Therapeutic Goods Order No. 34

Standard for diagnostic goods of human origin

Published in the Commonwealth of Australia Gazette, 7 November 1990

COMMONWEALTH OF AUSTRALIA

Therapeutic Goods Act 1966

THERAPEUTIC GOODS ORDER NO. 34

STANDARD FOR DIAGNOSTIC GOODS OF HUMAN ORIGIN

I, PETER STAPLES, Minister of State for Aged, Family and Health Services, pursuant to Section 17 of the Therapeutic Goods Act 1966, by this Order REVOKE Therapeutic Goods Order No. 19 made on the 23 September 1984, and pursuant to sections 13, 15 and 23F of that Act by this Order

1. DETERMINE that with respect to quality and method of preparation, the standard for goods which contain materials of human origin and which are intended as laboratory reagents for diagnostic tests, shall be the standard specified in this Order;
2. DIRECT that for the purposes of Sections 19, 20 and 22 of the said Act, such goods shall be labelled in the manner specified in this Order; and
3. DETERMINE that the procedures to be carried out in the production of such goods shall include the procedures specified in this Order.

Application

1.  
   1. Subject to sub-clauses (2) and (3), the goods to which this Order applies are goods which contain materials of human origin and which are intended as laboratory reagents in diagnostic tests.
   2. Clauses 7 to 9 inclusive do not apply to goods manufactured by a process such that human immunodeficiency virus (HIV) would be inactivated.
   3. This Order does not apply to
      1. goods which, due to either the nature or scarcity of the final product, cannot be prepared from material that is non-reactive when tested for hepatitis B virus surface antigen (HBsAg) or antibody to HIV; or
      2. goods which have been treated at 60°C for 10 hours.

Interpretation

2. In this Order -
   • "donor" means a person from whom body fluids or tissues are obtained for the purpose of preparing diagnostic goods;
   • "donor serum" means serum or plasma obtained from a donor and which is intended for the preparation of diagnostic goods of human origin;
   • "final bulk" means the finished homogeneous material present in the container from which the final containers are filled;
   • "final lot" means a collection of sealed final containers that have been filled during one working session from a single final bulk and further processed under conditions which ensure its physical, chemical and microbial homogeneity;
   • "goods" means goods for therapeutic use as defined in the Therapeutic Goods Act 1966;
   • "HBsAg" means hepatitis B virus surface antigen;
   • "HIV" means any human immunodeficiency virus known to cause acquired immune deficiency syndrome;
   • "manufacture" includes the process of collection and testing of starting material as well as subsequent processing of that material into diagnostic goods;
   • "pooled sera" means a pool of all donor serum or plasma which is processed into a final bulk or final lot; and
   • "reference panel of sera" means the panel of human sera which is designated by the Commonwealth Department of Community Services and Health as the Australian reference panel of human sera for tests for hepatitis B virus surface antigen.

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Source material

3. Goods shall consist of or be derived from source material obtained from donors who are free from -
   1. signs of infectious diseases transmissible by blood products; and
   2. signs of injection with narcotics,
   unless, by its nature, such source material must be obtained from donors suffering from specific illness.

Test for hepatitis B virus surface antigen in donor serum

4.  
   1. A serological test for HBsAg complying with the specifications of clause 6 shall be carried out on individual donor sera during manufacture.
   2. Donor serum giving a positive reaction for HBsAg shall not be used to prepare goods to which this Order applies.

Test for hepatitis B virus surface antigen in final bulk or final lot

5.  
   1. A serological test for HBsAg complying with the specifications of clause 6 shall be carried out by the manufacturer on the final bulk or the final lot.
   2. A final bulk which gives a positive reaction for HBsAg that can be neutralised with antibody to HBsAg shall not be used to prepare goods to which this Order applies.
   3. The final lot, when tested for the presence of HBsAg in accordance with clause 6, shall give a negative reaction.

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Sensitivity of hepatitis B virus surface antigen test

6.  
   1. The sensitivity of the serological test for HBsAg shall be sufficient to give a positive reaction in all twenty sera labelled FH001 -FHO17 and FHO23 - FHO25 in the reference panel of sera.
   2. A positive control serum known to be weakly reactive shall be included in each test and a positive reaction shall be obtained with this positive control serum for the test to be valid.

Test for antibody to human immunodeficiency virus in donor serum

7.  
   1. A serological test for antibody to HIV that is a test in accordance with clause 9 shall be carried out on individual donor sera during manufacture.
   2. Donor serum which gives a positive reaction to a test referred to in clause 9 shall not be used to prepare goods to which this Order applies.

Test for antibody to human immunodeficiency virus in final bulk or final lot

8.  
   1. Unless the sera to be used in the manufacture of diagnostic goods of human origin has been collected in premises licensed for such a purpose, being subject to inspection, and using tests approved by the competent Health Authority of a particular country, whose standards are recognised by the Secretary of the Commonwealth Department of Community Services and Health, and supplied with specific certification from the primary manufacturer that the units of blood used in the manufacture of identified production lots were tested for antibody to HIV and found non-reactive, then a serological test for antibody to HIV complying with the specifications of clause 9 shall be carried out by the manufacturer on the pooled sera prior to further consolidation, or on the final bulk, or the final lot.
   2. A pooled sera or final bulk which gives a positive reaction to a test referred to in clause 9, shall not be used to prepare goods to which this Order applies.
   3. The final lot, when tested for the presence of antibody to HIV in accordance with a test referred to in clause 9, shall give a negative reaction.

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Sensitivity and specificity of human immunodeficiency virus antibody test

9.  
   1. The test for the presence of antibody to HIV shall, if performed in Australia, be either:-
      1. a test performed using a test kit specified in the Schedule to this Order; or
      2. a test performed using a method of greater sensitivity and specificity than that used in a test kit which has been so specified.
   2. The results of a test referred to in paragraph 9 (I) (b) will take precedence over the results of a test referred to in paragraph 9 (I) (a).
   3. The test for the presence of antibody to HIV shall, if performed outside Australia, be either:-
      1. a test performed using a test kit of equal sensitivity and specificity to one specified in paragraph 9 (1) (a); or
      2. a test performed using a method of greater sensitivity and specificity than that used in a test kit which has been so specified.
   4. The results of a test referred to in paragraph 9 (3) (b) will take precedence over the results of a test referred to in sub-clause 9 (3) (a).

Labelling requirements

10. Unless the goods are goods manufactured by a process such that human immunodeficiency virus would be inactivated -
    1. the goods shall include an information leaflet containing -
       1. certification that tests for HBsAg and antibody to HIV have been performed on the goods and have been found to be negative; and
       2. a warning that the product may be infectious; and
    2. the label attached or affixed to goods shall contain an expiry date or recommended shelf life.

Dated this third day of August 1990

PETER STAPLES
Minister of State for
Aged, Family and Health
Services

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THE SCHEDULE

Test kit	Marketing companies
Genetic Systems LAV EIA	BioMediq Australia
Abbott Recombinant HIV-1	Abbott Diagnostic
ENI Virgo HIV PLA	Integrated Sciences Pharmacia Australia
Anti-HTLV III Wellcozyme VK 50/5zI	Wellcome Australia
WeIIcozyme HIV Recombinant VK 56/57	Wellcome Australia
Bio-Enzabead HTLV-III Elisa	Organon Teknika
Vironostika Anti-HTLV III Microelisa	Organon Teknika
OUVA 21 Enzygnost HIV	Behring Diagnostics
Dupont HIV-1 Elisa	Dupont Australia CSL
Biochrom HIV-1 Elisa	Clin-Path Services

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EXPLANATORY NOTES

THERAPEUTIC GOODS ORDER NO. 34

STANDARD FOR DIAGNOSTIC GOODS OF HUMAN ORIGIN

1. The risks of infection associated with the use of human diagnostic control sera have arisen because the sera may be potentially contaminated with hepatitis virus type B and human immunodeficiency virus. Recognition should be given to the need for good laboratory practice in handling these reagents. The risks associated with the use of human sera can be minimised by the use of non-human control sera wherever possible.

HEPATITIS VIRUS TYPE B

2. The procedure used in the serological test for HBsAg to ensure compliance with the standard needs to be either a radioimmunoassay (RIA) method, a reverse passive haemagglutination (RPHA) method, an enzyme-linked immunosorbent assay (ELISA) method or a method of sufficient sensitivity to ensure compliance when tested against the reference panel of sera. If a method other than RIA, RPHA or ELISA is used it is necessary for evidence supporting the sensitivity of the proposed test method to be made available to the Department of Community Services and Health.
   It is the intention of this standard that the national control authority uses the RIA method to test for the presence of HBsAg in official samples but that the manufacturer, although obliged to carry out a test, should not be specifically restricted to using any particular test method for HBsAg. That is, the manufacturer may use the test of his choice for in-house testing to ensure that a product complies with the standard. However in the case of a dispute or for testing of official samples the RIA method will be used.
3. It is intended that positive control reagents used in the tests for hepatitis virus type B together with those products which, due to the nature of the product, could only be obtained from HBsAg positive donors or are of a quantity which precludes adequate testing, shall be exempted from the requirements to be tested for HBsAg under this Order.
4. There are two reasons why it is necessary to carry out a serological test for hepatitis virus type B on individual donor serum as well as on pooled sera, final bulk or final lot:
   1. Pooled sera may give a negative test result even though it may contain a positive donor serum because the positive donor serum has been diluted by mixing with negative donor sera beyond the sensitivity of the test method. The pool should still be regarded as infectious.
   2. Secondly, the HBsAg in a positive individual donor serum may be neutralised by antibody to HBsAg present in other donor sera included in the pool so that the HBsAg is not detectable in the test. However, the infectivity of the hepatitis virus type B may not be neutralised and the pooled sera should be regarded as hazardous.
   Testing of the final bulk or final lot provides a check against poor screening tests or the possibility of a mix-up occurring during production of several products by the same manufacturer.
5. It is recognised that it may be difficult for companies to ensure donor acceptability when they do not have access to individual donor records. In many cases only the blood collection centres would be able to determine that donors are (i) free from a history of injections with narcotics, and (ii) free from a history of infection with hepatitis virus B for a period of not less than five years or that hepatitis B surface antigens or antibody to HIV are not demonstrable in the donor's blood. Manufacturers of goods covered by this standard should therefore, where appropriate, seek the necessary assurances of donor acceptability from the source of their raw materials.
6. The national reference panel of sera for evaluating methods of detecting hepatitis B surface antigen was established with the support and assistance of the Royal College of Pathologists of Australia. The reference panel has similar characteristics to the WHO reference panel and includes sera containing antigens of both major hepatitis B subtypes encountered in Australia ("ayw" and "adw") and a range of high and low antigen titres.

Requests for the reference material, or for further information should be directed to either the -

Virology Department
Fairfield Hospital
Yarra Bend Road
FAIRFIELD VIC 3078 Telephone (03) 488 2399

or the

Virology Section
Therapeutic Goods Administration Laboratories
Private Bag 7, P.O.
PARKVILLE VIC 3052 Telephone (03) 387 4211

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

7. There is a risk that diagnostic goods of human origin may be contaminated with human immunodeficiency virus (HIV), the causative agent of AIDS. Infectious HIV has been isolated from sera and other body fluids which might be used as control reagents in diagnostic work. In addition, experimental evidence indicates that samples which contain antibody to HIV may be infectious. Since sera in diagnostic goods are a potential source of AIDS infection for laboratory workers, it is now considered necessary to include testing for antibody to HIV in this Order. However, an exception is made for goods which have been processed in a manner which effectively inactivates HIV. In this case the Department of Community Services and Health may require details of the inactivation process.
8. Sensitive enzyme-linked immunosorbent assay (ELISA) tests and other tests for detecting antibody to HIV are currently available. A list of test kits approved by the Department of Community Services and Health for use in Australia is shown in the Schedule. However these tests may produce a proportion of false positive results that could result in the rejection of HIV-free sera. Therefore effective screening of sera for HIV antibody requires a two tier system where, if a manufacturer has reason to believe that the result obtained with a test is a false positive, an additional test may be performed using a different test method of greater specificity such as a Western Blot method. Persons intending to perform additional tests using other test methods should first seek the approval of the Department of Community Services and Health. Official testing, in the case of a dispute or for the testing of official samples, will be performed using an ELISA test and a Western Blot method.

LABELLING REQUIREMENTS

9. The requirement that the label attached to the goods should contain a warning that the product may be infectious has been reconsidered.
   It is now necessary to place such a warning on an information or instruction leaflet where such a leaflet is supplied with the product. In addition, the leaflet is to contain a statement that the product has been tested both for hepatitis B virus surface antigen and for antibody to HIV, and that the test results were negative.

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