2. Agenda
Introduction
Historyof GMP
Why GMP is important
GMP Coverage
Ten Golden Rules of GMP
cGMP for Animal Vaccine
Challenges with Vaccine
Dilemma faced by Industry
Summary
GMP Guidelines across the Globe
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3. Introduction
Good Manufacturing Practice is a set of
regulations, codes, and guidelines for the
manufacture of drug substances and drug
products, medical devices, in vivo and in
vitro diagnostic products, and foods.
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4. Introduction
A basic tenet of GMP is that quality
cannot be tested into a batch of product
but must be built into each batch of
product during all stages of the
manufacturing process.
Hence Good Manufacturing Practices
are control measures used to ensure the
quality, safety, purity, and efficacy of
products.
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5. History of GMP
1902 - Development of the Biologic Control Act
1906 - Development of the Pure Food and Drug Act
1938 - Federal Food, Drug and Cosmetic Act
1941 - Initiation of GMP
1944 - Development of Public Health Services Act
1962 - Kefauver-Harris Drug Amendments released
1963 - Establishment of GMPs for Drugs
1975 - cGMPs for Blood and Components Final Rule
1976 - Medical Device Amendments
1978 - cGMPs for Drugs and Devices
1979 - GLPs Final Rule
1980 - Infant Formula Act is passed
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6. History of GMP
1941 Initiation of GMP
December 1940, Winthrop
Chemical Company’s
Sulfathiaziole tablets
contaminated with
phenobarbital
1941 - 300 people died/injured
FDA enforced and revised
manufacturing and quality
control requirements
1941 - GMP is born
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7. History of GMP
1962 Kefauver-Harris
Drug Amendments
Thalidomide tragedy
Thousands of children born
with birth defects due to
adverse drug reactions of
morning sickness pill taken
by mothers
Strengthen FDA’s
regulations regarding
experimentation on humans
and proposed new way how
drugs are approved and
regulated.
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8. Why GMP is Important
A poor quality medicine may contain toxic
substances that have been unintentionally
added
A medicine that contains little or none of
the claimed ingredient will not have
intended therapeutic effect.
Most countries will only accept import of
medicines that have been manufactured to
internationally recognized GMP standards.
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9. GMP Coverage
All aspects of production; from the starting
materials, premises and equipment to the
training and personal hygiene of staff.
Detailed, written procedures are essential for
each process that could affect the quality of
the finished product.
Systems to provide documented proof that
correct procedures are consistently followed
at each step in the manufacturing process –
every time a product is made.
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10. Ten Golden Rules of GMP
1. Be fit for the job
2. Stay fit for the job
3. Have plant & machinery fit for intended
use
4. Maintain the plant & machinery always
fit for intended use
5. Have a stable, capable process
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11. Ten Golden Rules of GMP
6. Validate the process
7. Have written operating procedures for
the work
8. Follow the written operating procedures
in the work
9. Cross check and report the data as you
do it
10. Audit for continued conformance.
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12. cGMP for Animal Vaccine
1. Organization & Personnel.
2. Building & Facilities.
3. Equipments.
4. Control of Components.
5. Production & Process Control.
6. Packaging & Labelling Control.
7. Laboratory Controls.
8. Handling & Distribution
9. Records & Reports
10. Return & Salvaged Drugs.
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13. Organization & Personnel
Management Involvement & Responsibility
Policies & Procedures
Quality Manual
Personnel Qualifications
Job description.
Trainings on cGMP.
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14. Building & Facilities
FDA Approved layouts & design.
Classified Rooms
– HVAC
– HEPA filters
– Bio-containment – Access Controlled
Plumbing & Lighting
Sewage & Refuse
– Kill Tanks
– Bio-waste, Incinerator
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15. Building & Facilities
CLEAN ROOM CORRIDOR
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16. Equipments
Equipments design, size and location.
Equipment construction.
– SS 316 L
Equipment cleaning.
– CIP/SIP
Auto controlled Fermentors.
Ultra-filtration Units.
LAF Units, Bio-safety Cabinets.
Validated & Calibrated.
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17. Equipments
CELL FERMENTOR OPERATIONS
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18. Control of Components
Raw Material, Containers and Closures
– Receipt and storage
– Testing and approval or rejection
– Retesting
Seed (Virus / bacteria, Cells)
– Source – National / International
– Passage level
– QC – Purity, Sterility, Extraneous agents
– Storage in -70°C Deep Freeze, Liquid Nitrogen
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19. Control of Components
ISSUANCE OF RAW MATERIAL CELLS FROM LN2 CONTAINER
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20. Production & Process Control
Standard Operating Procedures (SOP).
Process Validation
Batch Manufacturing Record (BMR)
Identification of each stage.
In-process Quality Control (IPQC).
Aseptic Processing
– Cleaning
– Fumigation
– Clean Rooms / Closed operation
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21. Packaging & Labelling Control
Materials examination and release criteria
– Master with QC
– Specifications
Controlled Issuance (Kept in lockers)
Packaging and labelling operations
– Monitored
Over printing details approved
– Batch Number
– Expiry Date
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22. Laboratory Controls
Testing equipments & facility.
– Analytical Laboratory
– Microbiological Laboratory
– Biological Testing Laboratory
Pharmacopeia, Test procedures.
Control sample, Stability Chambers
Animal Testing
– Small Animal House
– Large Animal House
– Challenge Facility
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23. Handling & Distribution
Warehouse & Storage
– Cold Room
– Deep Freeze (-20° / -70° C)
– Liquid Nitrogen
Distribution procedures
– Cold Chain
– Cold Van
– Air
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24. Records & Reports
Equipment cleaning and use log
Master formula and control records (MFR)
Batch manufacturing record (BMR)
Laboratory Testing Records
Animal Testing Records
Certificate of Analysis
Distribution Records
Cold Chain Monitoring Records
Complaint files
Audit Reports
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25. Return & Salvaged Drugs
Returned products
– Kept under Quarantine in bonded room
Retested
– Complete testing for efficacy
Approved or rejected
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26. Unique challenges with
Vaccines
Unlike a substantial number of injectables
pharmaceuticals, vaccines are administered
to a large population of patients that are most
often young and healthy.
Starting materials may have inherent
bioburden, e.g. egg-based vaccines or may
be infectious until inactivated e.g. bacterial
vaccines.
From beginning to end, the manufacturing
process for a vaccine can take several
months to a year.
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27. Unique challenges with
Vaccines
Must be processed under defined
conditions/controls throughout production
to consistently produce a safe, pure and
potent product and preclude the
introduction of environmental
contamination.
Cannot withstand heat sterilization without
affecting product quality, hence must be
processed ‘aseptically’.
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28. Unique challenges with
Vaccines
Bioburden testing of the product at various
points in the manufacturing process.
Segregation of pre- and post-inactivation
steps and appropriate methods for
inactivation testing.
Cleaning of facilities and equipment using
procedures shown to be effective for removal
of residual product and bioburden.
Monitoring of the manufacturing environment
to continuously assess conditions.
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29. Unique challenges with
Vaccines
Product is filter sterilized at some point during
the manufacturing process.
For vaccines, this may be earlier in the
process than many products.
– Once conjugated to an adjuvant, sterile filtration no
longer possible
Subsequent steps must be carefully controlled
to avoid introduction of contaminants.
Careful adherence to aseptic technique
/practice by personnel is must.
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30. Dilemma faced by Industry
Defined conditions / controls not in place
throughout the manufacturing process, has
resulted in failures at the end of production. –
Automation
Issues with inactivation steps.
– Adverse affect of Inactivating agent - Alternate
Inadequate cleaning procedures that result in
cross-contamination. Robust CIP / SIP
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31. Dilemma faced by Industry
Environmental monitoring data collected but
not adequately evaluated or investigated when
levels exceeded or same organisms identified
in the in-process or final product.
Inadequacies in aseptic processing:
– Validation doesn’t simulate actual manufacturing
conditions
– Poor aseptic technique observed during aseptic
operations
PERSONNEL TRAINING
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32. Summary
GMP is a guideline
GMP is a control measure
GMP is to be read and learned
GMP is to be practiced & implemented
GMP is constantly evolving - currentGMP
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33. GMP Guidelines - Global
GMP as per Schedule “M” – Drugs & Cosmetics Act, 1940
www.cdsco.nic.in
GMP as per WHO – Over 100 countries
www.who.int
GMP as per MHRA (Medicines and Healthcare Products
Regulatory Agency)
www.mca.gov.uk
GMP as per TGA (Therapeutically Goods Administration)
www.tga.gov.au
GMP as per US FDA (Food & Drug Administration)
www.fda.gov
GMP as per ICH guidelines (International Conference of
Harmonization)
www.ich.org
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34. Questions ?
Balraj S Thapa
Email : rajthapa2006@gmail.com
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