Reference Laboratory &
Quality Assurance
of Biological Products
Teeranart Jivapaisarnpong
Institute of Biological Products
Department of Medical Sciences
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Biological Products
Definition according to the Drug Acts: Products
from biological origins which are intended to
use directly to human for prevention, control,
treatment and diagnostic of diseases, such as
• vaccines,
• blood products, anti-serum, anti-venom
• biotherapeutic products: cytokines, growth
factors, hormones, interferons, interleukins,
Immunoglobulins, monoclonal Abs and other
regulatory peptides and proteins
• allergens, Tuberculin test.
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Steps of Research & Development
Laboratory Research
Preclinical study
Clinical trial phase I
Clinical trial phase II
Large scale production
Clinical trial phase III
Licensing
Distribute to the market
Clinical trial phase IV
( Post- marketing surveillance)
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Quality assurance systems
• R&D
– Laboratory research : GLP (Good Laboratory Practice)
– Preclinical study : OECD GLP (for safety test of candidate
materials (in vitro & in vivo assays))*
– Clinical Studies: GCP (Good Clinical Practice)*, GMP
(Good Manufacturing Practice) *for production of
candidate vaccine, GLP* for testing clinical trial samples
• Manufacture
– QMS (Quality Management System) : all related
management
– GMP* : product consistency
• QC (Quality Control): product quality & consistency
• Marketing
– GDP (Good Distribution Practice)
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Quality Assurance (QA) System Concepts
• Reliability
• Transparency
• Traceability
Documented evidence
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Key elements in QA system
Organization: Policy Documentation
&Scope of work system (Records,
Personnel: Qualification Archive/Doc.
&competency Control)
Facilities: Appropriateness
(Ex: Biosafety level, Audit system
qualification, validation, (Internal/external )
calibration, maintenance)
Work Performance: SOPs/Protocols
(Qualification, verification, validation)
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Applicants
Dossier
(manufacturer or
Vaccine regulatory process
distributor)
Pre-marketing phase Post Marketing phase
Licensing/Registration= evaluation process Market distribution
Product Lot release Post marketing
Evaluation AEFI
surveillance
Dossier
Laboratory
testing
GMP
Quality Licensing Regulatory
Compliance
facility inspections
Safety
Clinical trials
(Ethical review process, compliance against GLP,GMP,GCP)
Efficacy
Marketing Authorization
(M.A.)
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World Health Organization HTP/IVB/ATT/L.Belgharbi
National Regulatory Functions
recommended for vaccine
development
Source of vaccines
Regulatory functions UN agency Procure Produce
Regulatory system
Marketing Autorization
Postmarketing: AEFI
Lot release
Laboratory access
Regulatory inspections
Authorization &
monitoring of CTs
For countries conducting Clinical Trials
CTs : Clinical trials, UN: United Nations, AEFI: Adverse Events Following Immunization
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World Health Organization HTP/IVB/ATT/L.Belgharbi
Preventive/corrective
actions/ Amendments if Marketing Authorization (MA)
required
MA
GMP inspection NRA/
NCL
Changes/inconsistency Lot release
findings/suspected in
quality and safety
Post Marketing surveillance
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Regulatory system for Biological Products in Thailand
Function Responsible IBP support
organization
1. MA Bureau of Drug Quality, safety and stability
Control (BDC), FDA evaluation and laboratory
testing
2. Regulatory BDC Product specialist and lab
Inspection expert in GMP inspection team
3. Lot release IBP (Designated by
(vaccines & some FDA)
biologic products)
4. Laboratory IBP
Access
5. Post marketing FDA, Bureau of Laboratory test to confirm
surveillance Epidemiology, DDC quality and provide technical
advice for management
6. CTs oversight FDA Quality and safety evaluation
upon request
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MA
Registration dossiers GMP inspection
• Source materials • Source materials
Validation
• Manufacturing
procedures
-Process
• Quality (QC test • Intermediates
methods & -Equipment
specifications) -Method
• Stability data -System
• Finished products
• Labeling
• Closure and • Facilities
container system
• Clinical trial data
Consistency
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Source materials
– Seed -To demonstrate that
source materials meet
– Cell substrate
standards appropriate
– Eggs/animals for their intended use.
– Culture -Tests and acceptance
media criteria required
– Chemicals
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Important points for source materials
– Seed & cell substrate: History/source, specific
characteristics
– Seed lot system
– Cell banking system
– Control passage number of seed and cell
substrate
– Safety
• Contaminants from the source of origin (Risk
analysis)
– Summaries of viral safety information for biologically-
sourced materials (Potential to be pathogen of human being)
– Ruminant-derived materials should be free from
bovine spongiform encephalopathy (BSE)
– Other possible adventitious agents.
• Tumorigenicity of continuous cell line
– Genetic stability
– Appropriate specifications
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Manufacturing process & QC tests
Process Validation
• critical manufacturing steps
– Culturing (fermentation)
– Harvesting
– Inactivation
– Purification
– Final formulation
– Filling
– Any process modification which may
effect the product quality and safety
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Important points for manufacturing process
• Critical steps and its test parameter and acceptance
criteria
–Enough sensitivity to detect changes in
manufacturing process which may have impact
on the quality, safety and efficacy of the
vaccine.
• Major & minor modification should be defined
–Comparability of the product characteristics
with the original
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Similar Biotherapeutic Products(SBPs)
• SBP is a biotherapeutic product that is
similar in terms of quality, safety , and
efficacy of an already licensed reference
biotherapeutic products .
• RBP is reference biotherapeutic product
used as a comparator for head to head
comparability studies with a SBP to show
similarity in terms of quality, safety and
efficacy. Only an originator product that was
licensed on the basis of a full registration
dossier can serve as a RBP.
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SBPs evaluation
• Quality: Head-to-head comparison with
the RBP : Thorough characterization
(physicochemical properties, biological
activity, immunochemical properties,
process- & product-related impurities)
• Nonclinical : Pharmacotoxicological
assessment
• Clinical evaluation: Demonstrate
comparable safety and efficacy of SBP
and RBP.
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Reference Laboratory
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Reference laboratory
• What are the terms of reference?
– Scope of works/services
• At what level to be recognized?
– Network
– National level
– Regional level
– International level
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Reference laboratory Example
• Reference laboratories to assure the
quality of vaccines :
– National Control Laboratory (NCL): For
assuring the quality of vaccines
produced/used in country (In Thailand,
Institute of Biological Products (IBP),
Department of Medical Sciences, is
recognized as NCL).
– WHO contracted laboratory: For assuring
the quality of vaccines prequalified by WHO
(IBP, Thailand is one of twelve laboratories
which are WHO contracted laboratories).
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Prerequisites
• Establish and implement the Quality Assurance
System (or QMS) to ensure the quality and/or
competency of work performances.
EX:
– Testing laboratory: ISO/IEC 17025
– Medical laboratory: ISO 15189
• Meet the requirements of the user.
– Meet the specifications and/or,
– Audit/Site visit and/or,
– Evaluation of results
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Challenges
• High maintenance cost for QA system
• Fast movement of technologies & requirements
• High turnover rate of competent staff.
• Increased competition at international level.
– Networking increases.
– Systematic work sharing required
– Equal partnership and support from recognized
international organization are important .
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