Aseptic filling—the final step before packaging parenteral small molecule and biotherapeutic drugs—represents one of the most technologically innovative and dynamic areas of downstream operations. Filling operations are changing in response to larger industry trends, explains Peter Soelkner, managing director of Vetter Pharma.
“Pharmaceutical development is evolving toward highly complex and sensitive biotech drugs including highly concentrated monoclonal antibodies and lyophilized products that present filling challenges that small molecule drugs, even parenterals and vaccines, do not.”
Biopharmaceuticals also raise dosage form and packaging issues that will continue to grow as the population ages. These necessities, Soelkner argues, require that delivery systems change and with them the way primary packaging systems are selected. “More than ever, fill/finish needs to reflect patient needs with the right delivery system.”
Vetter specializes in aseptic filling for high-value injected biopharmaceuticals, which is where Soelkner believes the industry is headed. “In the past, a blockbuster biotech product required 20 to 40 million syringe fills; today, it’s possible to achieve blockbuster status with just two million fills per year.”
Twenty-two commercial biopharmaceutical products with FDA approval use Vetter’s filling lines. In December, the company opened a new site in Skokie, IL, to assist with aseptic filling of clinical trial materials. Two-thirds of the current biopharmaceutical clinical Phase I–III projects come from North America. The challenge for such facilities, Soelkner says, is to realize the seamless integration of the development phase with the commercial launch of a new drug product.
Drugs that require special handling due to temperature or light sensitivity pose unique engineering issues for fill/finish. Other problem areas are highly viscous formulations and suspensions. Light-sensitive materials make visual inspection difficult since they are filled into opaque containers; thick formulations get stuck inside filling lines and promote formation of air gaps or bubbles that distort the extent of fill; and suspensions demand constant, steady mixing to the point of fill to maintain uniform ingredient concentrations.
Perhaps the greatest challenge is processing cytotoxic drugs, says Richard Snyder, Ph.D., director at Florida Biologix. Although it is not often a problem with biologics, parenteral small molecule drugs (notably parenteral cancer drug formulations) create worker exposure and product protection issues.
As a result, the industry is experiencing a shortage of sites suitable for aseptic filling of cytotoxic small molecule and biological drugs. “Not enough facilities are built out with the specific safety features for handling these drug substances,” notes Michael Frid, Ph.D., principal scientist at Wolfe Laboratories. Dr. Frid notes that sponsors are scrambling for open slots during early-phase clinical testing, a time characterized by small batches, but where timing becomes a critical issue.
“Companies have to be careful of getting ‘into the queue.’ Missing an opportunity can add weeks or months to a clinical program.” The capacity crunch, adds Dr. Frid, is more acute for small molecule cytotoxics than for biologicals.
Wolfe designs and develops lyophilization cycles and related analytical methods for prefilled syringes, mostly from late discovery through Phase I. The company is considering performing fill/finish for Phase I compounds as well.
Vaccines are creating new opportunities for vendors of filling equipment and companies that provide fill/finish-related services. Vaccine growth is being fueled by emerging medical markets particularly in China, India, and some regions of South America.
Vaccines must be maintained under strict temperature control, usually 5ºC, throughout processing. Similar requirements apply for many, but by no means all biotherapeutic classes, notes Pierre Brun, director of fill and finish at Sanofi-Pasteur. Sterility is another critical issue, Brun says, which has led to the adoption of sterile connectors and various barrier systems to protect products from workers and the environment.
The resurgence of vaccine markets has led to the implementation of dosing and delivery technologies that directly or indirectly affect filling. For example, Sanofi-Pasteur has developed syringe technology that employs a 1.5-mm needle (about the width of a human hair) that delivers vaccine painlessly and intradermally (vs. intramuscularly).
The most notable difference between protein therapeutics and vaccines is volume, a factor with immediate impact on filling. For example, GlaxoSmithKline fills more than one billion doses of vaccine per year, according to vp, John Picken, compared with millions of doses for leading protein therapeutics. Filling lines at vaccine plants tend to operate at the highest capacity and volume in the industry.