In Part 1 and Part 2 of my blog series regarding trends in container closure integrity testing, I summarized the shift from probabilistic to deterministic test methodology as well as the noticeable increase in “preventative” CCI programs. Part 3 of this blog series discusses a trend not unique to CCI, but rather one that can be seen industry-wide: the rise of the autoinjector device.

An autoinjector is designed to quickly deliver a pre-measured dose of medication in a single use. Like many consumer products and technologies that make it to the mainstream, the autoinjector’s origin lies with the United States Armed Forces, which was exploring ways to deliver antidotes for nerve agents. An autoinjector was the ideal solution, as it not only rapidly delivered a pre-measured dose, but also allowed administration by troops in the field with little to no training in medicinal administration. These devices became known as the AtroPen and ComboPen (A Rich Heritage of Innovation, 2015).

It was quickly realized that the qualities of an autoinjector were not only beneficial to combat units. In 1977, a commercial product using an autoinjector was patented, coming to market in the form of the EpiPen in 1980 (Kaplan et. al., 1977). The EpiPen revolutionized injectables as an emergency response to anaphylaxis that could easily be carried and administered. Despite this, the autoinjector’s use was not widespread for over a decade.

In the mid 1990s, the FDA began approving groundbreaking drugs such as Enbrel (Therapeutic Biological Products Approvals, 2003). What made these drugs revolutionary was their mode of synthesis: the drugs were biologics, the spawn of recent advancement in biotechnology, and used to treat autoimmune diseases ranging from rheumatoid arthritis to Crohn’s disease. From that point forward, biologics have been on the cutting-edge of medical research and treatment. Considering many of these products are parenterals that require regular doses, packaging these products in autoinjection devices yielded the same benefits seen with the ComboPen and EpiPen: they were portable, pre-measured, and easily administered by patients and caregivers. The biologics revolution that ensued was largely responsible for the initial rise in autoinjector usage. However, well after the initial wave of biologic autoinjectors came to market, Whitehouse Labs has seen a recent and dramatic increase in the number of autoinjector devices entering our CCI Method Development and Validation Laboratory.

The root cause of this trend was obscure at first. Why now, years after biologic products packaged in autoinjectors burst onto the scene, was there a dramatic rise in requests for CCIT of autoinjectors? The industry shift to deterministic test methods had caused an increase in requests for all package types, including vials, cartridges, and syringes. Yet, there was something exceptional about the rate at which our autoinjector services were growing. Then, I happened to stumble upon a 2012 article by Calo-Fernández and Martínez-Hurtado titled “Biosimilars: Company Strategies to Capture Value from the Biologics Market” (2012). Although no reader will find the words container closure integrity, or even “testing” within the article, I believe it answers the question: why are autoinjectors on the rise at Whitehouse Labs?

The article thoroughly discusses the biologics “patent cliff”, or the period of time from 2012 to 2019 in which the top 10 selling biologics, along with numerous others, will have their patents expire. In the pharmaceutical industry, patent expiration is frequently followed by exploitation, which comes in the form of generics. This process holds true for biologics, with generics referred to as biosimilars, or “a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product” (Biosimilars, 2015). The first biosimilar was approved by the FDA in March, 2015 (FDA approves first biosimilar product Zarxio, 2015).

Unsurprisingly, many of these biosimilars benefit from packaging in autoinjectors. The fledgling, yet rapidly growing biosimilar market, paired with the ever-increasing prevalence of biologics, is the reason for the remarkable increase in autoinjection systems passing though our CCI laboratory. This trend has been coincidental with the industry shift from probabilistic to deterministic test methodology, as discussed in Trends in CCIT Part I. These two trends, in tandem, have presented their own unique challenge to overcome: how to go about testing autoinjection systems by deterministic CCI test methods.

The challenge is two-fold. When choosing a test methodology to move forward with, both the package and product enclosed must be considered. Inside of an autoinjector is usually a prefilled syringe, or sometimes a cartridge. As liquid filled packages, these are ideal candidates for high voltage leak detection. However, a well-performing HVLD method is dependent on the electric current contacting various parts of the liquid-filled package, a feat made improbable by the autoinjector subassembly. Thus, for assembled autoinjectors, HVLD is essentially infeasible.

Without the ability to perform HVLD on the assembled autoinjector, we must rely on pressure-based analyses such as vacuum decay or mass extraction. However, such technologies are usually not ideal for packages containing liquid product, especially proteinaceous products, due to their propensity for clogging defect pathways. Additionally, the plastic casing of an autoinjector frequently yields a large amount of out-gassing, the process in which gas trapped in materials is extracted while under vacuum. Out-gassing from plastic materials results in a gradual increase in test chamber pressure levels, making it difficult to distinguish from small leaks. This background noise also limits the sensitivity of a pressure-based analysis of autoinjection systems.

Taking these complications into account, Whitehouse Labs typically suggests a two-pronged approach to container closure integrity testing of autoinjectors. Most commonly, two methods will be developed. The first method would be HVLD on the syringe or cartridge, which is often capable of finding defects down to about 3µm in nominal diameter. This method may be used to assess package integrity on the prefilled syringe or cartridge prior to its implementation into an autoinjector.

Concurrently, a method will be developed by a pressure-based analysis on the entire autoinjection device. As previously discussed, there are complications that come along with performing a pressure-based analysis on an assembled autoinjector. However, there are cases in which the complications can be overcome. For example, it is possible that product clogs smaller defects, but that defects 20µm and above are still detectable. While this method would have a higher limit of detection (lower sensitivity) than the HVLD method developed on just the syringe or cartridge, having a validated method to assess assembled autoinjectors is of high value for a number of reasons, not the least of which is to assess package integrity as part of a stability program. This is a benefit not provided by the HVLD method on just the primary package.

In some cases, product demonstrates the ability to clog all laser-drilled defects, even those up to 100µm in nominal diameter. If this is observed during method development, a client may consider using placebo or sterile water-filled packages to validate the method. While this method would not be applicable to product-filled samples, and therefore could not be used as part of a stability program, there are other applications of a CCI test method on a complete autoinjector. One use is the validation of the autoinjector assembly process; ensuring that high-strain forces of autoinjector assembly do not damage the primary package. Alternative uses include shipping qualification, in which autoinjectors are tested before and after a distribution simulation cycle to ensure no damage was incurred, or that no autoinjectors were actuated. Understanding the ways to go about testing autoinjectors is key, as approaches may differ depending on study goals or the product.

While autoinjector systems present specific challenges with respect to container closure integrity testing, they are becoming commonplace at the Whitehouse Laboratories CCIT Method Development and Validation Laboratory. As development of biologics and biosimilars forges on, the autoinjector shall remain on the rise. As industry shifts to deterministic test methods, the need to develop and validate methods for autoinjectors will do the same.

Brandon Zurawlow
Associate Director, CCIT

 

References

A Rich Heritage of Innovation. (2015, April 1). Retrieved July 13, 2015, from
http://www.meridianmeds.com/about-history-static

Biosimilars. (2015, March 6). Retrieved July 13, 2015, from
http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/default.htm

Calo-Fernández, B., & Martínez-Hurtado, J. L. (2012). Biosimilars: company strategies to capture value from the biologics market. Pharmaceuticals, 5(12), 1393-1408.

FDA approves first biosimilar product Zarxio. (2015, March 6). Retrieved July 13, 2015, from
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm

Kaplan, S., Calkins, G., Sarnoff, S., & Dalling, N. (1977, June 28). Patent US4031893 – Hypodermic injection device having means for varying the medicament capacity thereof. Retrieved July 13, 2015.

Therapeutic Biological Products Approvals. (2003, December 12). Retrieved July 13, 2015, from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080402.htm