26/27 September 2023
Stainless steel is predominantly used in pharmaceutical equipment engineering. The 316L variant is basically regarded as standard; material incompatibilities of the steel with the product are more or less neglected. This is different with plastics. In addition to leach-out, aging and surface finish, other quality characteristics are often specified. But are there generally applicable requirements for plastics in pharmaceutical equipment engineering?
Unfortunately, there is no simple answer to this question. As is well known, the applicable GMP regulations contain few technical details and in some cases even omit the subject of plastics. Nor is there any kind of "gold standard" for the pharmaceutical industry. The requirements always depend on the specific purpose of use.
Three types of plastics are used: Soft plastics (e.g. film), hard plastics (e.g. valve bodies) and elastomers (e.g. membrane for membrane valves or O-rings). The essential quality characteristics are surface finish and material compatibility.
An essential GMP requirement for equipment used in the manufacture of pharmaceutical products is that it must be easy to clean. Therefore, the smoothness of the surfaces in contact with the product is required. In the case of stainless steel, a surface roughness value of Ra ≤ 0.8 µm is common. This is then measured in parts of the plant as part of the qualification process or documented by certificates from the eqipment manufacturer. Determining the surface finish of plastics is more difficult. With mechanical scanners, there is a risk of scratching the plastic surface.
When specifying center roughness values for plastic parts, manufacturers often use statistical methods, i.e. some parts are measured (and then possibly discarded) or non-contact measurement methods may possibly be used (e.g. white light scanning).
In the case of thermoplastics produced by injection molding, where manufacturers use highly polished injection molds, the high surface quality is generally ensured by the manufacturing process. Here, surface roughnesses are achieved that are significantly better than Ra ≤ 0.8 µm for stainless steels. This is also confirmed in material certificates, which are considered sufficient if the supplier is qualified by the quality department of the pharmaceutical manufacturer. Suitable ISO standards for the roughness measurement of stainless steels are DIN ISO 4287 and 4288.
The SEMI F57 standard for the semiconductor industry (for ultra-pure media technology) deals with the surface of plastic components. There and in addition to others, SEMASPEC 92010950B (Preliminary Test Method for Visual Evaluation of Surface Roughness for Plastic Surfaces of UltraPurewater Distribution System Components), is used for the verification of surface quality. There is no comparable specification within the pharmaceutical world.
In the case of plastic parts produced by chip removing, it is usually only possible to achieve surface values of Ra <1 µm with special additional measures, i.e. it plays a significant role whether a component was produced by injection moulding or by milling.
It is much more difficult to make a statement about material compatibility. The basic GMP requirement is that the material of the equipment must not negatively affect the quality of the pharmaceutical product. Often, a certificate of food suitability is used as proof for this - i.e. that the material is not toxic when consumed in small quantities. Certificates with the following reference are used for this purpose:
However, it may also be useful to specify compliance with other requirements:
The USP, the American Pharmacopoeia, also makes statements on the pharmaceutical suitability of plastics and divides them into six biocompatibility classes (USP <88> Class I-VI). USP Class VI represents the most stringent class. In order for a material to receive a Class VI classification, tests are specified that usually have to be carried out in external testing laboratories. For this purpose, toxicity is determined in animal tests by applying plastic extracts systemically and intracutaneously and observing the reaction. In addition, an implantation test is also carried out.
This requirement is often but unnecessarily specified, as it does not justify the many animal tests and high costs. USP has now responded to this. The new proposals on in vivo biological testing are intended to avoid redundant testing and replace animal testing with more cytotoxic and genotoxic in vitro testing (proposed revisions of USP <88> and <87> were published in the USP Pharmacopeial Forum on July 1, 2021).
In biotechnological production, it is also useful to specify "ADI free" (ADI free = raw materials contain no Animal Derived Ingredients). This means that no material of animal origin was used in the plant construction. Such materials are accordingly also BSE and TSE free (BSE = Bovine Spongiform Encephalopathy; TSE = Transmissible Spongiform Encephalopathy).
Another GMP requirement regarding material compatibility is that the plastic does not react with the pharmaceutical product and is not adsorbed. The knowledge of the pharmaceutical manufacturer is required here, because only he knows which substances the equipment material will be exposed to.
The leach-out of plastic materials should also be mentioned here, i.e. the consideration of which substances could pass from the plastic into the pharmaceutical product. For this purpose, the plant manufacturers carry out studies in which model solutions are used to test which substances can actually be extracted from the plastic in a kind of worst-case scenario (determination of the extracables). In leachables studies, in cooperation with the pharmaceutical manufacturer, the pharmaceutical product is used to test which substances actually leak out under real conditions. The result of the studies must then be toxicologically evaluated, taking into account the process, product, application, etc. Whether leachables/extracables studies are required is determined by the pharmaceutical user himself by means of risk analyses. In the case of single-use systems, i.e. equipment made of plastic that is disposed of after a single use and in which entire processes such as fermentation or chromatography take place, this is the rule. Here, the first step should be to approach the manufacturer of the single-use equipment and discuss what information is already available and how a leachables study could be carried out together.
According to the valid GMP specifications (e.g. EU GMP Annex 15), a verification of the construction materials must be carried out in the qualification. The background to this is to ensure that the equipment was built from the materials that were required by the pharmaceutical manufacturer. Since not every pharmaceutical manufacturer has the necessary means for material testing or identification, this is where the material certificates come into play.
For stainless steel components, 3.1 certificates (according to EN 10204) are usually required. Here, traceability of the certificate to each component is guaranteed.
For plastic components, 2.1 certificates are generally accepted. With these certificates, the equipment manufacturer himself confirms compliance with the requirements. This does not provide one hundred percent certainty. On the other hand, this standard is also intended for metal products and less for plastics.