Pharmaceutical packaging is obliged to comply with many functions. And it has an influence on the quality, effectiveness and applicability of pharmaceuticals which cannot be underestimated. This particularly applies for primary packaging, i.e. packaging which comes or can potentially come into direct contact with the dosage form, such as ampoules, ready-to-fill syringes, blister packs, pharmaceutical stoppers or other types of pharmaceutical seals. Therefore, the requirement profile – protection, safety, compatibility and function – needs to be complied with as early as the packaging development phase. This is also regarded as key by the approval authorities who demonstrate the manifold requirements in the European Pharmacopoeia or the United States Pharmacopoeia (USP). Accordingly, proof is required for each new or modified packaging product suitable for designated use of the respective pharmaceutical. A variety of material characteristics require testing, e.g. physical and mechanical properties, processability, resistance to chemicals, cleanliness, hygiene or sterilisability.
Furthermore, test certificates in accordance with USP 381 are required for pharmaceutical stoppers (and other pharmaceutical seals) as primary packaging. As a general rule, the USP 381 regulates the properties of pharmaceutical seals (elastomeric closures for injections).
Specifically, the USP 381 includes both the certificate of bio-compatibility and physical-chemical tests and functional tests.
Evidence of bio-compatibility, i.e. proof that the materials or substances in direct contact with living tissue do not exert any negative influence on the metabolism thereof, must be provided in vitro.
In physical-chemical tests, various solutions are applied in extensive processes and their properties or modifications examined, e.g. whether they become cloudy or change color, how high the acid and lye content is, whether heavy metals, volatile sulfides or ammonium can be detected, or organic and inorganic contamination such as zinc.
Then function tests are carried out to examine penetrability, fragmentation and self-sealing.
Testing for penetrability involves measuring the force required to penetrate the septum. For the test in accordance with DIN 13097-4, the septum is pierced with an injection needle at a speed of 20 mm/min to 200 mm/min. The test is only passed if the force required does not exceed 10 N (1.02 kg).
A fragmentation test is used to examine for particle residue, whereby 12 injection bottles are filled with water, sealed and a needle used to pierce the septum at various points. After each piercing incident, 1 ml water is pulled up with the injection and the liquid used to examine whether and how many visible plastic particles have detached from the seal after piercing the septum. The test is regarded as having been passed if no more than five visible particles can be detected in the filter.
And then there is the resealability test, which again involves filling injection bottles with water, sealing them and piercing the septum ten times at various points. The bottles are immersed in a methylene blue solution and subjected to negative pressure (270 mbar) for ten minutes. Followed by 30 minutes under normal pressure, it is possible to ascertain whether the self-sealing characteristics have worked. If piercing has not been followed by resealing, the methylene blue would have penetrated the bottle during the test and caused the liquid to turn blue.
PROVAMED TPE for pharmaceutical stoppers have been compounded in accordance with various material approaches for a variety of raw materials and subjected to extensive testing. In view of the highest demands on low migration, compatibility on contact with the human body and FDA conformity, it has been possible to present formulae whose performance and conformity comply with USP 381. Evidence has been provided of the fact that even after multiple piercing of the TPE material, no residue adheres to the needle or can be found in the test solution. This ensures that effective action can be taken to counter the risks of particle contamination. The sealant function prevents leakage of any components of the medication or vaccination. The self-sealing features for safe resealing have also proved their worth, thereby extending the shelf life of the respective pharmaceutical as well as minimizing the risk of contamination and therefore improving patient safety. With a force of less than 5 N (force for piercing the septum), the penetrability test represented an outstanding result. After all, a particular degree of purity can also be certified as there is no interaction with sensitive pharmaceuticals or active ingredients as neither sulfur nor zinc or other cross-linkers are used which would be required in the case of vulcanized rubber, for example.
PROVAMED TPE 6145 TL, 6245 NC and 6345 NC were subjected to conventional sterilisation methods – superheated steam at 121 °C and 134 °C, ethylene oxide, and Gamma radiation (25kGy and 50 kGy).
For reasons relating to accountability, at Actega DS materials are subject to further tests, e.g. on the topic of oxygen permeability, non-intentionally applied substances (NIAS) or allergens. The TPE offered by Actega DS are also free of PVC, phthalates, latex and ADC and do not require any cross-linkers such as rubber or vulcanised rubber. These can disintegrate which is why reaction accelerators (amines, sulfides, resin) are required to control such disintegration and can, in turn, lead to changes in the pH values of pharmaceuticals. In contrast, TPE require neither cross-linkers nor vulcanisation which is intensive in terms of time and temperature. Thus also qualifies TPE as material for primary packaging.