Guidance Document: Human Plasma Collected by Plasmapheresis

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Contact: Regulatory Affairs Division

February 22, 2008

Notice

Our file number: 08-102026-988

Release of Guidance Document: Human Plasma Collected by Plasmapheresis

The final version of the Health Canada guidance document Human Plasma Collected by Plasmapheresis is now available. The document provides regulatory guidance to Canadian establishments that collect human plasma by plasmapheresis for use in the manufacture of human drugs.

This guidance document should be read in parallel with the Regulations Amending the Food and Drug Regulations - Human Plasma Collected by Plasmapheresis (also referred to as the Plasmapheresis Regulations).

Comments and suggestions received from the consultation on the draft version of the guidance were reviewed and considered in the finalization of this document.

Comments or questions related to this guidance document may be directed to:

Blood Establishment Regulation Unit
Blood, Tissues, Organs and Vaccine - Regulatory Affairs Division
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
Health Products and Food Branch
Address Locator: 0701A
200 Tunney's Pasture Driveway
Ottawa, ON
K1A 0K9

Fax number: 613-948-3564
Email: BGTD_D_Enquiries@hc-sc.gc.ca

Human Plasma Collected by Plasmapheresis

Published by authority of the
Minister of Health

Date Adopted
2008/02/22

Effective Date
2008/02/22

Available in Canada through
Health Canada - Publications
Brooke Claxton Building, A.L. #0913A
Tunney's Pasture
Ottawa, Ontario
K1A 0K9

Tel: 613-954-5995
Fax: 613-941-5366

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances.

Table of Contents

• 1 Introduction
  • 1.1 Objectives
  • 1.2 Scope and Application
  • 1.3 Regulatory Overview
  • 1.4 Acronyms and Definitions
    
    
• 2 Licencing Requirements
  • 2.1 Establishment Licence and Licence Application
  • 2.2 Licence Amendments
    
    
• 3 Roles and Responsibilities
  • 3.1 Fabricator
  • 3.2 Physician and Physician Substitute
    
    
• 4 Establishing Donor Suitability
  • 4.1 Informed Consent
  • 4.2 Donor Screening
  • 4.3 Donor Deferral
    
    
• 5 Collection of Source Plasma
  • 5.1. Good Manufacturing Practices
  • 5.2 Plasmapheresis Procedures
  • 5.3 Anticoagulant Solution
  • 5.4 Maximum Volumes and Minimum Intervals for the Collection of Plasma
    
    
• 6 Product Safety
  • 6.1 Containers and Labelling
  • 6.2 Storage
    
    
• 7 Adverse reaction reporting and product recall
  • 7.1 Serious Adverse Reaction Reporting
  • 7.2 Errors and Accidents and Recall of Source Plasma
    
    
• 8 Records Management
  
  
• 9 Additional Information

1 Introduction

1.1 Policy Objectives

The objectives of the Regulations Amending the Food and Drug Regulations - Human Plasma Collected by Plasmapheresis (also referred to as the Plasmapheresis Regulations) are to maximize the safety and quality of human plasma collected by plasmapheresis and to maximize the safety of the donors participating in plasmapheresis.

This document provides guidance on the regulatory requirements governing the collection of human plasma by plasmapheresis.

1.2 Scope and Application

The regulations and this guidance document apply to establishments in Canada that collect human plasma by plasmapheresis for use in the manufacture of human drugs. Plasma collected for this purpose is referred to as "source plasma".

This guidance document does not apply to recovered plasma or human plasma collected for the purpose of transfusion. In addition, this document does not apply to control reagents in diagnostic test kits or blood typing anti-sera; these are regulated as in vitro diagnostic devices under the Medical Devices Regulations.

This document should be read in parallel with the Plasmapheresis Regulations, under Part C, Division 4 of the Food and Drug Regulations. In the event of any perceived inconsistency or conflict, the Food and Drug Regulations take precedence over this guidance document.

In this guidance document, "shall" is used to express a requirement, i.e., a provision that the user is obliged to satisfy in order to comply with the regulatory requirements; "should" is used to express a recommendation or that which is advised but not required; and "may" is used to express an option or that which is permissible within the limits of the guidance document.

1.3 Regulatory Overview

Plasmapheresis is a process by which blood is collected from a donor, the plasma portion of the blood is separated out, and the red blood cells and formed elements from the blood are returned to the donor. This may be performed by manual or automated methods. Source plasma collected by plasmapheresis is used in the manufacture of human drugs, such as albumin, clotting factors, or immune globulins.

Human plasma collected by plasmapheresis is regulated as a Schedule D (biologic) drug under the Food and Drugs Act and is primarily subject to the following divisions of Part C of the Food and Drug Regulations: Division 1A, which contains requirements for Establishment Licencing, Division 2, which contains Good Manufacturing Practices (GMP), and Division 4, which contains regulatory requirements applicable to Schedule D drugs and specific regulations for human plasma collected by plasmapheresis.

The regulations specifically governing the collection of human plasma by plasmapheresis were originally promulgated in 1978 under Division 4 of the Food and Drug Regulations. Some of these regulations became outdated as they were written based on manual plasmapheresis processes rather than the current automated processes. These regulations have been amended to reflect current methods and practices used in plasmapheresis and current requirements for transmissible disease testing. The specific regulatory requirements are in sections C.04.400 to C.04.423 of the Food and Drug Regulations. The regulations are administered by the Biologics and Genetic Therapies Directorate (BGTD), in partnership with the Health Products and Food Branch Inspectorate (HPFBI).

Many plasmapheresis donors are 'repeat donors' (i.e. donate repeatedly at regular intervals). Some donors are immunized in order to donate plasma containing specific antibodies; hence the regulatory framework provides additional measures to protect the safety of the donor involved.

1.4 Acronyms and Definitions

1.4.1 Acronyms

AIDS

Acquired Immunodeficiency Syndrome

BGTD

Biologics and Genetic Therapies Directorate

CJD

Creutzfeldt-Jakob Disease

CSA

Canadian Standards Association

DIN

Drug Identification Number

EL

Establishment Licence

GMP

Good Manufacturing Practices

HBsAg

Hepatitis B Surface Antigen

HCV

Hepatitis C Virus

HIV

Human Immunodeficiency Virus

HPFBI

Health Products and Food Branch Inspectorate

vCJD

variant Creutzfeldt-Jakob Disease

1.4.2 Definitions

Note: The definitions listed below are obtained from section C.04.400 of the Plasmapheresis Regulations. During the development of these definitions, the National Standard of Canada CAN/CSA-Z902-04 entitled Blood and Blood Components and other relevant documents containing domestic and international definitions were considered. Regarding plasmapheresis, where there are discrepancies, the definitions prescribed in the regulations shall apply.

Accident - an unexpected event that is not attributable to a deviation from a fabricator's procedures or applicable laws and that could adversely affect the safety of a donor or the safety, efficacy, or quality of plasma.

Donor - a person aged 17 years or older and who has given their name to a fabricator for the purpose of participating in plasmapheresis with that fabricator.

Error - a deviation from a fabricator's procedures or applicable laws that could adversely affect the safety of a donor or the safety, efficacy, or quality of plasma.

Fabricator - a person who is the holder of an establishment licence issued under these Regulations that authorizes the person to fabricate source plasma.

Personal identifier - a unique group of letters, numbers or symbols, or any combination of them, that is assigned to a donor by a fabricator.

Physician - a person who is entitled to practise the profession of medicine under the laws of the province in which the person provides medical service in connection with plasmapheresis or specific immunization.

Physician substitute - a person who

1. acts under the general supervision and direction of a physician; and
2. is authorized to provide the services that may be provided by a physician substitute under sections C.04.401 to C.04.423, according to the applicable laws of the province in which the person provides any of those services.

Plasmapheresis - a process during which:

1. blood is taken from a donor from which plasma is separated; and
2. red blood cells and formed elements from the blood are returned to the donor.

Plasmapheresis session - a meeting between a fabricator and a donor held for the purpose of proceeding with plasmapheresis.

Serious adverse reaction - an unexpected and undesirable response in a donor, associated with plasmapheresis or specific immunization, that results in any of the following consequences for the donor:

1. hospitalization;
2. persistent or significant disability or incapacity;
3. a medical or surgical intervention to preclude a persistent or significant disability or incapacity;
4. a life-threatening condition; or
5. death.

Source Plasma - human plasma collected by plasmapheresis that is intended for use in producing a drug for human use.

Specific immunization - the administration of an immunogen to a donor with the intention of eliciting an immune response in their blood for the purpose of plasmapheresis.

Unique Identifier - a unique group of letters, numbers or symbols, or any combination of them that is assigned by a fabricator to source plasma or red blood cells to be used in specific immunization.

2 Licensing Requirements

2.1 Establishment Licence and Licence Application

Pursuant to section C01A.004 of the Food and Drug Regulations, fabricators who perform plasmapheresis in Canada shall do so in accordance with an Establishment Licence (EL). Laboratories performing transmissible disease testing in Canada also require an EL.

To obtain an EL, the fabricator shall submit an application to the HPFBI. A License Application must be submitted concurrently to BGTD. Review of the two applications is coordinated between the HPFBI and BGTD. The fabricator shall renew the EL annually with the HPFBI; whereas the Licence Application is not renewed after the initial application.

All foreign sites performing donor testing to determine the safety of source plasma are to be included on the Foreign Site Annex to the EL and evidence of compliance with GMP is required for each site.

Fabricators should refer to the Drug Establishment Licence Application: Form and Instructions for guidance on submitting an EL application and the Guidance for Industry: Management of Blood Establishment Submissions for guidance on submitting a Licence Application Submission.

2.1.1 Good Manufacturing Practices

A fabricator wishing to obtain an EL shall demonstrate that all applicable requirements for GMP have been met, as outlined in Part C, Division 2 of the Food and Drug Regulations and the Annex to the GMP Guidelines, Good Manufacturing Practices for Schedule D Drugs, Part 2: Human Blood and Blood Components. Blood establishments are inspected at least annually by Health Canada to assess their compliance with the applicable regulations. Fabricators that collect source plasma are also inspected according to requirements set out in Part C, Division 4 of the Food and Drug Regulations.

2.1.2 Annex to the Establishment Licence

Pursuant to section C.01A.008(4) of the Food and Drug Regulations, BGTD may set out terms and conditions relative to each fabricator's EL. Details of the terms and conditions will be provided to the fabricator in the Whole Blood and its Components Annex to Establishment Licences, which is affixed to the EL(s) issued to all Blood Establishments.

2.2 Licence Amendments / Notices

Once an EL has been issued by the HPFBI, changes to approved operations shall be submitted to BGTD for review prior to their implementation. Fabricators should refer to the Guidance for Industry: Management of Blood Establishment Submissions, and the Blood Establishment Licence Amendment Requirements for Information Technology Submissions for further guidance on filing licence amendments and notices.

3 Roles and Responsibilities

3.1 Fabricator

The fabricator's responsibilities with respect to plasmapheresis are outlined in section C.04.402 and throughout the Plasmapheresis Regulations. The scope of a fabricator's responsibilities ranges from ensuring that the premises used for donor screening enable communication in confidence, through ensuring proper testing of blood samples to detect evidence of disease agents, to ensuring that the storage environment of source plasma is adequate. Therefore, a fabricator shall be ultimately responsible for the quality and safety of the collected source plasma and ensure compliance with all applicable laws and regulatory requirements.

3.2 Physician and Physician Substitute

A licensed physician, qualified by training or experience to perform plasmapheresis shall be responsible for decisions related to the determination of donor suitability. Where the regulations allow, the duties of the physician set out in sections C.04.400 to C.04.423, may be delegated to a physician substitute provided that the physician substitute -

1. is authorized to carry out the duties in the province or territory where the service is provided;
2. works under the general supervision and direction of a licensed physician. Supervision may be exercised by the application of standard operating procedures by the physician substitute. The supervising physician should review and sign-off on the physician substitute's work on a bi-weekly basis (at a minimum);
3. consults with the supervising physician regarding decisions that require medical judgement and/or regarding any actions that are not clearly defined in established procedures;
4. has evidence of formal qualifications or certification for the work being carried out;
5. has a job description that clearly states their responsibilities; and
6. receives initial and continued training appropriate to their duties.

4 Establishing Donor Suitability

4.1 Informed Consent [C.04.403]

Written informed consent, given in accordance with the applicable laws governing consent shall be obtained from each donor prior to him or her participating in plasmapheresis, and only after the donor has been informed of:

1. a description of the procedures for plasmapheresis, including initial and ongoing questionnaires and/or tests for determining donor suitability and the length and frequency of the procedure;
2. any potential risks to his or her health arising from participation in plasmapheresis and with participating more frequently than once every eight weeks;
3. any other information that is necessary for that donor to make an informed decision to participate in plasmapheresis.

In addition to the above information, donors shall be informed prior to participating in specific immunization of the following:

1. a description of the procedures for specific immunization, including the name and nature of the selected immunogen, and the proposed frequency and maximum number of injections;
2. any potential risks to his or her health arising from the immunization and with receiving the selected immunogen;
3. they should participate in one immunization program at a time; and
4. any other information that is necessary for the donor to make an informed decision to participate in an immunization program.

Fabricators should have informed consent forms that communicate all of the above information in a language that is easy to understand by the donor. Donors should be given the opportunity to ask questions and to refuse consent. The forms shall be dated and signed by the donor and the individual that obtains the informed consent. The original or copy of the consent form shall be in the donor's record.

Procedures for obtaining subsequent informed consent from regular donors should be consistent with the principles in this guidance document and shall comply with applicable provincial legislation. Donors should have the opportunity to change their decision at any time.

4.2 Donor Screening

Donors should be in good general health to participate in plasmapheresis and be able to participate without any adverse consequences to their health. Donors should not have any evidence of disease or conditions that would adversely affect the quality and/or safety of the source plasma.

Donor suitability should be based on the absence of deferral criteria, on laboratory test results, and on the donor's medical history and/or medical examination. Donor screening should be carried out in private and the donor should be provided the opportunity to ask questions and to exclude themselves from donating.

4.2.1 Preliminary Evaluation [C.04.404]

The suitability of a donor to participate in plasmapheresis more frequently than once every eight weeks shall be determined based on the donor's medical history and a medical examination of the donor. A medical examination of the donor shall be completed by a physician or physician substitute less than 30 days prior to the first plasmapheresis session, and at least annually thereafter (for those donors planning to participate more frequently than once every 8 weeks).

If a donor is determined to be suitable but does not participate in their first session of plasmapheresis or specific immunization within 30 days of the determination, the fabricator can not proceed with plasmapheresis until the donor's suitability has been re-established pursuant to section C.04.404(1).

The fabricator shall comply with the requirements in section C.04.404 (2) of the Plasmapheresis Regulations to document the determination of the donor's suitability. In the case where a physician substitute has made the determination, the signature of the responsible physician should be obtained within 2 weeks of the determination of suitability.

Note: Staff other than the physician or physician substitute may conduct routine screening activities on previously screened donors who continue to present no situation requiring deferral; however, the physician remains responsible for the final decision on the determination of suitability. The criteria for education, training and qualifications of the screening positions should be approved by Health Canada.

4.2.2 Evaluation Before Each Plasmapheresis Session [C.04.406]

The suitability of a donor to participate in a plasmapheresis session shall be determined before each session. This determination shall be based on the criteria set-out in Tables 1 and 2 of the regulations, on the donor's test results, and any other medical reason justifying a determination of non-suitability. Refer to section 4.3 for further guidance.

4.2.3 Ongoing Review of Collection Records [C.04.408]

Every 4 months, the physician shall determine a donor's continuing suitability to participate in plasmapheresis more frequently than once every eight weeks. At a minimum, this determination shall be based on the donor's records for the preceding 4 month period, and this determination shall be documented.

4.2.4 Post-donation Information

Donors should be instructed to inform the fabricator following a plasmapheresis session if they discover or develop an illness or disease, or if they recall any information or history that may have been omitted during the screening process which they believe may affect their safety or the safety of the source plasma. This information should be considered in determining the donor's suitability to continue with plasmapheresis and in determining the safety of the source plasma.

4.3 Donor Deferral [C.04.406]

Establishing donor deferral criteria is essential for donor safety as well as for the safety of the source plasma. In many circumstances medical judgement, taking into account the specific health status of the donor, is required for decision-making.

The deferral criteria presented below are not exhaustive. It is the fabricator's responsibility to develop and maintain detailed procedures describing the criteria used in assessing donor suitability. These criteria and procedures and any changes to them are subject to review and approval by Health Canada. Fabricators should refer to the Guidance for Industry: Management of Blood Establishment Submissions. Refer to section 9 for contact information if further guidance is required.

On the day of the plasmapheresis session, a donor shall be assessed against the criteria set out in Tables 1 and 2, section C.04.406 of the Plasmapheresis Regulations, and against additional criteria set out in the fabricator's donor deferral procedures/manual. If a donor is not suitable to participate based on an assessment against the criteria, or due to any other medical reason, the donor is deferred, either temporarily or indefinitely. If a donor is deferred temporarily, the physician should consider whether an additional medical examination is warranted prior to their reinstatement into the plasmapheresis program.

The date and rationale for all deferrals shall be documented in the donor records. The fabricator's operating procedures should specify the time frames for deferral. The fabricator shall inform the donor of the reasons why they are not suitable and indicate the date when they may continue to participate, if applicable. The donor may be informed of the deferral either in person or in writing.

4.3.1. Temporary Donor Deferral Criteria [C.04.406 (Table 1)]

Note: Medical judgement is often involved in donor deferral. It is essential that conditions/factors that could potentially affect donor and/or product safety also be identified and managed via the screening process. Procedures describing fabricator's donor deferral criteria are reviewed and approved by Health Canada.

1. Weight of less than 50 kg

A donor who weighs less than 50 kg on the day of the plasmapheresis session shall be deferred. Procedures should be in place to follow-up with a donor if unexpected weight loss is observed. Unexpected weight loss can indicate sudden onset of illness or adverse events from frequent donation.

2. Temperature outside of normal limits

A donor with a body temperature greater than 37.5 °C (99.6 °F) shall be deferred.

3. Blood pressure above 100 mmHg diastolic or 180 mmHg systolic

A diastolic range of 50-100 mmHg and a systolic range of 90-180 mmHg are considered acceptable for donors.

4. Haemoglobin level of less than 125 g/L of blood or haematocrit value of less than 0.38 L/L of blood

A donor shall be deferred until their haemoglobin level is equal to or greater than 125 g/L of blood, or if using the hematocrit method, a donor shall be deferred if their hematocrit level is not equal to or greater than 0.38 L/L of blood.

5. Total protein level of less than 60 g/L of blood

Donors shall be deferred until subsequent testing shows that the total protein level is within acceptable limits.

6. Substantial blood loss

Donor records should be reviewed prior to each donation to assess past red blood cell loss and ensure that the cumulative loss of red blood cells remains less than the limit of 200 mL of packed red blood cells over a 56 day period (which is equivalent to a donation of whole blood).

This is meant to capture the loss of red blood cells during the collection process.

7. Prior donation of plasma or other blood components

Donors should only participate in one plasmapheresis program at a time. If the donor has donated whole blood, they should be deferred from participating in plasmapheresis for 8 weeks from the time of donation. A donor should be deferred for 8 weeks for a single donation of red blood cells and for a 16-week period following a double red cell donation.

8. Pregnancy

A donor shall be deferred during pregnancy and should be deferred for a minimum of 6 months following the conclusion of a pregnancy.

9. History of medical or surgical procedures

Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

10. History of convulsions requiring medical treatment

Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

11. Ability to answer questions compromised by alcohol or drug use

Donors should be deferred if they are intoxicated or suspected of being intoxicated by alcohol or drugs.

12. Prior transfusion of blood, blood components or a blood product, or prior transplantation of a cell, tissue or organ other than dura mater

Donors should be deferred 12 months from the date of receipt of a transfusion of blood, blood component or a blood product, or transplantation of a cell, tissue or organ. A donor shall be deferred indefinitely if they have received a dura mater transplant; refer to section 4.3.2, item 14.

13. Skin infection at the site of the phlebotomy

The skin of the donor at the site of phlebotomy should be free from lesion, rash or other source of infection. Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

14. Sign or symptom of infection

Donors shall be free of symptoms of infection.

15. Risk of infection with HIV, hepatitis B virus or hepatitis C virus based on, but not limited to, a history of acupuncture, skin piercing, tattooing, accidental needle-stick injury or occasional sexual relations with a person at risk of having these infections

A 6-month deferral following the at-risk exposure should be applied to:

1. persons who have had a tattoo;
2. persons who have had body piercing;
3. persons who have had acupuncture or electrolysis (except when disposable or personal-use needles are used);
4. persons who have had mucous membrane exposure to blood;
5. persons whose skin has been penetrated with non-sterile instruments or equipment contaminated with blood or body fluids;
6. persons who have had a sexual encounter with someone whose sexual background they are unsure of; or
7. persons who have had sex with an individual who has received plasma-derived clotting factor concentrates.

6. Current or past use of medication that poses a risk to a recipient of a product manufactured from source plasma

The clinical indication for any medication being used by the donor should be determined. Procedures to evaluate the risk(s) of specific medication as well as the risk(s) from the underlying condition or disease for which the medication is being taken should be maintained by the fabricator and periodically updated as deemed necessary.

17. Receipt of a live attenuated vaccine

Deferral periods associated with various types of vaccines should be specified within the fabricator's operating procedures. For additional information refer to the vaccination deferral periods provided in the CSA Standards on Blood and Blood Components.

4.3.2 Indefinite Donor Deferral Criteria [C.04.406 (Table 2)]

Note: Medical judgement is often involved in donor deferral. It is essential that conditions/factors that could potentially affect donor and/or product safety also be identified and managed via the screening process. Procedures describing fabricator's donor deferral criteria are reviewed and approved by Health Canada.

1. Abnormal cardiovascular function or serious or chronic cardiovascular disease

Donors should be deferred if there is any potential that their condition or disease could be aggravated by participating in plasmapheresis. Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

2. Abnormal respiratory function or serious or chronic respiratory disease

Donors should be deferred if there is any potential that their condition or disease could be aggravated by participating in plasmapheresis. Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

3. Bleeding disorder that poses a risk to the donor in relation to plasmapheresis

Donors should be deferred if there is any potential that their condition or disease could be aggravated by participating in plasmapheresis. Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

4. Serious disease or medical condition of the liver, kidneys, another organ or of a system or blood

Donors should be deferred if there is any potential that their condition or disease could be aggravated by participating in plasmapheresis. Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

5. Persistent abnormal plasma proteins including monoclonal or polyclonal gammopathy

A donor should be deferred for conditions resulting in abnormal serum proteins that do not correct themselves. Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

6. Current or past use of medication that poses an ongoing risk to a recipient of a product manufactured from source plasma

Procedures to evaluate the risk(s) of the medication(s) should be maintained by the fabricator and periodically updated as deemed necessary.

7. History of recurrent fainting associated with the donation of blood or plasma

Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

8. History, signs or symptoms of injectable drug abuse such as skin punctures, scars or sharing needles to inject drugs

Prior to donation, the donor's arms and forearms should be examined for signs of injectable drug use.

9. History, signs or symptoms of AIDS or HIV infection

A donor shall be deferred indefinitely if they have history, signs or symptoms of AIDS or HIV infection. Indefinite deferral is required in the case of a positive or reactive HIV test result. Refer to section 4.3.3.

10. Risk of HIV infection based on sexual practices

Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

11. History, signs or symptoms of a chronic or persistent infection or parasitic disease transmissible by blood

Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

12. History, signs or symptoms of hepatitis, other than hepatitis A

A donor shall be deferred indefinitely if they have history, signs or symptoms of hepatitis, other than hepatitis A. Indefinite deferral is required in the case of a positive or reactive Hepatitis test result. Refer to section 4.3.3.

13. Cancer, other than non-melanoma skin cancer or in-situ cervical cancer.

Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

14. Risk factor for Creutzfeldt-Jacob disease (CJD) or its variant (vCJD) based on, but not limited to, the receipt of dura mater transplant or a treatment using a human pituitary hormone

Specific conditions for deferral should be included in the fabricator's operating procedures for donor deferral.

15. Positive test result for any transmissible disease agent

Refer to section 4.3.3.

4.3.3 Transmissible Disease Testing [C.04.412, C.04.413]

The following donor screening tests shall be performed on a sample of blood or source plasma that is collected from the donor at the time of donation, in accordance with C.04.412. Health Canada authorized test kits should be used in accordance with the manufacturers' directions. The testing facility would require an EL for this activity. If testing is performed outside Canada, the test kits are to be authorized in accordance with the process outlined in the Guidance for Industry: Management of Blood Establishment Submissions.

All of the test results shall be negative for the disease agent; otherwise, the source plasma shall not be used for further manufacturing and the donor shall be deferred. Collected source plasma shall be retained until all test results have been determined to be negative for the disease agent.

Transmissible Disease Testing

Test	Acceptance Criteria	Action
Presence of antibody to HIV 1 and 2	Tests negative for the disease agent	In the case of a positive or reactive test result, the fabricator shall:
HIV nucleic acid testing		label the container holding the collected source plasma with
HPresence of antibody to HCV		the statement: "Caution: Not for Manufacturing Use" or "Précaution : Non destiné à la fabrication", and
HCV nucleic acid testing		the hazard symbol for Biohazardous Infectious Material set out in Schedule II to the Controlled Products Regulations
Presence of HbsAg		segregate and dispose of the source plasma
Serological test for syphilis		inform the donor, in person or in writing of the test result, and
		defer the donor - indefinitely if they test positive for any of the disease agents, other than syphilis in the case of syphilis, defer the donor until a subsequent test shows that the donor is not infected with syphilis and a physician determines that the donor can continue to participate.

NOTE: Re-entry procedures/algorithms for donors who have tested positive for transmissible disease markers listed in the table above should be submitted to Health Canada for review and approval in accordance with the Guidance for Industry: Management of Blood Establishment Submissions.

4.3.4 Plasma Protein Composition [C.04.407]

A blood sample shall be collected from the donor to determine plasma protein composition. The sample should be collected the same day or within 7 days prior to the first plasmapheresis session. The test results shall be reviewed and determined to be acceptable by a physician within 21 days after the sample was taken in order to continue plasmapheresis.

To protect the safety of the donor, plasma protein composition shall be evaluated no less than once every 4 months. Otherwise, the fabricator cannot continue with plasmapheresis.

If the protein composition does not fall within an acceptable range, as determined by results from an acceptable serum protein electrophoresis test or equivalent test, the donor shall be deferred until such time that it is acceptable. Acceptable limits should be defined in the fabricator's operating procedures.

If a period of 4 months has elapsed, a donation may be made at the time the sample is taken provided that the plasma protein composition results are examined by the physician, and that no further donations are allowed until the results are examined and determined acceptable by the physician.

4.3.5 Specific Immunization [C.04.405]

Prior to a donor receiving specific immunization, the physician shall establish the donor's suitability to be immunized and determine the proposed frequency and maximum number of injections the donor is expected to receive. A donor should only participate in one immunization program at a time.

The physician or physician substitute may administer the immunogen; however, the donor's clinical response shall be monitored by the physician to determine whether the donor can continue to participate in the immunization program. It is recommended that the fabricator have appropriate drugs or equipment necessary and personnel are trained in first aid in case the donor experiences an anaphylactic or severe allergic reaction to the immunogen.

Fabricators should have procedures that define the frequency and the maximum amount of immunogen to be administered in a single injection as well as over a specified period of time.

5 Collection of Source Plasma

5.1. Good Manufacturing Practices

Fabricators have a responsibility to comply with Division 2 of the Food and Drug Regulations (GMP) and the accompanying annex Good Manufacturing Practices for Schedule D Drugs, Part 2: Human Blood and Blood Components, which provides specific guidance for the application of GMP to blood establishments.

5.2 Plasmapheresis Procedures [C.04.409]

Fabricators shall comply with the procedures outlined in section C.04.409 of the Plasmapheresis Regulations.

5.2.1 Sterile Collection System [C.04.409 (a)]

The intent of this regulation is to maintain the sterility of the collection system used. Any event that has the potential to breach the sterility of the container used to collect source plasma is not acceptable. For example, the use of a new needle for venipuncture would be considered acceptable if the collection container has not been breached.

5.2.2 Emergency Medical Personnel [C.04.409 (d)]

The fabricator shall ensure that certified emergency medical personnel are able to attend to a donor who experiences a serious adverse reaction within 10 minutes after being contacted.

5.3 Anticoagulant Solution [C.04.411]

The fabricator shall ensure that the anticoagulant solution used has a Drug Identification Number (DIN) from Health Canada indicating that it is suitable for use in plasmapheresis.

5.4 Maximum Volumes and Minimum Intervals for the Collection of Plasma [C.04.410]

Upper limit volumes for the collection of plasma are maintained to protect donors, especially those that donate regularly, from excess volume collection, from losing essential plasma proteins (e.g. immune globulins, complement factors), and from the potential harm that such losses could have on their health over a long term period.

As a result of discussions and consultations on this issue, Health Canada did not amend the original upper limit volumes for the collection of source plasma in this regulatory amendment. This decision was endorsed by Health Canada's Expert Advisory Committee on Blood Regulation. Health Canada will continue to review data in support of raising the volume limits.

The limits for collection of source plasma are presented in the Table below. Note that the plasma collection limits are expressed in terms of volume of plasma collected according to the donor's weight, and the donor weight groups have been amended.

Maximum Volumes and Minimum Intervals for the Collection of Plasma

Donor Weight (kg)	Maximum amount of Plasma collected per donation (mL/g)	6 month cumulative volume limits (excluding anticoagulant solution) (L)
50 kg - 67 kg	625 mL / 640 g	11.5 L
68 kg - 79 kg	750 mL / 770 g	15.5 L
80 kg or more	800 mL / 820 g	18.5 L

The maximum number of plasma donations recommended within a given time frame as well as the minimum waiting period between donations of plasma and between a donation of plasma and a donation of blood or other blood components shall be specified in the fabricator's operating procedures.

6 Product Safety

6.1 Containers and Labelling [C.04.412, C.04.415, C.04.416]

Containers and the labelling of containers for source plasma shall conform with sections C.04.415 and C.04.416 of the Plasmapheresis Regulations. The containers shall be licenced under the Medical Devices Regulations for the purpose of collecting and storing source plasma.

At the time of collection, a specific individual shall be responsible for labelling the source plasma and all samples collected for testing. This shall include placing the unique identifier on the container of source plasma.

In the event that a manual collection system is used, a unique identifier would need to be assigned to the blood and the source plasma collected at each plasmapheresis session such that the two can be linked to each other and to the donor.

6.2 Storage [C.04.417, C.04.418]

Sections C.04.417 and C.04.418 contain the regulatory requirements applicable to the storage, including storage during transportation of source plasma. Fabricators of source plasma shall monitor and record the temperature of source plasma to ensure that it remains at a temperature of -20°C or colder while under their control.

If the temperature of the source plasma rises above -20°C at any time, the fabricator shall document:

1. the conditions that caused the inadvertent temperature increase;
2. the units of source plasma affected; and
3. the final disposition of the source plasma.

6.2.1 Temperature Variations [C.04.417 (3) to (6)]

Source plasma that has been exposed to a variation in temperature shall be labelled accordingly by the fabricator. Environmental temperature experienced by the plasma includes the temperature in the freezer, the temperature in the interior of the shipping coolers, or the ambient temperature for the duration of each exposure.

If the temperature rises above +10°C, the source plasma shall be disposed of.

If the plasma reaches temperatures between -20°C and +10°C, the container shall be labelled with the statement "Source Plasma - Salvaged" or Plasma destiné au fractionnement - recyclé".

To prevent unnecessary loss of plasma, Health Canada considers it acceptable if the temperature of the interior of the box used to store and transport source plasma rises to between -20°C and -5°C for a single occasion lasting less than 72 hours. In this situation, the source plasma would not have to be labelled as "Salvaged".

6.2.2 Inspection of Containers and Labels [C.04.418]

Labels and containers of source plasma should be inspected by the fabricator prior to storage and also shipping the source plasma to another establishment. The plasma shall be disposed of if the inspection shows that the container and/or label do not comply with the requirements set out in C.04.418 (2).

All information required on the label must be legible to maximize the safety of the source plasma. If this information is missing or illegible, the label shall be corrected by recovering the information from the donor file.

7 Adverse Reaction Reporting and Product Recall

7.1 Serious Adverse Reaction Reporting [C.04.421]

If a suspected serious adverse reaction [as defined in section C.04.400] occurs in the donor during or within a short time frame following the plasmapheresis session, fabricators shall inform Health Canada:

1. where it is fatal, immediately where possible, and in any event within 24 hours after becoming aware of the occurrence;
2. in any other case, within 15 days after the fabricator becomes aware of the occurrence.

If Health Canada is verbally informed of a serious adverse reaction, the verbal communication shall be followed up within 24 hours with a written report. The report shall be as complete as possible and at a minimum include a description of the serious adverse reaction and any steps taken to address it.

Serious adverse reaction reports should be submitted directly to BGTD at the following address:

Blood Establishment Regulation Unit
Blood, Tissues, Organs and Vaccine - Regulatory Affairs Division
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
Health Products and Food Branch
Address Locator: 0701A
200 Tunney's Pasture Driveway
Ottawa, ON
K1A 0K9

Fax number :613-948-3564

There are situations in addition to the above that may necessitate rapid communication to Health Canada, and appropriate scientific and medical judgement should be applied to each situation.

Terms and conditions respecting serious adverse reaction reporting requirements are set out in the Annex to the fabricator's EL(s).

7.2 Errors and Accidents and Recall of Source Plasma [C.04.422]

As stated within the Annex to a fabricator's EL(s), any major and/or serious errors/accidents that may impact the safety of the blood system must be reported to the HPFBI within 24 hours. Health Canada also considers incidents related to computerized blood systems to be a type of error/accident that require reporting.

Fabricators should refer to the Health Products and Food Branch Inspectorate Recall Policy (POL-0016) and Product Recall Procedures (1993) for the requirements and responsibilities that are applicable to parties planning for and carrying out recalls.

If source plasma is recalled, the fabricator shall report the reason for the recall, the number of units involved, and the location from which the units were recalled.

8 Records Management [C.04.419, C.04.420]

Records that permit traceability and recall of source plasma as outlined in sections C.04.419 shall be kept indefinitely.

Information may be retained in different files provided that it is easily accessible and the fabricator can ensure traceability.

In the event that a manual collection system is used, a unique identifier would need to be assigned to the blood and the source plasma collected at each plasmapheresis session such that the two can be linked to each other and to the donor.

9 Additional Information

If you have any questions or require clarification of issues that are not addressed in this guidance document, please contact:

Blood Establishment Regulation Unit
Blood, Tissues, Organs and Vaccine - Regulatory Affairs Division
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
Health Products and Food Branch
Address Locator: 0701A
200 Tunney's Pasture Driveway
Ottawa, ON
K1A 0K9

Fax number: 613- 948-3564
Email: BGTD_D_Enquiries@hc-sc.gc.ca

References

1. National Standard of Canada CAN/CSA-Z902-04, Blood and Blood Components. Canadian Standards Association (CSA), March 2004 edition.

2. Drug Establishment Licence Application: Form and Instructions. Health Canada, November, 2003.

3. Good Manufacturing Practices (GMP) for Schedule D Drugs, Part 2, Human Blood and Blood Components. Health Canada, December, 1999.

4. Guidance for Industry: Management of Blood Establishment Submissions. Health Canada, December 8, 2006.

5. Health Products and Food Branch Product Recall Procedures. Health Canada, December 10, 1993.

6. Health Products and Food Branch Recall Policy (POL-0016). Health Canada, April 18, 2006.