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FDA Quality Systems Approach to Inspection

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

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FDAs Mission

Protect consumers health and safety under


the Federal Food, Drug and Cosmetic Act

Two basic strategies:


Monitoring the quality of products through
surveillance activities, e.g. sampling and
analyzing products in distribution
Evaluating through factory inspections,
including the collection and analysis of
associated samples
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Sources of Risk from Drug Products

Known side effects Medication Product quality


errors defects
Unavoidable Avoidable

Preventable
adverse
events

Remaining
uncertainties
Unexpected side effects
Injury Unstudied uses
or death Unstudied populations

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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

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Background of FDAs 21st Century Initiatives

Limited resources and increased volume of work


August 2002 FDA announced the Pharmaceutical
CGMPs for the 21st Century A Risk Based Approach
Focus on the greatest potential risk to the public
FDAs intent to integrate quality systems and risk
management approaches - to modernize FDAs
regulations
Encourage industry to adopt modern and innovative
manufacturing technologies as well as modern quality
system approaches
Necessary to harmonize the CGMPs with other non-U.S.
pharmaceutical regulatory systems
Need to harmonize with FDAs own medical device
quality systems regulations

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Background of FDAs 21st Centurys Initiatives
(cont.)

Encourage Risk-Based approaches which focus on critical


elements
Ensure FDAs Review, Compliance and Inspection Policies
based on state-of-art pharmaceutical science
Risk-Based Approach to Manufacturing and Regulation
Pharmaceutical Inspectorate
Experienced Field Investigators
Process Analytical Technology (PAT) Guidance
Real-time measurements
Process Validation Guidance
Life Cycle Approach - Built-in Quality, not tested into product
21 CFR 11 Electronic Records Guidance
Quality Systems Guidance - September 2006 FDA issued the final
version of the Guidance for Industry on Quality Systems Approach to
Pharmaceutical CGMP Regulations
Systems-Based Inspection
6 systems
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Philosophy of
CGMP and Modern Quality Systems

Quality should be built into


the product, and testing
alone cannot be relied
on to ensure product
quality.

Ref: Guidance for Industry: Quality Systems


Approach to Pharmaceutical CGMP Regulations
September 2006

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Background of Risk-Based Approach

Focus inspections on highest risks


Priorities:
Sterile Manufacturing operations
e.g. injectables
Prescription drug manufacturers
Biotech therapies
New registrants - not previously inspected
Companys compliance History

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Scope of Quality Systems Approach

Human Drugs Centre for Drug Evaluation and


Research (CDER)
Veterinary Drugs Centre for Veterinary
Medicine (CVM)
Biological Drugs Centre for Biologics
Evaluation and Research (CBER)
Manufacturers of Components, including APIs

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Foreign Inspection by Firm Type in 2004

Both API and Dosage Control Lab


2% Micronizer
9%
1%

Intermediates
10%

API
51%

Dosage
27%

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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%

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Most Common GMP Deficiencies by Systems
- FDA Inspections in 2004 & 2005
Materials
6%
Packaging and Labeling Laboratory
1% 19%

Facilities & Equipment


17%
Production
11%

Quality
46%

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2005 Foreign inspections

234 pre-approval inspections (PAI) in support of:


143 new drug applications
120 generic drug applications
213 current good manufacturing practice (CGMP)
inspections
For most foreign inspections, both a CGMP and a
preapproval inspection take place and are counted twice,
once under each inspection program.
FDA issued 3 warning letters, 2 import alerts and several
regulatory meetings.

Referenced: 2005 FDA CDER Report to the Nation

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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
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Traditional vs Systems Based Inspection

Traditional Inspection Company History


FDA investigators checked
compliance across departments
Products
and systems

Focus on products profile class
Plant Tour
Inspectors inspect from
packaging areas to lab areas
No connection between a system Document Review
and infrastructure

Cant distinguish a
Observations
site/department problem or a
company wide problem

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Concepts of Modern Quality Systems

Quality Strength, Identity, Safety, Purity, Quality


SISPQ to ensure safety and effectiveness
Quality by Design and Product Development
Transfer of Product Knowledge and process Understanding
Quality Risk Management
set specifications, mitigate risks, investigate discrepancies
CAPA
Change Control
The Quality Unit QC & QA - Independent
Ensure controls
Approve or reject
Six-System Inspection Model

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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

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Quality Systems Approach

A. Management Responsibilities
B. Resources
C. Manufacturing
D. Evaluation Activities

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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

Everything to insure product quality, customer


satisfaction and
continuous improvement

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A. Management Responsibilities (cont.)

Structure the organization to ensure the


assigned authorities and responsibilities
Organizational structure is documented
Support the total quality model
Quality Systems departments have equal
standing with other departments within an
organization
The Quality Manager has the authority to detect
problems, implement solutions, and provide
prompt feedback on quality issues to the
organization.

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A. Management Responsibilities (cont.)

Play a key role in the design, implementation, and


management of a robust quality systems.
Align quality plans with companys visions and mission
Actively participate in Management Review meetings to
ensure continuing suitability, adequacy, and
effectiveness
Articulate their vision of and commitment to quality to all
levels of the organization.
Advocate continuous improvement of the operation of
Quality System
Strong and visible support for the quality system
Internal communication on quality issues at all levels
Commit necessary resources

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A. Management Responsibilities (cont.)

Management controls are always reviewed by


FDA
CAPA ***
People qualifications
Change control
Validation

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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

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B. Resources (cont.)

Appropriate allocation of resources = robust quality system


Supply and maintain the appropriate facilities and equipment
Acquire and receive materials that are suitable for their intended purpose
Process materials to produce the final products/services
Analyze finished products and materials collection, storage, examination of in-
process, stability, and reserve samples
Personnel
Succession planning, training, capturing institutional knowledge
Problem-solving and communicative culture
Encourage employee suggestions
Define qualifications and assign appropriate responsibilities
Education, training and experience
Continued Training GMP & Operational functions

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C. Manufacturing

Design, develop and document Product and


Processes
Experts
Documentation
Critical processes
Examine Inputs / Materials
Perform and Monitor Operations
Entire Product Life Cycle
Critical Processes Variability
Statistical Process Control (SPC)
PAT Monitor & reduce QC testing
Address Nonconformities

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C. Manufacturing (cont.)

Address Nonconformities /
Deviations
Investigations, conclusion and
follow-up must be
documented.
How to prevent recurrence
CAPA

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D. Evaluation Activities

Analyze Data for Trends


Problem resolution or problem prevention
Annual Product Review (APR)
Detection of potential problems
CAPA
Examine processes as a whole
Trends can help focus on internal audits

Conduct Internal Audits


Independent assessment of the effectiveness and sustainability of
Quality Systems
Management Responsibilities
Compliance Policy Guide 130.300 FDA is to refrain from both
reviewing and copying reports or records that result from internal
audits

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D. Evaluation Activities (cont.)

Quality Risk Management


Understanding of quality issues >effective decision-
making
Risk assessment = probability of occurrence of harm
and the severity of harm
Engage appropriate parties in risk assessment, e.g.
regulatory affairs, customers, appropriate
manufacturing personnel, development scientist,
other stakeholders
Risk management as a tool in the development of
product specifications and critical process
parameters
Repeat risk assessment to improve processes
Proactive approach to quality > Mitigate risk

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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

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D. Evaluation Activities (cont.)

Sources of recurring problems:


Nonconformance reports and rejections
Product Returns
Complaints
Internal and External audits
Trending data and risk assessment
Management review decisions
Effectiveness of CAPA

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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

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System Based CGMP Inspection

1. Quality System
2. Facility & Equipment
3. Materials

LABORATORY CONTROLS
4. Production

PACKAGING & LABELING


FACILITY & EQUIPMENT

MATERIALS
5. Laboratory Controls

PRODUCTION
6. Packaging & Labeling

Full Inspection = Inspect the quality system


and three of the five systems

Abbreviated Inspection = Inspect the quality


system and one of the five systems

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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

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1. Quality System

Assure overall compliance with CGMP regulations and all


quality systems.
Quality must be built into the process & Quality is not tested
into the product
Quality Assurance comes from
Design of robust process based on thorough knowledge of that
process and the sources of variability
Process Analytical Technology (PAT) is a system for designing,
analyzing and controlling manufacturing through real time
measurements of critical quality attributes of raw and in-process
materials and processes, with the goal of ensuring final product quality
science based approach
Process Validation Life cycle approach from development to market
Design of Experiment (DOE)
Quality System review and trending
Continuous improvement within well characterized process

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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

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2. Facilities & Equipment System
- Facilities

Location, design and construction of facility are appropriate


to facilitate operations, maintenance and cleaning
Layout and air-handling designed and constructed to prevent
cross-contamination
Flow of materials and personnel - designed to prevent mix-
ups or contamination
Incoming Materials ID, quarantine and segregation
Sampling Area Prevent cross-contamination, cleaning
Quarantine Area APIs and Intermediates
Released Area Labeling, MRP
Rejection of materials

Separate facilities or containment where needed, e.g.


penicillins, hormones, highly potent compounds, etc.

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2. Facilities & Equipment System (cont.)
- Equipment

Appropriate design, size, location, and non-reactive product


contact surfaces
Identification of equipment clearly marked
Equipment Qualification DQ, IQ, OP, PQ
Equipment Calibration
Preventive Maintenance Schedule and procedures
Equipment Cleaning procedures and Cleaning Validation
prevent contamination and mix-ups
Equipment Usage Log: cleaning, and maintenance
Lubricants, heating fluids or coolants not contact / alter
product quality
Closed or contained equipment
Inspection prior to use

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2. Facilities & Equipment System (cont.)
- Utilities

Electricity and wiring drawings


qualified, approved and appropriately
monitored
Pipework Permanently installed and
appropriately identified
Drains of adequate size

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2. Facilities & Equipment System (cont.)
- Water

Process water at minimum meeting WHO guidelines for


potable water
Justify and establish specifications
Validate water treatment facilities
API for Sterile Dosage Form Water used in later
stages should be monitored and controlled for total
microbial counts, objectionable organizations and
endotoxins

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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

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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

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3. Materials System (cont.)

MRP Systems, e.g. SAP, JD Edwards


Released materials storage and distribution,
traceability if product recall
FIFO First in First out
Rejected materials identify and control under a
quarantine system
Retested materials establish and justify the retest
periods
Expired materials quarantine and destruction

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4. Production System

Production and process controls ensure SISPQ of finished products


State of Control
Entire Product Life Cycle validation, consistency, continual
improvement
Process Validation based on knowledge of process scientific basis
for identifying critical steps / critical process parameters and control
points
Risk Management identify process weakness and critical quality
attributes
Justification for in-process specifications and final product
specifications
Monitor critical processes eliminate variability
Measure and analyze processes analytical methods, PAT, statistical
techniques
Process Capability Cp and CpK
Data documented and available to Quality Unit for review trending,
investigations, etc.

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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

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5. Laboratory Control System

Procedures in place to ensure the accuracy of test results


Quality Control Unit has adequate lab facilities
Independent from Production ***
Adequate staff supervisory and bench personnel
Written specifications raw materials, APIs, intermediates, labels,
packaging and finished products
Written procedures sampling, testing, approval or rejection of
materials, recording and storage of data
Change Control approval for written procedures
Method validation / revalidation

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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

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5. Laboratory Control System (cont.)

Samples - Description of samples


Methods - Identification of method used, method number,
compendial number
Raw data sample, standards, reagents, equipment, testing
results
Calculations manual, calculators, spreadsheets, software
program
Test Results Compare with established acceptance criteria,
statement of test results
Signatures
Person(s) who performed each test, date(s) performed
Second Person who reviewed original test records for accuracy,
completeness and compliance with established standards

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6. Packaging & Labeling System

Process Flows and Written Procedures


receipt, identification, quarantine, sampling,
testing and approval/rejection of packaging
and labeling materials
Specifications
Each shipment maintain records of receipt,
transportation, examination, test results
Containers & Closures protective, clean, not
alter product quality

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6. Packaging & Labeling System (cont.)
- Labeling

Label Storage Area enclosed (locked), limited access


Written procedures reconciliation, investigation if
discrepancy
All excess labels coded with batch number to be
destroyed and documented
Printing device controlled to insure accuracy of label
against batch record
Print labels checked against master and a copy placed
with the batch record

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6. Packaging & Labeling System (cont.)
- Packaging

Documented procedures to assure correct packaging


materials / labels used
Packaging operations designed to prevent mix-ups
Line clearance documentation
Shift changes documentation
Packaged and labeled intermediates
Tamper-evident seals
Child resistant features
Labels with barcodes

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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 $$$,$$$,$$$
Consent Decree $$$,$$$,$$$,$$$

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Most Common Observations

No or inadequate procedures or procedures not followed


No management review of procedures
Management oversight / QA oversight
QC unit did not follow procedures
No internal audits performed
Inadequate employee training
Process not validated
Inadequate laboratory controls
Raw data not reviewed / maintained
No procedures for handling OOS situations
No procedures for Corrective and preventive actions
Recurring deviations
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How to minimize the risk of receiving
warning letters?

Know regulations and guidelines the quality intent and


meaning
Know the consequences of deviations of non-compliance
Both staff and management
Study 483s and Warning Letters from internet Learn
about mistakes others have made
Build up a quality system in line with industry standards,
regulations and guidelines
Develop SOPs on Preparing for Inspections
Ongoing training to staff and management on GMP trends
and new regulations
Respond to FDA observations effectively and timely

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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
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References

U. S. Food and Drug Administration


5600 Fishers Lane, Rockville MD 20857-0001
1-888-INFO-FDA (1-888-463-6332)

Centre for Drug Evaluation and Research


http://www.fda.gov/cder/
Guidance for Industry: Quality Systems Approach to
Pharmaceutical CGMP Regulations September 2006
Pharmaceutical CGMPs for the 21st Century A Risk-
Based Approach September 2005
Warning Letters
www.fdawarningletter.com

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