Materials

The Use of PVC for Critical Medical Applications

Dr. CSB Nair, Director, Research & Development, TERUMO PENPOL Ltd, Trivandrum, Kerala State

British Standards

The requirements for blood bags are defined in British Standard BS 2463-"Transfusion equipment for medical use", Part 1: Specifications for collapsible containers for blood and blood components.

British Standard BS 5736 "Evaluation of medical devices to biological hazards" Parts 1 to 6 describes tests to be done to assess a device as being free from biological hazard.

Part 1 : Guide for the selection of biological methods of test, clearly defines medical devices into three distinct categories depending on their mode of application and also specifies the biological tests necessary for their evaluation (Table-3).

Categories of Medical Devices

BS 5736 Part-1

Category-A : External Contact

Those devices coming into contact either directly or indirectly :

• A1 With intact skin. (Eg. Electrodes and external prostheses)

• A2 With breached or otherwise damaged skin. (Eg. Wounded dressings)

• A3 With eyes. (Eg. Contact lenses and eye drop containers)

Category-B : Indirect Internal Contact

Those devices used to contain or administer substances including blood, which are introduced parenterally into the body.

Eg. Intravenoiss administration sets, Hypodermic syringes, Blood bags.

Category-C : Direct Internal Contact

• C1 With intact natural channels. (Eg. Urinary catheters, Intra uterine devices, Stomach tubes, Tracheal tube)

• C2 With circulating blood. (Eg. Haemodialysis equipment, Intra vascular catheters)

• C3 With other body tissues and fluids. (Eg. Hip prostheses, Breast implants, Ligation clips)

German Standard – DIN 58361

"Transfusion, infusion, transfusion containers and accessories, empty bags of plastics, safety requirements, testing supervision and labeling".

This standard specifies the physical, chemical and biological requirements for blood bags, the materials used in their manufacture and tests to be done.

The biological tests specified are systemic injection test on mice-using normal saline and vegetable oils as extracting medium and haemolysis.

Tests to be done on Blood based on the Specifications of various Standards

The International Standards ISO 3826 meets the requirements of all other standards. However, certain additional tests described in other standards are also included in the list below.

1.0 General

      Transparent, flexible, non-pyrogenic and non-toxic.

2.0 Design Requirements

• Collecting and transfer tubes

• Outlet ports

• Suspensions

• Provision for pilot samples

• Flexibility of container

• Emptying under pressure

• Air content

• Blood taking needle

3.0 Physical Requirements

• Manufactured under GMP requirements

• Sterilised by autoclaving

• Transparency

• Colouration

• Vapour transmission

• Resistance to distortion

• Resistance to leakage

• Thermal stability

• Performance of marking and labeling

• Legibility of printed matter on labels

• Resistance to dropping *

• Impermeability to micro-organisms *

Tubing – additional tests

• Heat resistance test #

• Reversion test #

• Imperviousness of knot on tubes *

[Note: * German Pharmacopoeia. # DHSS specifications]

4.0 Chemical Requirements

1. On water extract

• Oxidisable matter (0.5N Thiosulphate ml) < 2

• Ammonia (mg/l) < 2

• Chloride (mg/l) < 4

• Acidity / Alkalinity
  0.01 Mol / L NaoH < 0.4
  0.01 Mol / L Hcl < 0.8

• Residue on evaporation
  (mg/100 ml) 3.0

• Opalescence (Reference suspension 2) 3.0

• Colouration Nil

• UV Absorption (range
  230-360 mm) < 0.2

• Extractable (di 2 ethyl hexyl phthalate) (mg/100 ml) 10.00

2. On plastics

• Ash (Mg/g) 1.0

Heavy metals (mg/kg.)

• Barium 1.0

• Lead 1.0

• Copper * 1.0

• Chromium * 1.0

• Cadmium 0.6

• Tin 0.6

• Vinyl chloride monomer
  microgram / g 1.0

5.0 Recommended Biological Tests

• Sterility

• Pyrogenicity

• Haemolysis

• Systemic injection

• Intracutaneous injection / irritation

• Self culture cytotoxicity

• Sensitisation

Type and Lot Tests

It is utmost importance that the formulation of the PVC compound and the method of manufacture and processing should not be varied once a compound has been developed and validated. It is even desirable to procure raw materials and additives form a single supplier of proven consistency and reliability.

Type Tests

Type tests should be established on the basis of :

• Compatibility of the material of the plastic container with the anticoagulant/and/or preservative solution blood and blood components.

• Compatibility of the plastic container with the process of manufacture and sterilisation.

• General biological safety of plastics container

• Biological safety of plastics containers with cellular elements of blood and blood components.

The plastic containers should not release any substances which may adversely affect the therapeutic effectivensss of blood and blood components including substances which may exhibit toxic, cytotoxic, bacteriostatic, bactericidal, pyrogenic or haemolytic reactions.

Type tests are to be done on the following:

1. New plastic formulations i.e. when different plastics are introduced.

2. On already agreed formulations in which any change has been made i.e. when for example a pthalate is substituted by another type of plasticizer or when a stabiliser is replaced by another of different composition.

3. On change of anticoagulant and/or preservative solutions.

The type tests to be done as per ISO 3826 are :

• The full range of chemical tests

• A series of suitable biological tests

• Physical tests

Lot Tests

These are tests that should be done on each manufacturing "lot". ISO 3826 define "lot" as follows:

For plastics containers containing anticoagulant and/or preservative solution, "lot" is that quantity of plastics containers prepared, filled from a single batch of anticoagulant solution and sterilised within a continuous working period.

For plastics containers not containing an anticoagulant and/or preservative solution, the term "lot" means that quantity of plastics containers prepared within one working day and sterilised in one cycle.

However, a manufacturer may apply a different definition of the terms "lot" for his proprietary manufacturing process without sacrificing quality assurance (GMP) in any way.

GMP and Quality Assurance

In the above discussion, GMP and Quality Assurance have not been discussed in detail. It goes without saying that GMP and Quality Assurance procedures are strictly followed right from the selection of raw materials, their processing, preparation of anticoagulants, sterilisation, post sterilisation processing, packaging, labeling, cartoning and despatch. Most vital requirements are validation of every operation and equipment used, adequate documentation and traceability.

Conclusions

The use of PVC for critical medical products involves utmost care and dedication at every step. Testing, quality assurance and validation requires that quite a number of physical, chemical and biological tests have to be done on a regular basis to ensure that the products manufactured consistently conform to the high standards required for life saving devices.

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