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
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