Requirements for production of animal vaccines.

1. GMP in
Production of
Animal Vaccine
Balraj Singh Thapa
Quality Assurance

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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