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

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:

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)

< 24 h

Albumin/Immunoglob./Co
agulation factors

>24h, <72h

Albumin/Immunoglob

Aphaeresis
(=source
plasma)

Hyperimmune
plasma

Usage

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 + 22C
< 8 hrs at + 4C

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 - 20C 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
18

WHO Assessment Criteria for National

Blood Regulatory Systems* - II
WHO STRUCTURE OF THE ASSESSMENT TOOL
A

Two essential functions (National Regulatory System

and National Regulatory Authority)
Criteria and indicators
Twelve Core functions
Criteria and indicators

19

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

20

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
21

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

22

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)
ECBS: WHO Expert Committee on Biological Standardization*
October 2012
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

The mandate
WHA 63.12 on availability, quality and safety of blood products

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)

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://
http:// www.who.int/bloodproducts
www.who.int/bloodproducts

Web site addresses

http://www.who.int/bloodproducts
http://www.who.int/bloodproducts/catalogue