The document discusses FDA's quality system approach to cGMP regulations. It outlines six quality systems that FDA expects companies to have in place: quality, facilities and equipment, materials, production, laboratory, and packaging and labeling. The goal is to encourage a proactive, risk-based approach focused on critical processes to ensure product quality and safety.

2.  FDA’s Mission
 References
 Background
 Quality Systems
 Six Quality Systems
 Inspection Outcome
 Conclusion

3.  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 cGMP’s for the 21st Century – A
Risk-Based Approach – September 2005
 Warning Letters, www.fdawarningletter.com

4.  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

5. Source: CDER 2005 Report to the Nation
Reported Drug Quality Defects
Other, 9%
Contamination/
sterility, 3%
Fill problem,
4%
Packaging, 6%
Delivery
system, 10%
Product defect,
14% Formulation/
substitution,
22%
Adverse drug
reports, 18%
Labeling, 14%
Fiscal year 2005

6.  Limited resources and increased volume of work
 August 2002 – FDA announced the
Pharmaceutical cGMP’s for the 21st Century – A
Risk Based Approach
 Focus on the greatest potential risk to the public
 FDA’s intent to integrate quality systems and risk
management approaches - to modernize FDA’s
regulations
 Encourage industry to adopt modern and
innovative manufacturing technologies as well as
modern quality system approaches

7.  Necessity of harmonizing the cGMP’s with other
non-U.S. regulatory agency’s / systems
 Need to harmonize with FDA’s own medical
device quality systems regulations
 Encourage Risk-Based approaches which focus
on critical elements
 Ensure FDA’s Review, Compliance and Inspection
Policies – based on state-of-art pharmaceutical
science

8.  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 – Quality-by-Design,
not Quality-by-Testing

9. • 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

10. 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

11.  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

12. 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 (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

13.  Management Responsibilities
 Resources
 Manufacturing
 Evaluation / Review processes

14.  Quality System
 Facility & Equipment
 Materials
 Production
 Laboratory
 Packaging & Labeling

15.  Assure overall compliance with cGMP regulations and
all quality systems.
 Quality by Design in the processes
 Quality Assurance comes from
- Design of robust process based on thorough knowledge of
the, 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
– Quality System review and trending
– Continuous improvement within well characterized process

16.  Quality Function & Responsibilities:
- The Quality Unit and all of its review and approval duties.
- Assures overall compliance with cGMP’s
 Quality Unit reviews and approves:
- Annual Product Quality Reviews
- Complaints
- Deviations / Failure Investigations
- Change Control
- CAPA (Corrective and Preventive Action)
- Re-processing / Re-working
- Validation / Re-validation
- Rejections
- Stability Failures / Out of Trend data
- Quarantine Products
- Documented Training – GMP and Job Related

17.  Location, design and construction, is appropriate to
facilitate operations, maintenance and cleaning
 Layout and air-handling systems 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 – API’s and Intermediates
- Released Area – Labeling, MRP
- Rejection of materials
 Separate facilities or containment where needed,
e.g., penicillins, hormones, highly potent
compounds, etc.

18.  Appropriate design, size, location, and non-reactive
product contact surfaces
 Identification of equipment – clearly marked
 Equipment qualification – DQ, IQ, OP, PQ
 Equipment calibration – schedule & procedures
 Preventative maintenance - schedule & procedures
 Equipment cleaning procedures and validation –
prevent contamination and mix-ups
 Equipment usage log – use, cleaning & maintenance
 Lubricants, thermal fluids – not contact / alter
product quality
 Closed or contained equipment
 Line clearance & pre use inspection

19.  Electricity and wiring drawings – qualified, approved
and appropriately monitored
 Pipe work – Permanently installed and appropriately
identified
 Drains of adequate size
 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

20.  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
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

21.  Include measures and activities to control
finished products
 Purchased specifications vs agreed
specifications
 Change Control for changing suppliers and
suppliers’ processes
 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

22.  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

23.  MRP Systems, e.g. SAP,
- 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

24.  Production and process controls – ensure quality 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

25.  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.
 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

26.  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
 Reference Standards

27.  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

28.  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

29.  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
 Label Storage Area – enclosed (locked), limited
access
 Written procedures – reconciliation, investigation if
discrepancy

30.  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
 Documented procedures to assure correct packaging
materials / labels used
 Packaging operations designed to prevent mix-ups
 Line clearance documentation
 Shift changes documentation

31.  Packaged and labeled intermediates
 Tamper-evident seals
 Child resistant features
 Labels with barcodes

32.  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

33.  What is cGMP?
 cGMP refers to the Current Good Manufacturing Practice
regulations enforced by the US Food and Drug Administration
(FDA).
 cGMPs provide for systems that assure proper design, monitoring,
and control of manufacturing processes and facilities.
 Adherence to the cGMP regulations assures the identity, strength,
quality, and purity of drug products by requiring that
manufacturers of medications adequately control manufacturing
operations.
 This includes establishing strong quality management systems,
obtaining appropriate quality raw materials, establishing robust
operating procedures, detecting and investigating product quality
deviations, and maintaining reliable testing laboratories.
 This formal system of controls at a pharmaceutical company, if
adequately put into practice, helps to prevent instances of
contamination, mix-ups, deviations, failures, and errors. This
assures that drug products meet their quality standards.

34.  Implementation of a comprehensive, robust Quality
System Model
 Proactive approach to achieve long-term benefits
 Characteristics of a Successful Quality System:
- Science Based Approach
- Understand the intended use of a product
- Identify and control potentially weak processes
- Timely resolution 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