In the injectable pharmaceuticals market today, complexity is a given.  Overall, the number of biologics in development and production continues to rise.  Within this framework, demand for prefilled syringes, and movement into especially challenging new therapeutic areas such as antibody drug conjugates (ADC), is increasing demand for specialized contract injectable manufacturing services, from clinical through commercial production.

Although some large biopharma companies are building more injectable capacity in-house, more small to midsized companies are now outsourcing. The economic reasons are compelling: ADC’s for example, are highly toxic, and involve special manufacturing conditions. The risks of failure would be significant.

Companies are looking for partners who will ensure quality and regulatory compliance, and regulators expect reliable, consistent operations.

Contract manufacturers have responded by investing in aseptic fill, lyophilized vial and prefilled syringes and cartridge capacity, and expanding the range of specialized services they offer.  This article looks at market trends and how contract manufacturers are responding.

Injectable Trends
Outsourcing of injectable pharmaceutical manufacturing is growing, particularly in the U.S., and in the oncology drug area, notes Milton Boyer, president of OsoBio, who attributes this trend largely to regulatory concerns.

Big biopharma companies such as Amgen, which recently expanded in-house injectables capacity in Ireland, are less likely to outsource.  The move from vial to prefilled syringes and the increasing number of biologics in development and on the market are also driving demand.  The need for highly specialized services such as cytotoxic processing, is also increasing, he says.

Growth in injectables outsourcing currently outstrips that of solids and semisolids, says David Linn, director of business intelligence at Jubilant HollisterStier Contract Manufacturing & Services Division.  He expects further consolidation in the number of injectable service providers in North America, such as Emergent Biosolutions acquisition of Cangene in December. 

“We continue to see strong demand for specialized services such as cytotoxic manufacturing. Within this space, we increasingly see growing interest in ADC manufacturing for both clinical and commercial scale, says Jennifer Wendorf, senior marketing manager at Baxter’s BioPharma Solutions business.

Whereas 10 years ago most clients’ pipelines were driven by small molecules, today Wendorf sees a shift to biologics, and especially those that require specialized manufacturing capabilities.

Lifecycle management continues to be a critical consideration for pharma clients, she says, especially as more of their blockbusters face generic competition. “For these clients, we are able to offer solutions such as conversion from vial to prefilled syringes or flexible bag systems for added convenience, patient safety and differentiation,” she says.

Self-administration of injectable drugs, through the use of autoinjectors, pens and prefilled syringes, has become a strong end market, says Peter Soelkner, managing director at Vetter. Packaging has a major impact on overall trends, he adds, and the overall trends are on fill and finish innovations that improve dosing accuracy, reduce loss of API, and increase convenience for the customer.

Within the injectables market, North America and Europe account for nearly 70% of global injectable sales, according to Jubilant HollisterStier’s Linn, “A very large percentage of the products distributed in these developed markets are manufactured in these markets,“ he says. These companies continue to drive most R&D investments, but at modest growth rates, Wendorf says.  “Asian companies’ investments are growing at a faster rate,” she says.

OsoBio’s Boyer  sees the following considerations driving outsourcing decisions for injectables:

• regulatory records
• previous experience with the market involved
• location of the team that will manage the project

Supply and Demand
CMOs agree that there is a lot of overcapacity for sterile injectables now, and competition remains tight. Contract companies have been investing in manufacturing capabilities and offering ancillary services to keep up with customer demands. For example, Baxter’s BioPharma Solutions offers support services for production stability, quality and regulatory systems.  “Companies looking for a secondary supplier sometimes find that these qualities can help mitigate the risk of drug shortages or other dynamics relevant to their product offerings,” says Baxter’s Wendorf.

Single-plant sourcing is no longer a viable option for any drug company, so more name brand and generic companies are expecting more from contract partners, notes Vetter’s Soelkner.  “They are looking for a reliable long-term partner that can move their drug forward in the manufacturing and lifecycle process,” he says.

Flexibility is critical for any injectables CMO, he says, and Vetter has responded with modular filling lines and corporate quality and management programs such as  “permanent process optimization” and comprehensive cleanroom management.

Capacity and Capabilities
Many CMOs are adapting to changing market needs by investing in capabilities for cytotoxic manufacturing, lyophilization, and visual inspection. OsoBio is updating development capabilities, and converting analytical methods to best-in-class, such as ultra performance liquid chromatography (UPLC).

Noting some tightness in lyophilization service capacity, particularly in the U.S., OsoBio plans to expand its lyophilization
capacity. Vetter is expanding its lyophilization capacity at two of its German sites to enhance efficiency in up-and downstream processes, as well as to accommodate additional capacity.

Baxter has seen increased demand for lyophilization development services, and specifically for the optimization of lyo cycles for clinical molecules,” says Wendorf.

Baxter, meanwhile, is increasing production and packaging capacity.  Last November, the company launched a 1,750 square-meter capacity expansion of its fill/finish cytotoxic manufacturing facility in Halle, Germany, which will be completed in 2015, Wendorf says.

Vetter also has several expansion efforts underway at its production sites in Germany and the U.S., for both the development phase and commercial manufacturing of parenteral drugs. The company is implementing two new filling lines at its Ravensburg South facility, one for filling liquid cartridges and the other, vials. The company is close to completing work on a third new filling line, this one for pre-filled syringes, at its U.S. clinical manufacturing facility in Chicago.  This new capacity is expected to come onstream this year.

CMOs are investing in the equipment needed for safe manufacturing of cytotoxic compounds. Vetter, for instance, has upgraded its single-use isolator capacity at each of its sites, Soelkner says, and also plans to add an additional automated visual inspection machine, to increase its storage volume for cold, room-temperature and frozen products.

Despite the focus on prefilled and autoinjectables, contract manufacturers are ensuring a range of delivery options for their customers. Jubilant HollisterStier’s Linn sees continued demand for vials, where the company’s focus now lies. However, he says ampules have become a niche, since many suppliers have left the space.  The company has invested in new equipment for this sector, and is expanding its capacity and expertise in vial inspection.  “We should be able to offer a variety of options in this regard within a very short period of time,”  Linn says.

Automation
More emphasis is being put on containment strategies such as RABS and isolators, and, as products increase in complexity, a broader range of capabilities is needed for liposomes, suspensions, and cold chain,” says OsoBio’s Boyer.  “There should be a continued slow migration to disposable processing trains and adoption of RABS/isolator technologies. At the extreme, he says, there seems to be increasing talk of portable, modular off-the shelf aseptic processing, which could radically impact the CMO and
in-house aseptic infrastructure in the long term.”  

Automation has already become key to minimizing human intervention, according to  Vetter’s Soelkner. The company has equipped cleanrooms with RABS technology that meet various batch sizes combined with equipment designed to minimize valuable API loss, he says. In addition, he says, it is using such quality and tracking processes as Quality by Design, process analytical technology and track & trace methods.

Automation is also key to detecting potential contamination. “There is enormous focus on inspection of injectable drug products, specifically in detecting the presence of particulates,” OsoBio’s Linn says. “There are almost weekly reports of product recalls associated with this issue. There may not be just one capability solution to address this challenge, so CMOs and in-house inspections may need to rely on a combination of manual, semi-automated and fully automated processes.” 

CMO operations can help reduce some of the risks associated with the manufacture of injectable drugs. Staying competitive requires investing in new technology and maintaining expertise, and we can expect to see further change in this specialized sector as demand for outsourced services grows. 

Reliability and Control: FDA’s Friedman on Controlling Aseptic Processes Given some serious compliance problems at some sterile injectables facilities and their impact on supply, the world’s regulators are paying far more attention to the way that pharmaceutical companies and their CMOs handle aseptic processes, on a daily basis. FDA inspectors will focus on the way that processes are carried out, day to day, and how they are controlled. They will be looking for evidence of control and process reliability. Optimizing plant layout and design and using technology, including automation, automated transfers and advanced testing and analytical techniques can help any manufacturer make their processes more reliable, by limiting human interaction with product, and thus the risk of contamination. That was the clear message from Richard Friedman, associate director of FDA’s Office of Manufacturing and Product Quality at the Center for Drug Evaluation and Research’s Office of Compliance, who spoke on this subject at a PDA conference track at Interphex 2014 in New York City last month.   Noting the fact that manufacturing reliability is the key to consistent, dependable product quality and supply, Friedman discussed life-cycle based quality risk management, analyzed teachable moments from some sterile manufacturer warning letters, and outlined the basic principles of aseptic process design. (For a copy of his presentation, as well as videos in which he summarizes key aspects of his talk, please visit nitesh_cp.rodpub.com) Devoting one slide to the word latent, Friedman was clear on the importance of connecting the dots between seemingly unrelated process problems. “Do not see deviations as one-offs.  Look for connections between them,” he said.  He also stressed the importance of making an individual connection to the process and product. “Every vial is a patient,” he said. After quoting an 1897 pharmacy journal on the topic of sterility assurance, and noting that pharma “still makes mistakes that violate these principles,” Friedman ran through lessons from some recent Warning Letters that FDA sent to manufacturers, including the infamous case involving the reuse of disposable gloves, and outlined reliable process design. The key, he said, is minimizing the product’s exposure to potential contaminants during processing or product transfer. Plant design is important, particularly materials and personnel flow. Modern technology can help, Friedman said, including the use of isolators and RABS (especially closed systems) and automated transfers such as lyophilizer loading. But companies must be careful. For instance, he said, one can’t simply place a RABS in a traditional equipment spot. Manufacturers must demonstrate reliability and control.  “Older, less capable lines and facilities will get more attention,” he said. He quoted CDER director Janet Woodcock’s assessment of the Congressional Hearing on modernization held last year. “Taking advantage of advances in modern facility and process design, such as replacing manually-intensive processes with automation, using closed systems, integrating process analytical technologies into operations for better process control, and adopting continuous manufacturing platforms would help achieve improved manufacturing reliability, increased robustness, and lowered costs.” Friedman discussed FDA’s new guidance for sterile process inspections, and also touched on parametric release, something that can only be possible once a manufacturer has demonstrated that its sterility assurance program is in a state of control.