Parenterals/Injectables

Injectable dosage forms represent one of the highest risk drug products in relation to the potential introduction of impurities via container closure contact, since any leachable can be rapidly and completely introduced into the patient’s general circulation.

Table 1 of the FDA-Guidance “Container Closure systems for packaging Human Drugs and Biologics” classifies the “injections and injectable drug products” in the highest degree of concern associated with the route of administration, together with inhalation aerosols and solutions. In addition, the likelihood of interaction between the packaging and the dosage form is also considered to be high. The General “Safety” Considerations in the FDA-Guidance state that injectable drug products will categorize under “case 2s”, which requires in many cases extractables data with an associated toxicological evaluation, together with the standard USP Biological Reactivity tests. However, based upon the feedback from regulatory submissions, it is clear that since 1999, the FDA has gradually increased the level of required documentation. If the requirements for a container closure system would not be clear or conclusive, the FDA encourages discussing the documentation in container/closure requirements with the appropriate CDER chemistry review staff or CBER review staff.

Paragraph 4 “Extraction Studies”, as well as the decision tree of the European EMEA-Guideline, indicate that for non-compendial plastic material used for container closure systems for non-solid medicinal products intended for parenterals administration, extraction studies are required even when approved for use in food packaging. In addition, Paragraph 5 “Interaction studies” of this document states that – regardless if the materials comply with the European Pharmacopoeia – for non-solid active substances and liquid dosage forms, the risk of interaction requires comprehensive and suitable studies. These studies should ensure that no significant alterations are occurring, leading to lesser quality of the active or medicinal product.

However, it should be noted that this EMEA-Guideline specifies that “Elastomers and natural and synthetic rubbers are not within the scope of this guideline”. This is remarkable since pharmaceutical rubbers are the most complex materials in their composition (e.g. elastomers, fillers, antioxidants, curing agents, activators, accelerators, pigments, stabilizers, plasticizers...). In addition, during the rubber curing, a lot of chemical reactions are initiated to obtain the final rubber form and physical properties. These chemical reactions may sometimes lead to the presence of undesired/unexpected reaction products. Because of this complexity in composition and chemistry, rubbers are therefore more prone to leaching compared to many other plastic materials. This may explain why – based upon the feedback from regulatory submissions - European regulators tend to request the same level of E/L documentation for rubbers as for any other polymer material used in parenterals applications, based upon the decision tree of the EMEA-Guideline.

There is a long list of different types of container closure systems that are used for injectable/parenteral applications. Based on the US Pharmacopoeia, the FDA-guidance makes the difference between Small Volume Parenterals (SVP < 100 mL; examples are disposable syringes, prefilled syringes, cartridges, vials, ampoules or flexible bags) and Large Volume Parenterals (LVP > 100 mL; examples are glass/plastic bottles, flexible bags, vials or even disposable prefilled syringes).

The materials used for the manufacture of container closure systems for parenteral administration involve typically rubbers, glass (including concerns on Tungsten and glue migration for glass prefilled syringes), LDPE, HDPE, PP, PETg, COC, COP, PVC, multilayer films, etc... Each material will exhibit its own extraction profile and may therefore contribute to the risk of potential adulteration of the medicinal product. In addition, if the container is made of a relatively permeable material, label migration will be regarded as an additional concern.


In order to set-up the right set of testing conditions for E/L studies, it is imperative to have a good knowledge of the composition of these materials (e.g. production process, solvents used, potential impurities, polymer additives to increase end-use performance or to protect the polymer during its life cycle), but also to have a good understanding of the mechanism of polymer leaching and what the interaction of these materials with pharmaceutical formulations may induce.

Nelson Labs Europe is specialized in qualifying container closure systems for all parenteral applications, starting from the typical compendial EP and USP testing up to a high level of Extractables / Leachables studies.

Because of our vast experience in this field, Nelson Labs Europe has built a broad expertise in developing testing programs which require a combination of state-of-the-art analytical techniques, such as Headspace GC/MS, PTV-GC/MS, GC/MS, LC/MS, LC/MS/MS, ICP, IC... In addition, Nelson Labs Europe can offer its assistance in the elucidation of structural information for critical compounds, using GC-ToF, LC-ToF, FT-MS or NMR.

Nelson Labs Europe works together with a broad base of container closure manufacturers in order to develop en qualify their products, as well as with pharmaceutical companies to give guidance in developing a strategy to comply with the regulatory requirements and to assist in their worldwide Regulatory Submissions.

If you would be interested to find out more about our services and testing programmes, please feel free to contact us at InfoEurope@nelsonlabs.com or call us at ++32 (0)16 400.484.


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Contact a Study Director:


lhabel@nelsonlabs.com
nvanderlinden@nelsonlabs.com

Nelson Labs Europe | Parenterals/Injectables