Design the Change Control System and Team
Types of Changes
New product / process
Existing product / process
Design Qualification & Specifications
User Requirement Specification
Functional Requirement Specification
Facility Constructions, Start-up and
Commissioning
Revisions to design, drawings and specifications
Process Validation during and after
Post Change Control Implementation
18
Quality Systems Approach
A. Management Responsibilities
B. Resources
C. Manufacturing
D. Evaluation Activities
19
A. Management Responsibilities
Provide Leadership
Structure the Organization
Resources Management
Build Your Quality System to Meet Requirements
Establish quality standards
Establish Policies, Objectives, and Plans
Review the System
Suitability, adequacy, effectiveness
20
A. Management Responsibilities (cont.)
21
A. Management Responsibilities (cont.)
22
A. Management Responsibilities (cont.)
23
B. Resources
General Arrangements
Infrastructure, materials, products, testing
Personnel Development
Organizational culture Communicative
Qualifications and responsibilities
Facilities and Equipment
Control Outsourced Operations
Quality Agreements
Qualifications and standards
24
B. Resources (cont.)
25
C. Manufacturing
26
C. Manufacturing (cont.)
Address Nonconformities /
Deviations
Investigations, conclusion and
follow-up must be
documented.
How to prevent recurrence
CAPA
27
D. Evaluation Activities
28
D. Evaluation Activities (cont.)
29
D. Evaluation Activities (cont.)
Corrective Action
A reactive tool for system improvement to ensure that
significant problems do not recur
Root cause is investigated
Possible actions are determined
Preventive Actions
Being proactive
Identify potential problems and root causes
Assess possible consequences
Consider appropriate actions
CAPA
Understand different sources of CAPA
Managing and tracking CAPA
Risk based categorization for each CAPA to address the
level of detail of the evaluation process
How to verify / validate that the CAPA have been effective
Internal audits to verify effectiveness
30
D. Evaluation Activities (cont.)
31
D. Evaluation Activities (cont.)
Promote Improvement
Effectiveness and efficiency of a quality system
Senior Management involve in the evaluation of
improvement process
Keep abreast of changes in scientific developments and
regulatory requirements
32
System Based CGMP Inspection
1. Quality System
2. Facility & Equipment
3. Materials
LABORATORY CONTROLS
4. Production
MATERIALS
5. Laboratory Controls
PRODUCTION
6. Packaging & Labeling
33
State of Control
FD&C Act and other laws to ensure that products
are developed, manufactured and held in a state
of control, i.e. contribute to SISPQ
SISPQ = Safety, Identity, Strength, Purity,
Quality
Detailed inspection of a system so that the
findings reflect the state of control in that system
for every product / profile class
If one of the six systems is out of control, the
company is considered out-of-control
34
1. Quality System
35
1. Quality System (cont.)
Quality Function & Responsibilities:
The Quality Unit and all of its review and approval duties.
Assures overall compliance with CGMPs
Quality Unit reviews and approves:
1. Annual Product Quality Reviews
2. Complaints
3. Deviations / Failure Investigations
4. Change Control
5. CAPA (Corrective and Preventive Action)
6. Reprocess / Rework
7. Validation / Revalidation
8. Rejects
9. Stability Failures / Out of Trend data
10. Quarantine Products
11. Documented Training GMP and Job Related
36
2. Facilities & Equipment System
- Facilities
37
2. Facilities & Equipment System (cont.)
- Equipment
38
2. Facilities & Equipment System (cont.)
- Utilities
39
2. Facilities & Equipment System (cont.)
- Water
40
3. Materials System
Materials can include items such as:
Components e.g. APIs, raw materials, process water, gas, etc.
Containers & Closures
Reliable input materials
Qualified internal and external sources/suppliers
applications and submissions (e.g. NDA)
Suppliers for critical materials select, evaluate, audit, qualify
Supplier evaluation should include three fully tested batches initially,
and one fully tested batch per year
Periodic audit of suppliers
CGMP requires either testing, or use a C of A plus an identity analysis
Include measures and activities to control finished products
Purchased specifications vs agreed specifications
Change Control for changing suppliers and suppliers processes
41
3. Materials System (cont.)
Process Flows and Written Procedures receipt, identification,
quarantine, storage, handling, sampling, testing and approval / rejection
of materials
Receipt check for correct labeling, transportation conditions, seals, etc.
Assurance obtained from non-dedicated tankers / trucks
Product codes of received batches status and identity
Written sampling plan with justification
Specific ID test on incoming batches + Certificate of Analysis
Sufficient initial tests establish reliability
Periodic reassessment trending data
Prevent contamination of sampled containers
Before and during manufacturing
Identification and test
Store in manner to prevent degradation, contamination, and no adverse
effect on quality
Drums, bags, boxes off the floor
42
3. Materials System (cont.)
43
4. Production System
44
4. Production System (cont.)
Training documented
GMP and job related
Records
Master Production and Control Records
Batch Production and Control Records
Change Control Procedure
Complete Batch Production Documentation contemporaneous
and accurate
In-process Controls charts, tests, examinations
Equipment Logs Cleaning, Calibration, Qualifications
SOPs
45
5. Laboratory Control System
46
5. Laboratory Control System (cont.)
Reference Standards primary, secondary
Equipment Qualification
Calibration & Maintenance Written procedures, schedule,
documentation
Computerized System Validation and security of test results
and related data; system for assuring integrity of all lab data
Out-of-Specification (OOS) Procedures for the timely
investigation, documentation and conclusion of OOS
investigation.
FDA Guidance on OOS issued in October 2006
Due to testing problems or manufacturing problems
Invalidation of a test results should be scientifically sound and
justified
Identify CAPA and Implementation
Report in Product Quality Reviews
47
5. Laboratory Control System (cont.)
48
6. Packaging & Labeling System
49
6. Packaging & Labeling System (cont.)
- Labeling
50
6. Packaging & Labeling System (cont.)
- Packaging
51
Outcomes of FDA Inspections
No Observation
Inspectional Observations Form, i.e. Form 483 $,$$$
Withhold product Approvals $$$,$$$,$$$
Establishment Inspection Report (EIR) Deviations cited $,$$$
No Action Indicated (NAI)
Voluntary Action Indicated (VAI)
Official Action Indicated (OAI)
Warning Letter $,$$$,$$$,$$$
Product Recall $$,$$$,$$$
Import Alert $$$,$$$,$$$
Civil Money Penalties $$$,$$$
Product Seizure $$$,$$$,$$$
Consent Decree $$$,$$$,$$$,$$$
52
Most Common Observations
54
Conclusion
Implementation of a comprehensive, robust Quality System
Model
Proactive approach to achieve long-term benefits
Characteristics of a Successful Quality System:
Science Based Approaches
Understand the intended use of a product
Identify and control potential weak processes
Timely remediation of deviation and investigation
Sound methods for assessing and reducing risks
Well defined processes and products Product life
Cycle
Systems for careful analysis of product quality
Supportive Management philosophically and
financially
55
References
56