GMP for Blood

Component Processing
FACT 2011
Fresenius Kabi Advanced Course on Transfusion
Technology October 12-13, 2011 Chiang Mai, Thailand

1
Introduction
David Howe, Executive Director, Product and
Hospital Services, Canadian Blood Services
2
Overview of Presentation
GMP For Blood Component Processing
GMP a working definition
Brief History of GMP US The Early Years
GMP for blood - The Canadian Context
Applying GMP To Blood Component
Processing
Conclusions
3
Good Manufacturing
Practices
A Working Definition
4
Good Manufacturing Practices
a working definition
The integration of personnel with facilities,
including utilities, equipment, materials and
components, procedures and control systems
which ensure that drug products are
consistently produced to predefined quality
standards that are appropriate to their
intended use and in accordance with their
marketing authorization.

5

Law vs. Policy
Food and Drugs Act
Valid federal legislation
Covers pre-market and
post-market sale
Powers of Inspectors
Prosecution
Governor-in-Council
may make regulations
to carry out the
purposes of the Act
6
Good Manufacturing Practices
The F&D Act and
the regulations are
law. They are
legally binding.
Policy and
guidelines are
interpretations of
the legal
requirements and
are not binding per
se.
7
History of GMP
United States - The Early Years
8
Major Events in the development of GMPs
(United States)
Year Legislation Background
1902 Biologics Control Act - requires
inspection and testing of
manufacturers of biologics facilities
and products
Enacted following the death of 12 children
who contracted tetanus from
contaminated diphtheria vaccine
1906 Pure Food and Drug Act:
illegal to sell adulterated or
misbranded food & drug
labelling must be truthful, and
include dangerous ingredients on
all drugs
misbranding becomes illegal
Enacted following publication of The
J ungle (Upton Sinclair), which detailed the
unsanitary conditions of the meat industry,
specifically in Chicago

Responsible for creation of what is now
known as the FDA
1938 Federal Food, Drug and Cosmetic
(FD&C) Act:
requires manufacturers to
demonstrate the safety of any
product prior to releasing to market
Enacted following the deaths of 107
people who were prescribed sulfanilamide
made with poisonous solvent.
1941 Insulin Amendment:
- dramatically increased
manufacturing and quality controls
Enacted following the deaths/injuries of
nearly 300 people from prescribed
sulfathiazole tablets tainted with
Phenobarbital
9
Major Events in the development of GMPs
(United States)
Year Legislation Background
1962 Kefauver-Harris Drug Amendments:
requires manufacturers to
demonstrate the efficacy of any
product prior to releasing to
market;
more rigorous controls for drug
testing
regulation of clinical trials
manufacturers required to report
any/all adverse events
Enacted following the severe birth defects
linked to thalidomide; estimate of 10,000
infant deformities in Europe. Product not
permitted for use in US.
1963 GMPs for Drugs (28 FR 6385): - the minimum GMP requirements for the
manufacture, processing, packaging or
maintaining (i.e., storage) of finished
pharmaceuticals

1975 GMPs for Blood and Blood
Components
- the minimum GMP requirements for the
collection, processing, testing
(compatibility), storage and distribution of
blood and blood components
10
World Health Organization - GMPs
Quality assurance of pharmaceuticals
A compendium of guidelines and related
materials, Volume 2, 2
nd
updated version,
Good manufacturing practices and
inspection
WHO Technical Report Series:
Annex 3: Good manufacturing practices for
biological products
Annex 4: WHO guidelines on good
manufacturing practices for blood
establishments, 2011

11
GMPs for Blood
The Canadian Context
12
Canada - GMPs
Regulations comparable to GMPs were first issued by the
Canadian Specifications Board of the Supply and Services
Department in 1957. These regulations were issued to ensure
that military personnel received drugs that met quality
specifications
Food and Drugs Regulations, Part C Division 2 codify good
manufacturing products for blood manufacturing, 1989
Blood Collection and Blood Component Manufacturing, Drugs
Directorate Guideline, 1992
Annex to the GMP Guidelines, Good Manufacturing Practices
for Schedule D Drugs, Part 2 Human Blood and Blood
Components, December 1, 1999
13
Canada - GMPs
HPFBI: GUI-0001 Good Manufacturing Practices
(GMP) Guidelines 2009 Edition, Version 2, March 4,
2011
Draft Blood Regulations are anticipated to be
published in Canada Gazette Part in 2011. The
stand-alone Blood Regulations -- under the authority
of the Food and Drugs Act -- will contain safety,
quality and efficacy requirements with respect to
blood for transfusion or for further manufacture
CSA Z902, Blood and blood components
standard
14
Good Manufacturing Practices for
Schedule D Drugs, Part 2, Human Blood
and Blood Components
The purpose of the document is to provide
specific guidance for the application of good
manufacturing practices to blood establishments
in accordance with the F&D Regulations
It is a fairly high level document and doesnt go
into the level of detail that a standard would
It instead translates the requirements of GMPs
for drugs into blood specific GMP guidelines

15

CSA Z902, Blood and blood
components standard
Updated in February 2010
Intended to be referenced in the
new Blood Regulations as the
specific requirements for blood and
blood components
Currently a voluntary standard but
will become compulsory in
accordance with the F&D
Regulations
Unlike GMPs the Standards will span
from vein (donor) to vein (recipient)
so will apply to the Blood Operator
as well as the Hospital Blood Bank
16

Health Canada Directives,
D98-001 Pre-storage Leukoreduction
In November 1998, Health Canada mandated the
implementation of pre-storage leukoreduction of Cellular Blood
Components
The leukoreduced blood and blood components should be
prepared by a method known to reduce the residual leukocyte
content to levels below 5 x 106 cells per component.
The blood operators were given 4 months to submit a license
amendment and 8 months to implement!
Health Canada have not issued another Directive since this one,
questionable regulatory practice
Tight timelines aside, the directive has decreased mortality as
well as decreased fever episodes and antibiotic use after red
blood cell transfusion in high-risk patients
1


1
Hebert et al, Clinical Outcomes Following Institution of the Canadian Universal Leukoreduction Program for
Red Blood Cell Transfusions 003;289(15):1941-1949. doi: 10.1001/jama.289.15.1941

17

18
19
# Section
C.02.004 Premises
C.02.005 Equipment
C.02.006 Personnel
C.02.007- 008 Sanitation
C.02.009 - 010 Raw Material Testing
C.02.011 012 Manufacturing Control
C.02.013 - 015 Quality Control Department
C.02.016 - 017 Packaging Material Testing
C.02.018 - 019 Finished Product Testing
C.02.020 - 024 Records
C.02.025 - 026 Samples
C.02.027 - 028 Stability
C.02.029 Sterile Products
C.02.004 Premises


The facility is designed, constructed and maintained to prevent
contamination of the drug product, cross-contamination between drug
products and mix-ups
The premises is laid out in a manner that allows a natural and controlled
flow of personnel and materials
The section specifies segregated, secure areas for various blood processing
activities such as;
Donor screening
Quarantine storage of product and supplies
Processing and Testing
It also provides some provision for collection of blood in mobile locations
This section is not as critical for blood components compared with other
pharmaceuticals, since production is maintained in a closed system

20


Purpose built facility with unidirectional flow
21
22

C.02.005 Equipment
Requires all equipment used in the collection, processing and
testing of blood component to be validated, maintained and
calibrated according to pre-defined schedules
Requires that Operating Procedures must be available for all
equipment
Requires computers, which maintain data used to identify
donors, to make decisions regarding the suitability of blood
components for transfusion or further manufacture, and/ or to
maintain data used to trace a unit of blood or a blood
component from collection to its final disposition, must be
validated in accordance with current Health Canada guidelines
(Validation of Computerized Systems in Blood Establishments)
23


C.02.006 Personnel
Requires;
An organizational chart be available
Suitably qualified staff suitably vague!
All staff to be trained and assessed for
competency
That the specific roles of Production
Manager, Quality Assurance Manager (must
be independent) and Medical Officer be in
place
If it breathes train it.
It it doesn't breath
calibrate it!
24

C.02.007 / 008 Sanitation
Requires
Clean and sanitary conditions
Pest control program
Sanitation program
Method for disposal of blood as
biohazardous waste
Clothing and behavior standards
25

C.02.009 / 010 Raw Material Testing
Raw material translates to
blood donors!
The facility will have
operating procedures for
donor selection...
Outlined in a Donor Selection
Criteria Manual and contain
criteria to protect the donor
and criteria to protect the
recipient
Donor information elicited
through a comprehensive
health screening
questionnaire (Record of
Donation)
26
C.02.009 / 010 Raw Material Testing
- challenges to compliance
Donor selection criteria are
getting more and more
complex
If you are relying on paper
records and manual
transcription it can be difficult to
maintain process control
To eliminate the human
variability, the use of Electronic
Registration and Questionnaire
Systems is recommended

27

C.02.009 / 010 Raw Material Testing
- Methods to reinforce compliance
Pre-screening of donors before they
reach the blood donor clinic
Make basic donor eligibility
criteria readily available to
potential donors
Have qualified staff readily
available to respond to donor
eligibility questions
Canadian Blood Services
operates a call centre 24 x 7
with Registered Nurses
available to respond to donors
28

C.02.009 / 010 Raw Material Testing
- Methods to reinforce compliance
Vital Signs Monitors should
be used to measure donor
pulse, blood pressure, and
temperature
Hemoglobin assessment
should be conducted via
an automated device
For apheresis procedures
the use of point of care
hematology analyzer will
optimize the collection
procedure
All of these devices
should ideally
communicate results
directly to your
Blood Information
System
29
C.02.011 / 012 Manufacturing
Control
Requires:
Operating Procedures for all
critical parts of the operation
A process for change control
A process of recall
A process for internal audit
Controls for product labelling
Circular of information
30
C.02.011 / 012 Manufacturing Control
Labelling
Sample / Unit Labeling - a critical
control point outlined in GMPs
Starts with the collection process
with a unique number sequence
linking the donor samples and unit
The same donation number is then
used to ensure the traceability of
any components manufactured
from the donation
Label sets can be pre-produced
or printed on demand
31
C.02.011 / 012 Manufacturing Control
Labelling
GMPs and CSA Z902 Standards do
specify certain label content but
do not specify format
ISBT 128 Labeling - Not mandated
by Canadian GMP or CSA
Standards however is a
requirement of some hospital
blood bank standards, e.g. AABB
Canadian Blood Services
implemented ISBT 128 but has
maintained an extended label
in the old codabar format for
hospitals who are late adopters

32
C.02.011 / 012 Manufacturing Control
Methods to optimize compliance
Optimizing Process Control connecting the pieces
33
C.02.011 / 012 Manufacturing Control
Methods to optimize compliance
Optimizing Process Control
Or you can improve process
control by limiting the number
of pieces
Apheresis Devices
Fully automated Whole
Blood processors
Both have their pros and cons
34

C.02.013 Quality Control Department
There is a formally defined
quality unit that has authority
and autonomy to act
independently - production,
sales
Exercises effective control
over release/rejection of all
materials and blood
components, as well as all
operating procedures,
specifications, and protocols.
The specifics of the QC
program are not in the GMPs
but are included in the CSA
Z902 Standards for Blood &
Blood Components

35
C.02.013 Quality Control
Department
This section also includes the requirements for Serological and Transmissible
Disease Testing
Unlike other sections the GMPs are quite prescriptive however they look a little
dated when compared to current practices (no NAT, WNV, Chagas)

All donors of whole blood must be tested for the following serological tests at the time of each
donation:
ABO group, including forward and reverse grouping
Rh group (D and weak D testing)
Antibody screen
All donors must be screened for the following transmissible disease markers at the time of each
donation:
Syphilis
Hepatitis B surface antigen (HBsAg)
Antibody to Hepatitis C virus (HCV)
Antibody to HIV type 1 and 2
Antibody to HTLV-I/II (except plasma for further manufacturing use only) HIV-1 p24 Ag
Any disease marker(s) specifically required by the Minister

36

C.02.020 Records
The 2 simple rules of records
1. If it isnt written down, its just
rumor.
2. If you didnt record it, you didnt
do it.

Records need to be kept for
each critical step of the process
to allow for traceability
Records of manufacturing need
to be maintained indefinitely

37

C.02.027 / 028 Stability
Blood components need to be
stored under predefined
storage conditions with
continuous monitoring
These rules apply for interim
storage during transportation
Temperatures specified in Z902
Standards for Blood & Blood
Components
Z902 Standards due allow for
the 24 hr hold of blood at room
temperature (RT) if units are
rapidly cooled to RT
38

Temperatures specified in Z902 Standards
for blood & Blood Components
39
C.02.029 Sterile Products
GMPs require periodic testing to
ensure sterility and implementation
of methods to minimize the risk of
contamination
Closed bag systems for blood
component manufacturing make
compliance a less onerous task than
other pharmaceuticals
Methods used to reinforce
compliance
Skin disinfection technique
Sample diversion pouch
Bacterial Detection
40
C.02.029 Sterile Products
Methods to reinforce compliance
Ascetic Technique Skin Disinfection Technique
Bacterial contamination of blood products, particularly platelets, can
cause severe septic transfusion reactions
Experience with routine platelet cultures has demonstrated that skin
flora are the most frequent organisms
Factors that have been shown to be important in optimizing arm
scrubs in studies of blood components include;
staff training,
one vs. two step (both can be fine, but in some studies 2 step was
better, in others, not),
type and concentration of disinfectant,
and type of applicator (swab stick, brush, etc.)
Blood operators in Canada , UK, and most of US currently using a one
step chlorhexidine and alcohol disinfection kit
41

C.02.029 Sterile Products
Methods to reinforce compliance
Ascetic Technique Sample Diversion Pouch
Even the most stringent skin disinfection techniques
may not be able to ensure a sterile venipuncture
because:
Subcutaneous hair follicles, sebaceous glands
and skin dimpling may contain bacteria that are
not disinfected using the normal processes.
Skin plugscan occur during needle puncture.
The skin harbors bacteria
Blood collection processes designed to discard or
divert the initial 10-20 mL of blood during blood
donation result in a significant reduction in the
incidence in bacterial contaminated blood
products
1
In one study, the incidence of bacteria
contamination was reduced from 0.35% to 0.21%
following diversion of the first 10 mL of blood from
the donation
1

1
.
de Korte D, Marcelis J H, Verhoeven AJ , Soeterboek AM. Diversion of the first blood volume results in a reduction of
bacterial contamination for whole-blood collections. Vox Sang 83: 13-16, 2002

42
C.02.029 Sterile Products
Bacterial Detection of platelet concentrates
Maintaining the sterility..
The first edition (2007) of the CSA Z902 Standards for Blood and Blood
Components required that all platelet concentrates be tested for
the presence of bacteria. The standards were however silent on
whether this needed to be completed by the blood operator or the
hospital
In 2004 CBS begun bacterial detection for apheresis platelets only
In 2006 CBS made the decision to implement bacterial detection for
all platelets prior to publication of the CSA standards
Bacterial screening of apheresis PLTs in Canada was successfully
implemented, and transfusion of contaminated units was
prevented. Rapid bacterial detection systems that could be used
before transfusion, however, may further reduce the risk of
transfusion reactions
1
Canadian experience with detection of bacterial contamination in apheresis platelets, Sandra Ramrez-Arcos et al,
Transfusion, Volume 47, Issue 3, pages 421429, March 2007
43

C.02.029 Sterile Products
Methods to reinforce compliance
Pathogen Reduction
Not contemplated in the GMPs
or standards but will likely be in
the future as devices get
licensed
Process changes like pathogen
reduction are based on the
proactive principle of acting
now to avoid trouble in the
future
This is the same principle behind
GMP, build the quality into your
blood components, dont just
test for it
44

In summary
45
Conclusions
GMPs have been around in various forms for
many years
More recently they have been applied to blood
Ive focused on Canadian GMPs and how they
are applied by Canadian Blood Services
With harmonization of GMPs the differences
between country specific guidelines are
diminishing

46

Conclusions
A working definition revisited

The integration of personnel with facilities,
including utilities, equipment, materials and
components, procedures and control systems
which ensure that blood components are
consistently produced to predefined quality
standards that are appropriate to their intended
use of saving lives, not causing harm.

47

Conclusions
A continued focus on GMP for Blood
Component processing will prevent us from
revisiting our past
48

Thank you for your attention

Questions?
49