COUNCIL OF EUROPE

European Agreement on the Exchange of Therapeutic Substances of Human Origin

Freedom from toxicity of plastic blood transfusion equipment

I. Chemical tests

The tests are intended to be applied to plastics blood transfusion equipment. This equipment consists of two main categories:

(1) plastics containers for the collection, separation and storage of blood and blood products;

(2) plastics sets for taking and giving blood.

The tests shall be carried out on the materials after they have been sterilised by the method to be used in the final sterilisation of the equipment. These materials shall include:

1) the plastics used to make the containers,

2) the tubing used in the containers and

3) the blood-taking and giving sets.

The tests on containers shall be carried out before the containers are filled with anticoagulant solution. However, if the tests are carried out on containers which have been filled with anticoagulant solution, the limit tests in Section III on the anticoagulant solution itself shall be taken into account when evaluating the results of the tests on the container.

The manufacturer of the transfusion equipment is required to disclose to the appropriate health authority the detailed formulations of the plastics material or materials and other materials used in the manufacture of the equipment, the source of the components of the material or materials and their methods of manufacture (or alternatively, the compound reference numbers), details of manufacture of the equipment, the nature of any processing additives and adhesives and the method of sterilisation. No change shall be permitted in any of the foregoing without prior submission to and approval of the appropriate health authority.

Each batch of raw material used in the manufacture of the equipment shall be identified by a batch number, which shall be recorded by the manufacturer of the equipment together with the identification numbers of all batches of transfusion equipment made from it and the results of all tests relevant to these batches.

Every practicable precaution must be taken to reduce the risk of adventitious contamination at each stage of the manufacturing process.

A. Preparation of extract and blank

(a) A total test as described below requires 1250 cm2 plastics (total surface area, both sides, of a plastics sample in sheet form with surface area of 625 cm2). The sample - without any printing or label on it - should be cut into pieces of not more than 10 cm2.

For tubing the length (L) in cm is calculated as follows:

D1 = inner diameter in cm

D2 = outer diameter in cm

The tubing should be cut lengthwise into sections measuring approximately 10 cm. For the extraction 10 ml of water is used per surface area of 50 cm2.

(b) The pieces of plastics film or tubing should be placed in a container of borosilicate glass with 250 ml pyrogen-free distilled water obtained from an efficient still having glass condensation surfaces and collecting tubes.

1 If the plastics have been in contact with an anticoagulant solution, the pieces should first be placed in a similar container with cold distilled water (100 ml) and shaken several times. This should be repeated once.

The opening of the container is covered with an inverted beaker and the container is then heated in saturated steam at 110° C for 30 minutes (autoclaving) and then quickly cooled to room temperature and the volume adjusted to 250 ml with pyrogen-free distilled water. It is of no significance if the plastics specimens tend to stick together slightly.

Heat-sensitive plastics material, instead of being heated in an autoclave, may be heated at 70° C for 72 hours.

A blank preparation is made in a corresponding manner omitting the plastics.

B. Tests on the extract

1. Oxidisable matter

To 20 ml of the extract in an Erlenmeyer flask of borosilicate glass add 20 ml of 2 millimole potassium permanganate solution per litre and 1.0 ml of 1 mole sulphuric acid per litre and boil the mixture for 3 minutes. Cool the solution rapidly and add 0.1 g of potassium iodide and 5 drops of starch solution. Titrate with a solution containing 10 millimole sodium thiosulphate per litre. At the same time carry out a blank titration. The difference in the volume of thiosulphate used in the two titrations does not exceed 2.00 ml a solution containing 10 millimole sodium thiosulphate per litre.

2. Chloride

The extract complies with a suitable limit test for chloride equivalent to not more than 11.2 µmole chloride per litre.

3. Ammonia

The extract complies with a suitable limit test for ammonia equivalent to not more than 120 µmole NHs per litre.

4. Phosphoric Acid - Phosphate

The extract complies with the limit test for phosphate.

Limit test for phosphate

Evaporate 25 ml of the extract almost to dryness in a Kjeldahl flask, cool the residue, add 2 drops sulphuric acid and 1 ml nitric acid, heat the mixture until white fumes appear, then cool. Add 1 drop of perchloric acid and heat gently for half an hour. Cool the residue and add water to 25 ml. Transfer 10 ml of the solution to a 25 ml titration flask, add 8 ml ammonium molybdate-sulphuric acid solution and 2 ml of freshly prepared solution of ascorbic acid, having a concentration of 100 g/l. Heat on a water bath at 50° C for thirty minutes, cool and dilute the mixture to 25 ml. The green or blue colour of the solution is not more intense than that obtained by treating 25 ml of the blank solution in the same manner.

5. Acidity or alkalinity

10 ml of the extract is not coloured red on the addition of 2 drops of phenolphthalein solution and requires not more than 0.4 ml solution containing 10 millimole sodium hydroxide per litre to produce a red colour. After removal of the colour by the addition of 0.08 ml solution containing 10 millimole hydrochloric acid per litre, the addition of 5 drops of methyl red solution produces a red or orange-red colour.

6. Residue on evaporation

Evaporate 100 ml of the extract to dryness on a water bath and dry at 105° C to constant weight. The residue weighs not more than 5.0 mg.

7. Clarity and colour

The extract when viewed through a thickness of 5 cm is clear and colourless when compared with the blank.

8. Taste and smell

The extract compared with the blank is odourless and tasteless.

9. Special elements

The extract complies with suitable limit tests for

(i) any of the following elements: arsenic, chromium, copper, lead, silicon, silver and tin, equivalent to 1 µg/g

(ii) cadmium, equivalent to 0.1µg/g

10. Residue on ignition

1.0 g of the plastics material when ignited to constant weight leaves not more than 1 mg of residue.

11. Heavy metals

Dissolve the residue on ignition in the minimum quantity of a solution of 2 mole hydrochloric acid per litre, heating if necessary. Carry out a suitable limit test for heavy metals. The plastics material complies with a limit not exceeding 5 microgrammes per gramme as calculated as Pb.

II. Biological tests

(1) A test for undue toxicity shall be carried out in the initial evaluation of plastics formulations intended for the fabrication of containers and taking and giving sets, using extract A, and on each new batch of materials of the approved formulations, using extract B, by the procedure specified in the national pharmacopoeia or some other method approved by the national control authority. (Extracts A and B are defined in the note below.)

(2) A test for freedom from pyrogens shall be carried out in the initial evaluation of plastics formulations intended for the fabrication of containers and taking and giving sets, using extract A, and on each new batch of materials of the approved formulation, using extract C, and in the routine control of containers and taking and giving sets, using extract C, by the procedure specified in the national pharmacopoeia or some other method approved by the national control authority.