Continuous Processing in Pharmaceutical Manufacturing

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Continuous Processing in Pharmaceutical Manufacturing
Matthew J. Mollan Jr., Ph.D. and Mayur Lodaya, Ph.D., Pfizer Inc.
1.0 Introduction
Pharmaceutical processing in the manufacturing environment is synonymous with batch processing in the sense that each unit dosage form is identified by a unique batch. This simplified tried and true approach has been used for decades as it served well for both the industry and the regulatory bodies. In comparison, other industries that also produce and process materials, such as petrochemical, chemical, polymer, food etc., have steadily moved to continuous processing technologies in manufacturing, driven mainly by cost and quality considerations. A recent article [1] comparing batch vs continuous processing discussed some examples of the reason, other than tradition, why the pharmaceutical industry is dominated by batch processing. The lack of flexibility in batch processing to respond to increasing levels of growth was cited as the primary driver for why other industries have moved to continuous processing technologies. Other goals that influence the decision to move from batch to continuous processing included the desire to minimize the required size of new manufacturing plants, as well as the need to efficiently use the available capacity [1]. Recently, both the pharmaceutical industry and the FDA agreed that an overhaul of the manufacturing regulations that apply to innovative processing methods will prove beneficial for the patient that both of them serve [2]. A highlight of this was illustrated in a recent article in Wall Street Journal [3], which provided a description of how the industry and the FDA are working together in several joint initiatives to apply new quality testing methodologies.
Historically, pharmaceutical companies have competed solely on the basis of innovation through new drugs for medical needs. A recent review of drug development costs stated that capitalizing out-of pocket costs to the point of marketing approval yields a total pre-approval cost estimate of US $802 million (2000 dollars) per new drug [4]. In a best case scenario, the R&D costs can be expected to remain the same or increase slightly in the future. When combined with other factors, such as increases in competition, further increases in proportion of generic utilization, opening of new markets, and the socioeconomic pressures for price controls, it is evident that the industry has to look for other ways to reduce costs. Currently, new technologies and techniques, including proteomics, genomics, and the use of biomarkers, appear to be creating a future where blockbusters, as we currently define them, may or may not exist. The future instead will consist of many "customized" small volume drugs that take into consideration a patient's specific subcategory of disease and genetic makeup. These overall shifts will translate into manufacturing many more new products. When all of the above factors are summarized, the same cost and quality drivers that have affected other industries are forcing the pharmaceutical industry to look for ways to improve quality while maintaining or reducing manufacturing costs, which today account for 36% of the industry's cost [3]. Continuous processing technologies provide one possible path forward for the industry to reduce the cost of manufacturing, with the objective to convert selected unit operations and processes from batch to continuous mode along with appropriate real time characterization using state of the art process analytical technologies.
2.0 Regulatory Aspects
The FDA regulatory definition of batch is:
A specific quantity of a drug or other material that is 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 [5].
It appears, therefore, that regulatory definitions are already in place to support the concept of a period of time, being a "batch" for the sake of tracking and quality assurance. This interpretation, if accepted, would assist in moving to continuous processing which is by definition a single cycle of manufacture.
The overall issue of new technology introduction into the pharmaceutical manufacturing area has been very restrained, however this is changing quite rapidly from the regulatory perspective. The FDA has recently issued a draft guidance [2] to the pharmaceutical industry in its; Guidance for Industry "PAT A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance." The goal of this guidance is to describe a regulatory framework on which industry and government can together increase the level of innovative pharmaceutical manufacturing technologies by the removal of actual and perceived barriers. The draft guidance document [2] states, "Process Analytical Technology, or PAT, should help manufacturers develop and implement new efficient tools for use during pharmaceutical development, manufacturing, and quality assurance while maintaining or improving the current level of product quality assurance." The background of this guidance is centered around the concept that while conventional pharmaceutical manufacturing is accomplished using batch mode, new opportunities exist to improve the efficiency and quality of the pharmaceutical manufacturing process. This is an attempt to introduce 21st century technology into the pharmaceutical industry to better respond to the rapidly changing marketplace for ethical pharmaceutical products. The utilizing of new approaches to pharmaceutical manufacturing, while maintaining the concept that quality cannot be tested into a product, but must be built in by design, leads to the concept of continuous processing. In specific, the draft guidance document [2] states, "Facilitating continuous processing to improve efficiency and manage variability." These regulatory statements should further encourage pharmaceutical manufacturers to begin to exploit the benefits of continuous processing.
3.0 Drug Substance Manufacture
The manufacture of drug substance, or API (active pharmaceutical ingredient), involves several unit operations/processes. Typically, it involves several stages of reactions in which different functional groups are attached to the starting raw material. The products formed after each stage of reaction are termed as intermediates. In many cases, some downstream processing of the reaction mixture such as filtration, distillation etc. is also conducted prior to the next reaction step. The final reaction mixture, also termed as the mother liquor, goes through multiple steps of downstream processing to produce the desired active in solid form. These steps almost always include filtration, distillation, precipitation (reactive crystallization), crystallization, drying and milling. Figure 1 illustrates this in a schematic form. Of these, milling is inherently continuous in nature. Also, filtration and distillation can be made to operate in continuous mode without much difficulty. For filtration, two equivalent filtration units can be operated alternatively to achieve continuous operation. Once a set pressure drop is reached, the feed stream is diverted to the stand by unit, while the first unit is serviced. Continuous distillation is the norm in crude petroleum and most commodity chemical/fine chemical production. That leaves precipitation (reactive crystallization), crystallization and drying.
3.1 Continuous Chemical Reactions
Advances in reactor design and particularly in the area of microreactors over the last decade has allowed a leap in research efforts involving continuous chemical reactions. For example, a two stage continuous process was recently reported [6] for commercial manufacture of statin intermediates that are used in the manufacture of atorvastatin (Lipitor?), currently the single largest revenue generating ethical product on the market. Researchers from the same company [7] have published their work regarding continuous processing for generating between 50 and 60 tons per year of diazomethane, while maintaining the inventory of this highly reactive gas at less than 80g. The diazo-methane production unit is part of an integrated multistage continuous process that produces key intermediates for the latest generation of HIV protease inhibitor drugs.
Continuous stirred tank reactors and plug flow reactors have been developed and successfully used for many years. Tubular reactors [8], loop reactors [9] and recent advances culminating in several designs of microreactors [10,11] have enabled the researchers to have the appropriate tools to conduct continuous reactions. One such reactor is the spinning tube-in-tube (STT) system (Figure 2) being developed [12]. A key feature of the STT reactor's design is being able to precisely control the fluid dynamics of the reaction stream to achieve nearly instantaneous and complete molecular scale mixing of the reactants. The annular gap between the spinning and the stationary tube is reduced to less than 0.25 mm that helps to convert a volume based flow to an area based flow. Another example of a successful microreactor design is an exchangeable microreactor. The design of this reactor makes it very easy to incorporate it into an integrated system [13]. Each individual reactor is the size of videotape with a hold up volume of 1.8ml. The high surface to volume ratio provides excellent heat transfer and improved mixing as in the previous example of STT reactor. Using the microreactor design, researchers have published their work on successful multi step synthesis of ciprofloxacin [13]. Yet another example of a small continuous reactor design is that of a spinning disk reactor [14]. The spinning disk reactor (SDR) has been found to be a very suitable alternative to conventional stirred tank reactors, especially for reactions involving intrinsically fast kinetics.
Continuous processes can avoid sca