According to the US Centers for Disease Control and Prevention's (CDC) vaccine price list, US vaccine manufacturers receive a wholesale price of between $9 and $109 per dose for pediatric and adult vaccines (1). For influenza vaccines, the wholesale price paid to manufacturers ranges from $5 to $9 per dose (2). Doses that reach the market early in the season command a higher than average price, and prices decline throughout the season. Any excess inventory is destroyed at the end of the influenza season. Small batch sizes, the high cost of labor involved in egg or cell culture based production, and the cost of filling results in a profit margin that is quite low relative to that of the rest of the biopharmaceutical industry. Such low profit margins affect manufacturers' willingness to invest capital in a commodity business such as influenza or other vaccines. This consideration is particularly true when providing vaccines to developing countries, where the price for vaccines per dose are a fraction of those in the US. Table I provides average reimbursement prices paid by UNICEF in 2010 and vaccine prices in high income countries are represented by the CDC vaccine price list for 2011 (1, 3).
Applicable to both clinical and full-scale manufacturing, single-use systems have become a mainstay of flexible and adaptable process and facility design. Although disposables provide opportunities, they also introduce challenges for biopharmaceutical manufacturing. This article discusses facility and process-design issues that should be examined when considering or implementing single-use technology.THE EFFECT OF THE ROOM ENVIRONMENT
To evaluate the potential risk of contamination or adulteration involved in a production process, one must first examine the potential sources, which include carryover between batches, cross-contamination between products, and the introduction of contaminants from the environment, raw materials, or from inadequate cleaning.
In the US, FDA recognizes the cleanroom standards of the International Organization for Standardization, specifically ISO 14644-1 (4). European standards go further in distinguishing between static conditions at rest and dynamic conditions in operation (5). Controlled nonclassified (CNC) is a classification often used in noncritical areas in GMP manufacturing facilities. CNC areas are designed to provide a consistently controlled environment, but are not monitored to the same levels as ISO or Grade classified areas. The International Society of Pharmaceutical Engineering (ISPE) has similarly defined CNC as a nonclassified room environment where closed processes and their immediate support systems may be located. CNC spaces are cleanable, have access control, and are served with filtered HVAC air, but do not have the ridged procedural controls and personal gowning requirements of classified areas.
Room classifications and the heavy burden they carry were considered in a recent article prepared by biopharmaceutical industry representatives that examined environmental controls in the context of current manufacturing technology (6). The authors discussed the rational for breaking the cleanroom paradigm and lowering room classifications using risk-based approaches to reduce capital and operating costs.