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by Satish Singh

Satish SinghAll product development scientists understand the importance of container closure to the sterility, stability, and delivery of a parenteral drug, including biotherapeutics. The glass vial remains a mainstay, while a number of biotherapeutics are targeting or becoming available in prefilled syringes. Subcutaneous (SC) administration is a desirable route of parenteral administration for biopharmaceuticals.

Novartis has introduced a prefilled syringe (PFS) version of Lucentis (ranibizumab) in Germany, with a bespoke syringe designed especially to improve safety as well as dose accuracy. Other examples include the European Union approval of a new SC formulation of Herceptin (trastuzumab) and more recently of MabThera (rituximab), through the use of Halozyme rHuPH20 technology. The former product remains in a vial and probably so is the latter, likely due to the dose, but there may be other products where a syringe presentation is feasible in an IV to SC switch.

PFSs are particularly desirable for products targeted for chronic use and/or home use. Autoinjectors and pen devices are the next steps in making these more convenient to use. Other delivery platforms such as needle-free or patch pumps remain interesting but will likely remain in niche applications. There is a very strong awareness of the impact of the PFS container closure on product quality and use. A PFS has multiple modes of integrity (sterility) failure compared to a vial. Therefore, maintaining and monitoring the integrity of the PFS has received considerable attention although not a lot has been published.

Assessing extractables and leachables from the components is an important aspect of the container closure selection. For PFS (with or without staked-in needles), tungsten is a key “leachable” to be studied in development. The report by Seidl et al basically implicates tungsten-induced aggregation for two cases of pure red cell aplasia in an epoetin alfa trial. Multiple articles and discussion forums have been dedicated to the impact on subvisible particles count from the siliconization of syringes (see e.g., Felsovalyi et al, Majumdar et al). Investigational and spiking studies have assessed the impact of tungsten and silicone oil (see e.g. Auge et al, Bee et al). It is clear is that such studies must be designed and executed carefully so as to not risk creating a very narrow design space for these parameters, since detrimental effects will be seen above certain spiked concentration levels.

The impact of high concentration products and their viscosity, and thereby injectability, is also a hot area of research. Component manufacturers have responded with a variety of offerings to help address these issues with stricter tungsten control, novel siliconization strategies, innovative needle designs, etc (see, e.g., Wright and Soukiassian). The FDA has also been active with an April 2013 draft guidance on glass syringes to supplement testing under ISO 11040-4 and finalized regulations on combination product good manufacturing practice (CPGMP) requirements (21CFR4; Jan 2013), which went into effect on July 22, 2013 and which clarifies a PFS as being a combination product. A warning letter was issued to a major pharmaceutical company in January 2014 for failing to meet certain requirements of the combination products current GMPs, including aspects of the design history file. It is highly likely that the FDA would require relevant tests defined in the draft guidance be part of submissions, and also of the design history files under the new CPGMP requirements.

A number of scientific, technical, regulatory, and operational aspects of the container closure system are evolving rapidly, and an AAPS National Biotechnology Conference open forum session, scheduled for May 22, 2014, will focus on some of the latest developments in this area. We look forward to continuing discussion of this important topic with you there.

Satish Singh, Ph.D., is a research fellow at Pfizer in the Biotherapeutics Pharmaceutical Sciences group. He has expertise in formulation, product and process development activities for biologics and therapeutic vaccines, and is involved with regulatory aspects of biologics development.