By Tim Crosby

The FDA’s initiative promoting continuous processing systems for the pharmaceutical industry and its subsequent PAT guidelines are helping to promote a revolution in solid dosage pharmaceuticals manufacturing methods and facility design. Promising improved yields, increased quality control, better inventory management and vast improvements in lead times by moving from current batch technology toward continuous manufacturing processes, the FDA has removed the last great roadblock to innovation in the solid dosage manufacturing industry, Regulatory Constraint. (By fostering continuous processing system implementation.) The FDA is clearly telling the pharmaceutical industry; don’t blame your high production times, quality rejection rates and lack of achieving real time release on us. Pharmaceutical manufacturers, equipment suppliers and process controls developers have heard the call and are moving quickly to develop new manufacturing processes and equipment that will make the industry more capable of competing in a global marketplace with products of exceptional quality and efficacy. At the same time, new facility models are being developed that will be smaller, more energy efficient, less wasteful, more productive and significantly less costly to build and operate.

What Is Continuous Processing

The solid dosage pharmaceutical industry, since its inception, has been based on a batch processing system. Batch processing is a manufacturing method that takes “a specific quantity of a drug or other material intended to have uniform character and quality, within specified limits and is produced according to a single manufacturing order during the same cycle of manufacture (FDA parts 210 and 211)”. Quality is assured by sampling each batch through each unit of operation in quality control laboratories by destructive analytical tests and measurements. The processing cycle is stopped until quality is assured. The in-process materials are staged in work-in-process areas in the manufacturing plant until preset quality parameters are met. If the quality standards are not met, the entire batch is rejected or sent back to be reprocessed.

Continuous processing is not a new concept, but is a radically different system than batch processing Continuous process manufacturing systems have been employed for many years in the chemical, food, automotive and electronics industries. In its simplest form, continuous processing is a method of manufacturing in which new materials are added and products removed continuously at a rate that maintains the volume at a specific level. It is often referred to as a “one in, one out” system. Quality is assured by designing quality measurements into the process system. Quality inspection is part of the making of the product and assured by “at, in/on” measurements by a diverse set of predetermined quality parameters and performance attributes of both raw and in-process materials. Continuous processing is a risk-based manufacturing system that does not rely solely on visual inspection or out of process measurements.

Batch processing at some facilities is typified by low quality outcomes, high labor costs and excessive inventories that inflate production costs. Continuous processing, on the other hand, promises a new business model that will radically improve quality control, decrease scale up issues and cycle time and allow for faster release of new products.

Why Change Now--The Need For Process Innovation

Process innovation rarely comes from just the desire to create the better mousetrap. Innovation in manufacturing settings is a result of pressure on one or more of five interconnected business variables that are the bases of a manufacturing operation. The five variables are Quality, Operational Cost, Production Volume, Competitive Forces and Profitability/Shareholder value. If all of these variables are at or above the expectations set in the business model, little fundamental process innovation can be expected. In some industries, including solid dosage pharmaceutical manufacturing, outside forces may prevent innovation even when one or more of the business variables are operating below expectations. For solid dosage manufacturers, that barrier has long been identified as regulatory restraint. However, with PAT and the advocacy of the FDA for basic process innovation, these barriers are slowly disappearing.

The move to process innovation in solid dosage manufacturing is long overdue. For many years, the solid dosage pharmaceutical industry enjoyed high profit margins, overall market control and a regulatory environment that stifled competition, lessening the need to look to innovative methods to produce their product. In the last five years, however, the reality of the changing marketplace forced manufacturers to seek out ways to better compete, retain profitability, improve quality and continue to increase shareholder returns.

Antiquated manufacturing processes cost pharma money – a fact widely known and accepted in the industry. At some facilities, rejected batches, rework and lengthy investigations have become a way of life, and by some estimates consume 25 percent of drug company revenues (P.Cini, Phd, R. Schneider, 2004). Many manufacturers are operating below expectations in most of the business drivers and no longer have the market control or profit margins that, in the past, let them ignore their manufacturing deficiencies.

The solid dosage manufacturing sector faces many challenges to succeed in meeting the expectations defined by the five business variables. Some of the challenges the industry faces are a rapidly changing and more competitive marketplace, the complex global regulatory environment, extreme quality deficiencies, global branding and mounting consumer pressure to lower drug costs. The increasing costs of drug development and drug marketing and distribution are additional factors that, in combination with the market forces, makes solid dosage manufacturers look to process innovation strategies to lower manufacturing costs. Continuous processing technologies provide one possible path forward for the industry to reduce the cost of manufacturing (M. J. Mollan, Jr, Phd, et.al.).

The New Facility Model - Leaner And Greener

Many solid dosage manufacturers have heeded the call of the FDA and are actively pursuing the development of continuous manufacturing system technologies. PAT teams have been created at most manufacturers’ sites and are actively pursuing plans to change from batch processing technologies to ones based on continuous processing principles. As a result of this focus, the facilities housing solid dosage manufacturing operations will radically change. New facility prototypes are being developed that will significantly reduce the operational and capital cost required for their construction and operation.

An ongoing study by O’Neal’s Advanced Technology Research Group confirms that new solid dosage facilities will be much smaller, cost less to construct and require much less labor and energy to operate at current production levels.

Our study reviewed 12 solid dosage facilities, six new or proposed and six existing, with a focus on what differences would occur as a result of employing continuous processing technologies versus batch processing. The study assumes that the facilities would employ continuous processing as the primary manufacturing technology that operations would continue to be “unit” based, packaging would be a separate production unit and solvents would remain integral to formulation and manufacturing.

Six primary factors were considered in the facility review. Included were the building volume, waste generated, manpower required, operating costs, solvent usage and overall capital cost to construct. The results have been dramatic for grassroots facilities but many challenges remain for renovating existing solid dosage facilities.

Building Volume

The incorporation of continuous processing technologies will greatly reduce the building volumes required in solid dosage facilities. Continuous processing equipment will be exponentially smaller than batch processing equipment as a result of their continuous operation. Systems will be closed and require less mechanical and electrical support areas. Quality will be designed into the processing system. Smaller and fewer Quality Control and Assurance areas will be required as a result of the new processing approach. Warehouse space will be dramatically reduced. WIP areas will not longer be required as a result of the manufacturing process and the areas required for raw material and in-process product storage will be far less than current needs because a continuous process allows for better management of the many components of a solid dosage manufacturing operation. To date, our study indicates that building volumes for new facilities will be reduced by up to 55-65 percent from current levels.

Waste

Waste generation and management is a major problem for solid dosage manufacturers. As result of quality designed into the manufacturing process, fewer rejected batches will occur and fewer products will have to be discarded as waste. Smaller warehouse space will result in smaller amounts of packaging materials entering the waste stream. Closed systems will reduce the air and power required for manufacturing and result in less pollutants released to the atmosphere. Overall, the employment of continuous processing systems is expected to dramatically reduce the amount of waste the facility produces by up to 85 percent of current levels.

Manpower

Continuous processing technologies will have their greatest impact on the manpower levels currently employed in solid dosage facilities. Continuous operating manufacturing systems will require significantly less labor to operate and maintain. Personnel currently assigned to quality operations which in some solid dosage operations can amount to 40 percent of the work force, will no longer be needed because quality will primarily be controlled by the manufacturing process. Reductions will occur in logistics, maintenance, administrative and quality assurance personnel levels. Manpower levels will be reduced in solid dosage facilities employing continuous systems by 55 to 60 percent of current levels.

Solvents

Another area that will be greatly affected by the move to continuous processing will be the usage of flammable solvents. Because of the reduction in the size of the equipment and continuous operation of the manufacturing lines, the amount of solvents used per unit of production will be significantly reduced. Additionally continuous processing systems will afford the possibility of capturing and reusing the solvents instead of releasing them to oxidizers or to the atmosphere. Solvent preparation and storage requirements will be reduced. Management of the solvent transportation issues will be made simpler and safer. Continuous processing systems will greatly reduce the complexity of using solvents in the manufacture of solid dosage pharmaceuticals.

Operating Costs

With smaller building volumes, building support systems and fewer personnel, solid dosage facilities employing continuous manufacturing systems will be easier and much less costly to operate. New facilities will be able to employ more energy efficient power and HVAC systems, incorporate advanced control systems and be constructed using more sustainable materials, reducing both the day to day operating costs and significantly reducing life cycle costs. Our study indicates that new facilities incorporating continuous processing systems can expect that operating costs will be reduced by as much as 50 percent of current levels.

Capital Costs

Capital costs to construct new solid dosage facilities that incorporate continuous manufacturing systems will be significantly reduced allowing for more of pharma revenue to be dedicated to shareholder value. With smaller and more energy efficient buildings requiring less land, new facilities will be less challenging parts of an overall capital expenditure program. Our study shows that a new facility constructed using a batch processing model with an expected production of 4 billion SDU’s will require approximately 460,000 square feet and a capital expenditure of approximately $135,000,000.00. A new facility based on a continuous processing model will only require construction of approximately 190,000 square feet at a cost of $60,000,000.00 to produce the same product volume. This amounts to a capital cost reduction of 60 percent. New facilities will undoubtedly be leaner and greener when using continuous processing as its manufacturing system.

Existing Facilities

Renovation of existing solid dosage facilities will be much more difficult than grassroots projects. Existing facilities are over sized, over powered, underutilized, inflexible, over equipped and over populated. While many of the benefits outlined above would still result from incorporating continuous processing into existing facilities, continuous manufacturing options are limited. Continuous processing will be introduced slowly if at all. When introduced it will most likely still be unit based. The costs to innovate in existing facilities will for the near future exceed the benefits. Power restructuring challenges and operating constraints will cause the focus for process innovation in existing facilities to be on new drug formulations and the manufacturing processes required to produce these new products.

The Path Forward

The solid dosage pharmaceutical industry is poised to change radically in the next five to 10 years in response to a changing marketplace. The urgent need to dramatically improve efficiency and productivity within the pharmaceutical manufacturing sector will be a requirement for the future (M.J. Mollan, Jr. Phd, et. al.) In the future, solid dosage manufacturers will need to employ innovation and cutting edge scientific and engineering knowledge and the best principles of quality management to respond to the challenges of new discoveries (Pharmaceutical CGMP’s for the 21st Century). Development of continuous processing manufacturing systems affords the solid dosage pharmaceutical industry their best chance to remain productive, profitable and able to meet the global competitive challenges of the 21st century.

About the Author: Crosby is Director of Architecture and Director- Advanced Technology Research Group at O’Neal, Inc., an integrated planning, design and construction company, headquartered in Greenville, SC with additional offices in Atlanta, GA, Charleston, SC and Raleigh, NC. www.onealinc.com