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Outsourcing sterile manufacturing involves an integrated approach in product life-cycle management.
Biopharmaceuticals are an increasingly important part of the pharmaceutical industry’s pipeline. Biopharmaceuticals account for roughly 10% of the global pharmaceutical market, and 25% of the pipeline, according to industry estimates. As biotech-based products become more prevalent, managing the life cycles of these products is a critical consideration. Strategies in reformulation, common in solid-dosage product forms, also play and will continue to be part of the life-cycle management of parenteral drugs.
Injection systems are a common delivery method for a parenteral drug, where syringes, vials, or cartridges may be used. “Increasingly complex substances are making more and more demands on the composition of injection systems,” says Herman Piana, key account manager with Vetter Pharma-Fertigung GmbH (Ravensburg, Germany). “Regulatory authorities keep making safety laws more stringent, and drug manufacturers and users are calling for more patient-friendly application systems.”
Prefilled syringes, cartridges, or vials illustrate that trend. The market for prefilled syringes is projected to exceed 1 billion units and achieve annual revenue growth of more than 10% (1). The container-closure system used in prefilled syringes offers several benefits such as simplified drug delivery, greater accuracy in filling, and lower incidience of misidentification, improper dosing, and contamination (1). Given these benefits, prefilled systems can be used in extending product life cycles. A parenteral drug, for example, may be initially packaged in a traditional vial system and later the product form can be changed to a prefilled syringe.
The initial selection or change in the delivery system of a parenteral drug is critical. “Biopharmaceutically manufactured drugs are extremely sensitive to their environment,” says Piana. “All materials that are used such as the type of glass, the various components such as the stoppers and other parts, and the degree of siliconization must be optimally matched with the respective active substance to ensure effectiveness.”
Examples of potential interactions that could lead to unacceptable changes in product quality include:
• Loss of drug-product potency owing to absorption and/or adsorption of the active drug substance or formulation excipient by the syringe
• Accelerated or modified degradation of the drug substance or formulation excipient induced by a chemical leached from the syringe
• Change in drug-product properties (e.g., pH, biological activity)
• Discoloration of either the dosage form or packaging system (1).
Viewing the product life cycle
The extension of the life cycle of drug through a change in delivery system is one side of the spectrum in drug development. Supporting early-stage development through the supply of clinical trial material supply is the other side. Serving all aspects of the value chain is an important consideration in the business model of contract manufacturers. “The ability to service the entire value chain is particularly important for small biotechnology companies,” says Piana. “A smaller biotech company, for example, may have less experience with commercial manufacture or regulatory filings at that stage as they are working on early-stage drug candidates.” Although the initial relationship of the biopharmaceutical company and a contract manufacturer may focus on the supply of clinical trial materials, that relationship may be expanded to include commercial manufacture depending on the progress of drug development.
In developing a business model, contract sterile manufacturers, must consider how they plan to service the various aspects of the value chain. As an example, Vetter is positioning itself as a service provider throughout the value chain. For early-stage development, Vetter Development Service (VDS) provides services and proprietary expertise in the preclinical phase in process development and in clinical production. Support services include pharmaceutical analysis, regulatory affairs, and the development of primary packaging supplies.
As an another example, for lyophilized drug substances, dual-chamber syringes may be an option for originators that traditionally market their product in a lyo-vial. A switch to a dual-chamber solution before patent expiry may offer an opportunity to differentiate the product from biosimilars. Vetter is positioned in this area through its “LycoJect” dual-chamber syringe.
For commercial manufacturing, the company recently completed several expansions. Vetter added a new 19,000-m2 facility for visual inspection and secondary packaging close to Ravensburg Vetter South, its existing facility, at an investment of approximately EUR 20 million ($29 million). Secondary packaging involves the final packaging of the application system in blister packages and cardboard boxes. The new facility is designed to meet homecare applications, including dual-chamber syringes and cartridges for pen- and autoinjectors and to meet new international requirements, such as the adoption of safety systems for anticounterfeiting. The construction of the new production facilities was completed in August 2008. In September, the first of seven packaging lines started operating. The other six lines will start producing step by step by the spring of 2009.
The expansion is in addition to a $100-million investment for a new 16,000-m2 facility near Vetter's headquarters in Ravensburg, Germany, which began full production in early 2007. The facility increased Vetter's production capacity for prefilled injection systems by roughly 30% to 400 million units per year. The facility has a capacity of approximately 90 million units per year. The new facility supports dosage-form studies in the early phases of product development, material for clinical studies, and full commercial manufacturing. The facility has two filling lines for liquid and lyophilized injectable drugs in dual-chamber syringes, single- and dual-chamber cartridges, and vials.
1. D. Jenke, “Suitability For Use Considerations for Prefilled Syringes,” Pharm. Technol.32 (4) Drug Delivery Supplement, s30–s33 (2008).