Transcript Guidelines

Regulation of Plasma and Plasma Products
How Should We Regulate Blood and Blood Products?
Dr Ana Padilla
Blood Products and related Biologicals
Quality Assurance and Safety: Medicines
Essential Medicines and Health Products
Kuwait, 30 November 2012
Outline
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WHA Resolution 63.12 on blood products
Blood safety strategy
Criteria for suitability of recovered plasma
WHO assessment criteria for national blood
regulatory systems
Summary
Blood Products: Life-Saving Medicines
WHA Resolution 63.12
Blood products are defined as
therapeutic substances derived from
human blood, including whole blood,
labile blood components and plasmaderived medicinal products (WHA 63.12,
adopted 2010).
The World Health Assembly (WHA) Resolution 63.12*:
Need for Blood Products Regulation
 WHA resolution 63.12 recognized that:
 “stringent regulatory control is vital in assuring the quality and
safety of blood products…” and
 urged Member States to “update their national regulations … in
order to ensure that regulatory control in the area of quality and
safety of blood products across the entire transfusion chain
meets internationally recognized standards.”
 Strengthening regulatory systems for blood products and building
technical capacity of national and regional blood regulatory
authorities is recognized as a fundamental need to assure global
availability of safe blood products
*How to improve quality in BE for the production of BC, including plasma
TRACEABILITY
FROM DONOR TO PATIENT
Blood
donation
DONATION
INFORMATION
Blood
Components
Patients
Plasma for
Fractionation
Plasma-Derived
Medicinal Product
COMPONENTS
PREPARATION
FRACTIONATION
VIRAL
INACTIVATION
Good Manufacturing Practices
TREATMENT
The General Blood Safety Strategy
• Appropriate selection of blood donors
– Volunteer, non-remunerated donors
– Donor education and science-based risk factor screening
– Medical interview and physical examination
• Infectious disease testing on blood plasma donations: screening
strategies and selection of test kits and validation
– HIV, hepatitis B, hepatitis C
– Additional testing is based on regional epidemiology
(e.g. HTLV, West Nile Virus, T. cruzi)
• Epidemiological surveillance of donor population
• Adherence to GMP in blood collection and processing
• Vigilance systems: adverse reactions in donors and recipients
Viral safety testing
Individual donations/plasma units
 Serological tests: blood establishment
– HBsAg, HIV-Ab, HCV-Ab (§)
 Nucleic acid based technology (NAT):
– HCV in plasma pools (mini-pools) (§),
– HIV*, Parvo B19*, HAV*, HBV*
(§) mandatory tests; *additional tests may be required by some NRAs
* some countries
Selection of viral test kits
• The precise selection of viral test kits should take into
account several scientifically-based aspects including:
– Specificity/sensitivity of tests
– Donor characteristics (e.g. first time vs repeat donors)
– Local epidemiological situations (e.g. viral genotypes*)
– Evolution of testing technologies
– Understanding the risks and limitations of the assays
*Relevant reference panels established by WHO:
http://www.who.int/bloodproducts/catalogue/en/index.html
Residual Infectious Risk
• Residual infectious risk due to:
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Limitations of screening methods
Errors in blood/plasma virus testing
Plasma donation mishandling
Window period: test negative/virus present
 Can be significant when subsequent pooling is used to
prepare a manufacturing batch
 Resulting products derived from a contaminated plasma
pool may infect a large population of recipients
 Finished product safety testing is not a substitute for
effective quality systems and arrangements for
regulation/control
Window period estimates
 HIV - the infectious window period is estimated to be:
– 19 days for anti-HIV
– 15 days for HIV p24 antigen and
– 5 days for sensitive NAT testing
 For HCV, the infectious window period is estimated to be
– 65 days for anti-HCV
– 3 days for sensitive NAT testing
 For HBV, the infectious window period is estimated to be
– 36 days for HBsAg and
– 21 days for sensitive NAT testing.
Operational parameters affecting
quality of plasma for fractionation
• Plasma separation method
• Anticoagulant
• Time to separation from cells
• Time and temperature from collection to freezing
• Cell content
• Rate of freezing
• Storage time and temperature, including during transport
Types of plasma
WHO recommendations for Plasma for Fractionation
Frozen
Whole blood
(=recovered
plasma)
Usage
< 24 h
Albumin/Immunoglob./C
oagulation factors
>24h, <72h
Albumin/Immunoglob
Aphaeresis
(=source
plasma)
Hyperimmune
plasma
Usually frozen
after collection
Albumin/Immunoglob./Cl
otting factors
Specific
Immunoglobulins
Freezing and storage
WHO recommendations for Plasma for Fractionation
 Whole blood holding time before plasma separation:
– < 18 – 20 hrs at + 22˚C
– < 8 hrs at + 4˚C
 Plasma holding time and freezing conditions:
– Freezing asap after separation
– Freezing rapid rate, important quality factor (specified by the
fractionators)
– Validated freezing process: consistency
 Storage and transportation at - 20˚C or colder,
constant
Factors influencing quality and safety of
Plasma Derivatives
– Quality & safety of plasma (starting material)*
– Process design:
– Fractionation process
– Viral Inactivation/Removal Procedures (#)
– Strict adherence to GMP for production processes
* WHO recommendations for production, control and regulation of plasma for fractionation (2007):
http://www.who.int/entity/bloodproducts/publications/TRS941Annex4blood.pdf
(#) WHO guidelines on viral inactivation and removal procedures intended to assure the viral safety of human
blood plasma products (2005): http://www.who.int/entity/bloodproducts
Regulatory considerations
• Regulatory oversight serves to ensure that blood
establishments, plasma fractionators and care
providers
– have control of the entire production process
– monitor the safety and quality of products, and
– take appropriate action if adverse events occur
• Regulation, national standards for blood
establishments, is needed to assure that unused
plasma is suitable for fractionation
Assessment Criteria for National
Blood Regulatory Systems - I
 Consistent with WHA Resolution 63.12, WHO has developed
Assessment Criteria for National Blood Regulatory Systems
– To provide a tool to assist capacity building of National Regulatory
Authorities (NRAs) for blood and blood products
– For both developed and developing countries, a benchmarking
and/or assessment process that could serve to highlight strengths
of the NRA while identifying gaps or areas for future development
– Global criteria also promote international standardization, which
may reduce burdens to product developers
* WHO BRN includes representatives from Health Canada, ANSM,
Paul Ehrlich Institute, Swissmedic, TGA Australia, US FDA and
MHLWL Japan. WHO provides the Secretariat.
WHO Assessment Criteria for National
Blood Regulatory Systems* - I
PURPOSE & OBJECTIVES
1. To identify essential control functions that should be
undertaken by an effective/functional NRA to assure the
quality, safety and efficacy of blood and blood products as
well as associated substances and medical devices
including in vitro diagnostics
2. To establish standard indicators for these essential
functions in order to allow NRAs to assess their
performance in the regulation of blood and blood products
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WHO Assessment Criteria for National
Blood Regulatory Systems* - II
WHO STRUCTURE OF THE ASSESSMENT TOOL
A
B
Two essential functions (National Regulatory System
and National Regulatory Authority)
Criteria and indicators
Twelve Core functions
Criteria and indicators
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National Blood Regulatory Systems:
Core Functions
1. Licensing/registration of blood establishments
2. Licensing/registration of manufacturers and
distributors of plasma derived products
3. Approval of blood and blood components
4. Approval of plasma derived products
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National Blood Regulatory Systems:
Core Functions
5. Regulatory oversight of associated substances
and medical devices including in vitro diagnostics
6. Access to a laboratory independent of
manufacturers
7. Control of clinical trials
8. System for lot release of plasma derived products
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National Blood Regulatory Systems:
Core Functions
9. Regulatory inspections and enforcement activities
10. Vigilance systems
11. Ensuring traceability and record keeping by
manufacturers for all regulated products
. 12. International cooperation
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Conclusions – Blood Regulation
 Blood regulation within a legal framework is an
essential element of any national blood system
– Meeting evidence based standards for blood collection and
processing minimizes the inherent risks of blood transfusion
– By assuring that standards are met, blood regulation serves
to protect donors and to promote and maintain the quality
and safety of both blood components for transfusion and
plasma for fractionation
 The acceptability of plasma for fractionation depends
upon a system in which compliance with recognized
standards is verified through regulation
Conclusions – Plasma Derivatives
 Plasma for fractionation is needed to generate
essential plasma-derived medicinal products (e.g.
clotting factors and immune globulins)
 National and global sufficiency in plasma products
can be achieved only by reducing wastage of nontransfused plasma
 Suitability of plasma for fractionation depends on
meeting evidence based quality standards for
blood collection and component manufacturing
National Regulation of Blood Components
as Medicines
Blood is regulated as a medicine in many jurisdictions, either
directly or indirectly, e.g.
 In the US, Canada, Germany and Switzerland, blood and blood
components are directly regulated as biological medicines
 In Japan, Blood and Blood Products are regulated as safety
measures by the “Pharmaceutical Affairs Law” and under the
“Law on Securing a Stable Supply of Safe Blood Products”
 In Australia, blood component manufacturers are subject to
licensing to assure that the products meet standards as per the
Council of Europe “Guide”
Common to all blood component regulations are requirements to
assure that blood components meet product standards through
controls on manufacturing, often explicitly stated as Good
Manufacturing Practice requirements
The concept of Whole Blood and
Blood Red Cells as Essential Medicines
has been unanimously endorsed by the
WHO ECBS*, the WHO BRN and the
International Conference of Drug
Regulatory Authorities (ICDRA)
October 2012
*ECBS: WHO Expert Committee on Biological Standardization
*BRN: WHO Blood Regulators Network
Overall objectives*
• Assist countries to use recovered plasma to
generate essential medicines
• Assist countries to improve quality and
safety of all blood components
• Improve quality production systems in blood
establishments
* WHO Report to be published shortly
WHO available tools
www.who.int/bloodproducts
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The mandate
 WHA 63.12 on availability, quality and safety of blood products
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The tools (internationally agreed standards)
 Assessment criteria for national blood regulatory systems (2012)
 WHO Guidelines on GMP for blood establishments (2011)
 WHO Guidelines on Production, control & regulation plasma for
fractionation (2007)
 WHO Guidelines on Viral Inactivation and Removal procedures(2005)
 WHO catalogue of biological reference materials: blood products and blood
safety IVDs (on-going development and establishment)
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Collaboration with government organizations: national regulatory authorities,
national blood programmes and Inspectorate
 Training experience strengthening implementation of regulatory systems
 Wide international expert networks: ECBS, BRN, WHOCC, others
 Worldwide network of National Regulatory Authorities (ICDRA)
WHO guidance documents: website addressed
www.who.int/bloodproducts
• Reference on GMP for blood establishments (2011):
http://www.who.int/entity/bloodproducts/publications/GMP_Bloodestablishments.pdf
• Reference on production, control and regulation of plasma for fractionation (2007):
http://www.who.int/entity/bloodproducts/publications/TRS941Annex4blood.pdf
• Reference on viral inactivation and removal procedures (2005):
http://www.who.int/entity/bloodproducts/publications/GMP_Bloodestablishments.pdf
• Catalogue of blood products and blood safety related reference materials:
http://www.who.int/bloodproducts/catalogue/en/index.html
http:// www.who.int/bloodproducts
Web site addresses
http://www.who.int/bloodproducts
http://www.who.int/bloodproducts/catalogue