General requirements for Plastics in Pharmaceutical Engineering

The main material used in plant engineering is stainless steel. The variant 316L is regarded as standard; material incompatibilities of steel with the product play almost no role. This is different for plastics. Beside the leach-out, ageing and surface finishing, other quality features are often specified. Now, what are the general requirements for plastics in pharmaceutical plant engineering?

There is no simple answer to this question. The GMP regulations partially exclude this topic - there is no "gold standard" either. The requirements always depend on the concrete application purpose.

Three types of plastics are used: soft plastics (e.g. foil), hard plastics (e.g. valve bodies) and elastomers (e.g. membranes for membrane valves or o-rings). The essential quality features are surface finishing and material compatibility.

1. Surface finishing

One GMP requirement for pharmaceutical plants is that they must be easy to clean. Therefore, the surfaces in contact with products must be smooth. For stainless steel, Ra <= 0.8 µm is the usual surface roughness requirement. This value is measured in some parts of the plant during qualification or documented by certificates from the plant manufacturer. Verification by means of a profilometer/perthometer is still state-of-the-art.
It is more difficult to determine the surface of plastics. Indeed, mechanical detectors pose a great risk of scratching the plastic surface.

When specifying average roughness values for plastic parts, manufacturers often use statistical methods, i.e. some parts are measured (and then thrown away). Alternatively, contact-free measuring methods may be used (e.g. white light scanning).

In the case of thermoplastics, which are produced by means of injection moulding and for which the manufacturers use highly polished injection moulds, the high surface quality is generally ensured by the manufacturing process. Here, a surface roughness can be achieved which is significantly better than the Ra values of stainless steel (e.g. <= 0.8 µm). This is also confirmed in material certificates and can be regarded as sufficient if the supplier's quality system is trusted. ISO standards for the roughness measurement of stainless steels are DIN ISO 4287 and 4288.

The SEMI F57 standard for the semiconductor industry (ultrapure media technology) deals with the surface of plastic components. SEMASPEC 92010950B (Preliminary Test Method for Visual Evaluation of Surface Roughness of Plastic Surfaces of UPW Distribution System Components) is used for the verification of surface quality. However, there is no such comparable specification within the pharmaceutical world. In the case of plastic parts produced by cutting, it is sometimes only possible to achieve surface values of Ra <1 µm with specific additional measures, i.e. it plays an important role whether a component was produced by injection moulding or cutting/milling.

2. Material compatibility

It is much more difficult to make a statement about material compatibility. The basic GMP requirement is that the plant material does not negatively influence the quality of the pharmaceutical product. A certificate of food suitability is often used as a proof - i.e. that the material is not toxic when consumed in small quantities. Certificates with the following reference serve this purpose:

• US Federal Standard CFR 21.177
• The positive list of the Federal Institute for Risk Assessment "Recommendations on Materials for Food Contact" (formerly "Plastics Recommendations; Health Safety Food, Commodities and Feedstuffs Code" (LFGB))
• EC1935/2004 (Materials and articles intended to come into contact with food)
• EC2023/2006 (Good manufacturing practice for materials and articles intended to come into contact with food).

However, it may also be useful to provide specifications for compliance with further requirements:

• 3A Sanitary Standard
• EHEDG (European Hygienic Engineering & Design Group)
• DIN 26055 - hose assemblies or use in the pharmaceutical and biotechnical industry
• DIN ISO 3601-3 Form and surface deviations of o-rings (for pharmaceuticals, observe "Grade characteristic S")

The US Pharmacopoeia also makes statements on the pharmaceutical suitability of plastics and divides them into six biocompatibility classes. USP Class VI represents the strictest class and is equivalent to a pharmaceutical authorisation for polymer materials. In order for a material to receive a Class VI classification, tests are specified which must be performed in external test laboratories. For this purpose, animal testing shall be carried out to determine acute toxicity (irritation when swallowed or inhaled), intra-cutaneous reactivity (tissue test) or an implantation test. This requirement is often unnecessarily specified. It is important to be aware that not only money is wasted, but also unnecessary animal testing is indirectly caused.

In biotechnological production, it can also be useful to specify "ADI free". This means that no materials of animal origin are used in the plant construction (ADI free = raw materials contain no Animal Derived Ingredients). Such materials are also BSE and TSE free (BSE = Bovine Spongiform Encephalopathy; TSE = Transmissible Spongiform Encephalopathy).

The pharmaceutical manufacturer himself must clarify whether the plastic used is chemically not reacting or interacting with the pharmaceutical material. Furthermore, the leach-out of plastic materials is critical in biotechnology, i.e. the clarification of which substances can pass from the plastic into the pharmaceutical material. For this purpose, the plant manufacturers carry out studies in which - in a worst-case scenario using model solutions - it is tested which substances can be extracted from the plastic at all (= determination of extractables). In leachable studies, the pharmaceutical material is used to check which substances actually leach out under real conditions. The results of the studies must then be evaluated toxicologically, taking into account the process, product, application, etc. The results of the studies must then be evaluated toxicologically. The pharmaceutical user himself determines whether leachable/extractable studies by means of risk analyses are required.

According to the applicable GMP specifications (e.g. EU GMP Annex 15), verification of the construction materials must be carried out during qualification. The reason for this is to ensure that the plant was built from the materials required by the pharmaceutical manufacturer (the material of the plant must not have any negative influence on the product). Since not every pharmaceutical manufacturer has the necessary means for material testing or identification, the material certificates come into play:

• As a rule, 3.1 certificates (according to EN 10204) are required for stainless steel components. This ensures that the certificate can be traced back to each component.
• In the case of plastic components, 2.1 certificates are generally accepted. In the case of certificates used, the system manufacturer himself confirms compliance with the requirements. However, this does not provide one hundred percent legal certainty. On the other hand, this standard is also intended for metal products and less for plastics.