Verification of the biocompatibility of filter products used in the pharmaceutical processing industry is vitally important component of product validation. To ensure that final produced drug safety cannot be compromised under the worst case situation, materials of construction coming into contact with the filtered solution must be tested for biological safety.
1. Introduction
Filter products used in pharmaceutical processing applications mostly fall outside the scope of the European Medical Devices Directive 93/42/EEC. No specific testing requirement has been specified by regulatory bodies, however a minimum standard has been adopted throughout the pharmaceutical filtration industry to ensure that materials meet USP Plastics Class VI requirements. In accordance with the worst case approach adopted by domnick hunter, the elastomers, plastics and other polymeric materials used in the construction of pharmaceutical grade products are submitted to a battery of tests for biocompatibility. The testing is carried out by an approved independent Laboratory against USP and, equivalent ISO standards / protocols for Biological Safety (from January 2002). In addition, materials used comply with the requirements of the US Food and Drug Administration, Title 21 CFR 177 “Indirect contact with food - Polymers”. domnick hunter’s policy is to avoid any unnecessary use or duplication of animal testing. To this and, unless changes in the regulatory approach are identified in terms of methodology, testing results may refer to previous issues of the Pharmacopoeia’s than are current.
2. Summary of testing specified by Regulatory Bodies Specified Testing
The United States Pharmacopeia defines two fundamental Biological Reactivity tests,
- <87> Biological Reactivity Tests, in vitro, ‘Cytotoxicity Test’ and
- <88> Biological Reactivity Tests, in vivo, the ‘Plastics Class Tests’.
In addition <151> Pyrogen Test is also defined to identify the risk of febrile reaction to an injected solution, although most in the industry are moving to the <85> Bacterial Endotoxins Test protocol where possible. Further applicable test protocols are given in <661> Containers, sections under Biological Tests and Physicochemical Tests – Plastics. The European Pharmacopoeia applies ISO 10993 Biological Evaluation of Medical Devices, which defines a range of tests applicable to Medical Device Testing and CE marking:
- Cytotoxicity
- Sensitisation
- Irritation
- Systemic Toxicity
- Subchronic Toxicity
- Implantation
- Hemocompatibility
- Chronic Toxicity
- Carcinogenicity
USP tests and the equivalent ISO testing requirements differ slightly. The FDA has only recently started harmonising screening submissions for biocompatibility data according to the ISO guideline for Medical Device approval.
3. Standard Test Summaries
(i) USP <87> Biological Reactivity, in vitroThree tests are described:
- Agar Diffusion Test
- Direct Contact Test
- Elution Test
The tests are designed to determine the biological reactivity of mammalian cell cultures following contact with the elastomeric, plastics and other polymeric materials or extracts prepared from the materials. All three tests use L929 mammalian (mouse) fibroplast cells in serum-supplemented MEM (minimum essential medium) as the culture. domnick hunter uses the defined Elution Test, which has an equivalent in ISO 10993, hence the common reference to ‘L929 MEM Elution’ or ‘Cytotoxicity Test’. Full details of testing can be found in the Current volume of the Official Compendia of the USP / NF.
(ii) USP <88> Biological Reactivity, in vivo
Three tests are described:
- Systemic Injection Test
- Intracutaneous Test
- Implantation Test
To determine the biological response of animals to elastomerics, plastics and other polymeric material with direct or indirect patient contact, or by injection of the specific extracts prepared from the material under test. The classification is based on the responses to a series of tests for which extracts, materials, and routes of administration are specified. (See table 1 for details) With the exception of the implantation test the procedures are based on the use of extracts prepared depending on the temperature resistance of the materials, at one of three standard temperatures: 50°C (122°F) for 72 hrs, 70°C (158°F) for 24 hrs and 121°C (250°F) for 1hr. domnick hunter products are rated to at least 121°C (250°F) and therefore extracts are taken under the worst case conditions of 121°C (250°F) for 1hr. The class designation for domnick hunter materials of construction is therefore; USP Plastic Class VI – 121°C
(the centigrade symbol is added for clarity) 
KEY
A(iv) Systemic Injection Test (intravenous)
A(ip) Systemic Injection Test (intraperitoneal)
B Intracutaneous Test
C Implantation Test
Note: domnick hunter has defined a new SOP incorporating additional testing, in conjunction with an independent testing laboratory, which will be applied to testing of new materials from January 2002. A full summary of this protocol can be requested from domnick hunter.
5. Technical Support Group activities
domnick hunter have a trained team of scientists and engineers available to answer questions regarding the technical capabilities of our products, to assist in the selection and design of appropriate filtration systems and to provide user training programs. The following services can be delivered both on site and in-house;
- filterability testing to optimise filter system design
- advice on the development of integrity testing, steam sterilisation and clean in place procedures
- development of validation procedures
- troubleshooting
- facility audits to ensure continued optimisation of filter use
- operator training including filtration theory, filter system design and management, validation, etc.
For more information on any of the above support services please contact your local domnick hunter representative. email: tsg@domnickhunter.com
