April 1, 2010 (Vol. 30, No. 7)
Angelo DePalma Ph.D. Writer GEN
Complex and Sensitive Drugs Necessitate High-Tech Manufacturing Operations
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.
Isolators have been used in filling lines since the mid-1990s and are now common in advanced lines, particularly new installations. “Isolators represent the high point of aseptic processing, and we now have a path for qualifying them without major issues,” observes M. Ryan Hawkins, director of parenteral manufacturing at Cook Pharmica.
Hawkins notes that RABS (restrictive access barrier systems), which have many of the same attributes as isolators, are less expensive but their value for aseptic filling is elusive since their major benefit—access to the process inside—is moot. “People spend a lot of time compiling pro and con lists of which is better, but the bottom line is that regulators don’t want you opening the doors anyway, so any perceived advantage of a RABS goes by the wayside.”
The exception, according to Hawkins, is a retrofit filling installation where facility factors restrict what type of system may be installed.
Yet not every company is sold on the superiority of isolators. Vetter’s new Skokie site operates three cleanrooms and employs isolator and RABS technology throughout. One room fills all available primary packaging systems including vials, cartridges, and syringes (single- and dual-chamber) for early clinical trials and proof-of-concept studies; the second services both liquid and lyophilized vials using disposable filling technology; and the third room fills presterilized syringes for higher quantities.
Sandy Khan, Ph.D., senior designer at Shibuya Hoppmann Engineering, believes that U.S. investment in filling technologies is falling behind Europe and Asia, particularly with respect to automation. For example robotic manipulation within aseptic isolators is common overseas but not stateside. “With robotics, it’s a simple matter to transfer from lab-scale to full manufacturing because the robot remembers the necessary operations. In this respect, we are doing better in aseptic beverage processing than aseptic pharmaceuticals.”
Part of the problem has been consolidation through acquisition, which continues unabated in the U.S. pharmaceutical industry. Another is low manufacturing costs as a percentage of total costs, which Dr. Khan estimates at about 10% for pharmaceuticals but as high as 40% for beverages. “With that kind of cost structure it’s impossible to justify any kind of investment in manufacturing.”
The technology gap between U.S. and overseas companies is by no means universal. GlaxoSmithKline, for example, has been steadily upgrading its filling lines with isolator systems for the past decade. Picken, who oversees vaccine production at GSK’s Quebec and Dresden locations, notes that the use of aseptic connectors provides a high level of contamination control, while innovation in the format of dosage containers (vials, syringes) allows filling without having the container open for extended periods of time.
Enclosures and classified space are by no means the only way to achieve aseptic conditions during filling. Low-energy electron beams, an alternative to gamma irradiation, have a long history of safe use in many industries. Moreover, the systems have been miniaturized, with emitters the size of a large flashlight, and the entire system fitting inside a desktop-sized housing.
“Electron beams can’t blast through a crate like gamma rays,” explains Josh Epstein, director of marketing at Advanced Electron Beams (AEB), “but they allow you to change the way terminal sterilization is carried out and bring the process in line. Their adoption coincides with the move toward isolators versus cleanroom filling and of plastic packaging versus glass.”
AEB works with filling system manufacturers to create custom sterile filling machines. The company’s systems use electron beams for aseptic transfer into the filling line but other applications are possible.
Sidebar: Disposable Filling Line
Readers may be wondering what has happened with Bosch Packaging Technology’s disposable filling line. The PreVAS single-use dosing system debuted in prototype form at “Interphex 2008”, when the company expected full commercialization within 12 months. Now we hear that, due to extended manufacturing and validation efforts, the debut of PreVAS been delayed by approximately one additional year.
Bosch is known for its stainless steel filling (and other) equipment, but was new to single-use systems. Perhaps, more importantly, single-use dosing systems, containing a disposable filling pump, were an entirely novel concept when Bosch introduced PreVAS.
PreVAS materials of construction are industry-standard, Class VI, animal derived component free. Systems are constructed of platinum-cured silicone tubing and polypropylene fittings, while pump product contact components are made from platinum-cured silicone and polycarbonate. The filling needles are stainless steel with a polycarbonate overmold.
Bosch is planning to complete the validation package for PreVAS within the next several months. “We are currently working on obtaining sterility and extractables data,” says Jessica Frantz, product manager for single-use dosing systems.
“Beyond that, we will complete stability and shelf-life determinations, which will take longer than the sterility and extractables work due to the nature of these tests.” Bosch will also analyze the systems for endotoxins, particulates, and function. The gamma-irradiated products will undergo real and accelerated aging tests, with the goal of putting an expiration date of several years on the package.
“We noticed some design improvements that should be made when we reached the mass production phase for the pumps and that pushed back our validation efforts. Once these design changes were made, we discovered several steps in our assembly process that we wanted to change to improve repeatability. Then, the validation consultants we’d been working with closed their doors before validation was complete. There has been a lot of learning along the way. But everything we’ve learned has made the product better.”