Successful generic oral solid dosage (OSD) drug manufacturers and contract manufacturing organizations (CMOs) strike a seemingly impossible balance between low cost and high flexibility. Current research suggests that the pressure on these organizations to continue to drive down costs while simultaneously positioning themselves to exploit new business opportunities will only greaten in the foreseeable future. According to the Generic Pharmaceutical Association (GPhA) 2014 annual cost savings report, generics saved the U.S. economy $239 billion in 2013, a 14% increase over cost savings achieved in 2012. The growth inherent to this overall cost savings is astounding. New generic products entering the market in 2013 saved the national healthcare system $140 billion alone. The roughly $98 billion in savings provided by established generic products has remained fairly constant over the past decade. This means that to remain competitive in the exploding generic OSD market, manufacturers must find ways to expand their product portfolios while continuing to supply their customers with established products at historical volumes.
For leading generic OSD suppliers and their CMOs, expanded portfolios will include potent compounds, and potentially special class products, such as hormones, steroids, cytotoxic products, or beta-lactams. With increasing pressure to control capital expenditures, generics and CMOs will not have the luxury of building lavish Greenfield campuses with dedicated single-product facilities. Rather, low cost suppliers will be faced with the challenge of retrofitting existing plants, many of which were not designed to manufacture potent or special class products. Organizations with the benefit of sound forecasts may be able to justify new facilities, but these will likely be required to handle a multitude of current and future products with diverse potencies and characteristics.
Our friends in operations are cringing at the preceding allusion to “…sound forecasts....” Generics suppliers may accurately project demand for established products, but the reliability of the forecast crumbles at new or future products. This unpredictability drives up the capital investment risk of construction, expansion or retrofit for the purpose of new or future product manufacturing. The challenge in assigning product development and technology transfer resources is equally daunting, and the investment risk extends to new equipment and facilities required for product development and scale-up.
On the bright side, OSD suppliers and CMOs that manage these investment risks effectively stand to reap vast rewards by capitalizing on the unprecedented growth of the generic drug market. Successful manufacturers will align themselves with experienced professional resources who understand the intricacies of OSD facility master planning, design, construction and validation.
The winning team must first identify the business drivers for the project. Drivers may include the need to achieve or improve regulatory compliance, or the expansion of manufacturing capacity (quantified, perhaps in annual unit volume) for a specific product portfolio. Business drivers may emphasize schedule, if an organization aims to capitalize on a time to market opportunity, or cost, if an opportunity to gain market share or profitability via lower pricing or greater profit margin exists.
Reality dictates that constraints exist. Project constraints must be identified as early as possible, either to define project scope boundaries or, perhaps, to introduce a new business driver, if it is deemed necessary to aim capital at the elimination of a constraint. Existing utilities generation or distribution capacities are examples of potential constraints that could be eliminated, if justified or required, to meet the business needs of the project. Other facilities related constraints might include waste or solvent handling capabilities, HVAC systems limitations, site size or local code restrictions. Operational constraints include maximum staffing and allowable working hours. Business related constraints include capital budget and project timeline.
Once drivers and constraints have been set, the product portfolio, volume demand forecast, and potency profile for the range of compounds to be handled must be established. Occupational Exposure Levels (OELs) and Acceptable Daily Exposures (ADEs) must be assigned to potent products, so that project containment and cleaning philosophies can be drafted. Many organizations have documented banding systems that govern how process and equipment containment, room pressurization, air handling methods, personnel gowning and personal protective equipment are employed, based on varying levels of product potency. OELs are needed to categorize products in bands, and ADEs are required to assess cross-contamination risk as it relates to cleaning, and the potential decision to dedicate equipment or areas to special class products. It must be unmistakably clear when engineering controls are necessary, in lieu of procedural solutions. If the organization does not have established rules of containment, then these must be developed, prior to any significant expenditure of design or construction resources.
Once the production volumes, containment and segregation requirements have been determined, the process can be designed. The team will work through each unit operation and consider containment measures where potent products may be exposed, such as in sampling or dispensing, or during material transfers between unit operations. The analysis will be used to identify the inputs, outputs, and corresponding work-in-process (WIP) staging requirements of each unit operation. This is also the time to address cleaning requirements and equipment, which will depend greatly on containment needs.
Organizations will confront highly complex decisions at this stage of the project. Recently, a new facility was designed for a generics company to manufacture both established non-potent products and future highly potent products. The following are examples of issues that the project team faced during the planning stages:
- Can the same process rooms and equipment be used to manufacture both potent and non-potent products if they require common unit operations and have similar batch size ranges?
- Will equipment be specified for high containment, even though it is not required initially?
- Will the profitability of non-potent, established products be adversely affected if they are manufactured using sophisticated equipment and components with containment features?
- Can the investment in containment technology be deferred without sacrificing the ability to manufacture potent products in the future?
- Will separate physically segregated areas be required to manufacture special class products, such as hormones or cytotoxic drugs?
- How will the above decisions to share or dedicate manufacturing resources according to potency classification affect the design and sizing of cleaning equipment and areas?
The size, cost and complexity of the facility can vary tremendously depending on how these issues are addressed. Potential solutions will vary among unit operations, as well as equipment manufacturers. For example, several major tablet press manufacturers offer equipment capable of achieving OELs down to 1.0 micrograms/cubic meter or below, but their approaches to containment and cleaning are quite different. Some companies offer washable presses with separate cleaning skids, which are typically located in a mechanical area. Another supplier offers a unique system where product contact parts are removed in the form of a sealed compression module, placed on a custom cart with wash fittings and taken to a cleaning skid to be cleaned-out-of-place. Although it is certainly desirable to have these options, having to select from among them adds yet another layer of complexity.
The opportunities for generic OSD manufacturers and CMOs to grow their businesses have never been greater, nor have the challenges that accompany these opportunities. It is more important now than ever for these organizations to align themselves with resources experienced in confronting the vast complexities inherent to designing a flexible potent-compound multi-product generic OSD facility.