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

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Introduction David Howe, Executive Director, Product and Hospital Services, Canadian Blood Services

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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

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Good Manufacturing Practices

A Working Definition

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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.

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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

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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.

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History of GMP United States - The Early Years

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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 Jungle (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

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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

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World Health Organization - GMPs

Quality assurance of pharmaceuticals A compendium of guidelines and related

materials, Volume 2, 2nd 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

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GMPs for Blood The Canadian Context

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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

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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

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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

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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

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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

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# 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

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Purpose built facility with unidirectional flow

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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)

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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!

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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

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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)

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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

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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

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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

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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

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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

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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

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C.02.011 / 012 Manufacturing Control Methods to optimize compliance Optimizing Process Control connecting the pieces

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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

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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

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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

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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

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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

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Temperatures specified in Z902 Standards for blood & Blood Components

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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

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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

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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 products1

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 donation1

1. de Korte D, Marcelis JH, 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

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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

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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

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In summary

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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

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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.

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Conclusions A continued focus on GMP for Blood

Component processing will prevent us from revisiting our past

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Thank you for your attention

Questions?

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GMP for Blood Component ProcessingIntroductionOverview of PresentationGood Manufacturing PracticesGood Manufacturing Practices a working definitionLaw vs. PolicyFood and Drugs ActGood Manufacturing PracticesHistory of GMPMajor Events in the development of GMPs (United States)Major Events in the development of GMPs (United States)World Health Organization - GMPsGMPs for BloodCanada - GMPsCanada - GMPsGood Manufacturing Practices for Schedule D Drugs, Part 2, Human Blood and Blood ComponentsCSA Z902, Blood and blood components standardHealth Canada Directives, D98-001 Pre-storage LeukoreductionSlide Number 18Slide Number 19C.02.004 PremisesSlide Number 21Slide Number 22C.02.005 EquipmentC.02.006 PersonnelC.02.007 / 008 SanitationC.02.009 / 010 Raw Material TestingC.02.009 / 010 Raw Material Testing - challenges to complianceC.02.009 / 010 Raw Material Testing - Methods to reinforce complianceC.02.009 / 010 Raw Material Testing - Methods to reinforce complianceC.02.011 / 012 Manufacturing ControlC.02.011 / 012 Manufacturing ControlLabellingC.02.011 / 012 Manufacturing ControlLabellingC.02.011 / 012 Manufacturing Control Methods to optimize complianceC.02.011 / 012 Manufacturing Control Methods to optimize complianceC.02.013 Quality Control DepartmentC.02.013 Quality Control DepartmentC.02.020 RecordsC.02.027 / 028 StabilityTemperatures specified in Z902 Standards for blood & Blood ComponentsC.02.029 Sterile ProductsC.02.029 Sterile ProductsMethods to reinforce complianceC.02.029 Sterile Products Methods to reinforce complianceC.02.029 Sterile Products Bacterial Detection of platelet concentratesC.02.029 Sterile ProductsMethods to reinforce complianceIn summaryConclusionsConclusionsConclusionsThank you for your attentionQuestions?