Chemical engineering principles can be applied to scale-up formulations of drugs into large production in continuous manner. There are number of advantages for preferring continuous processes over batch modes. The quality will be higher, process cost will be lower. Capital investment and plant costs can be depreciated over reasonable periods of time. Centralized control is possible in continuous processes. The raw materials can be procured in whole sale prices. The finishing operations for the product such as formation of capsules, coating, coloring etc can be sewn into the process flow with benefit. Productivity will be higher and product uniformity will be more. The residence time in the reactors can be lowered and the throughput can be increased. Less manual labor is required. Inventory costs will be on the lower side. Enviromental impact is more benign in the case of continuous process compared with batch mode. Depending on the demand optimal strategies can be devised. Some times space can be minimized for the same throughput.

Some of the hurdles that needs to be overcome in order to have widespread use of continuous processes for pharmaceutical production is the misperceptions of higher risk. A paradigm shift and outside the box thinking is needed for continuous production of drugs. Investors who are happy with current methods need be better informed. They may be used to the conventional pharma units with stepwise reactions, purifications and final product formulations were performed in the batch mode. Change to continuous does not mean that there is need for more engineering and operating skill. Chemical engineers are trained in order to accomplish some of the goals such as crystallization, purification, reaction, separation and heat transfer steps needed in pharmaceutical production. Handling solids need expertise in powder technology, continuous crystallization and particulate processing. Use of continuous crystallization can result in cost savings of about 50%. Start-up and shut down procedures in the continuous processes can be optimized using transient models tested on the computer. FDA approvals for the drug can be used effectively using quality inspections in process implementation. FDA encourage continuous production. Optimization of the total cost of operation with tradeoffs of operating costs and capital costs can result in arrival of certain number of stages for each unit operation used. Expertise in separation, purification and integration of biocatalysis are needed for continuous pharmaceutical production.

The industrial controls market size is expected to reach ~ 150 billion dollars world wide. Process dynamics can be studied using desktop computers and proactive process solutions can be sought. Stability analysis using a pencil and paper can lead to a better perspective on the range of operation of the process variables. Control and automation have grown tremendously with the advent of computers and programmable logic controllers, PLCs. Plant start-up, Plant Shut-down operations gets more attention of the lead engineer compared with those during steady-state operation of the plant. Transient analysis is not well studied.. Transient behavior of chemical reactors, distillation columns, absorption towers, adsorption beds, extraction units and other unit operations needs to be better studied.

Collegiate education methods have to keep pace with the developments in the field of industrial controls. Moore’s law states that computing speed of microprocessors double every 18 months. Biological databanks double in size every 10 months. Mathematical methods for model development have been refined over centuries. The methods and means available to the engineer need be better utilized.

Computer simulation and model development can be an integral part of an engineer’s endeavors. The days when the effect of professionals who do mathematical modeling and computer simulation on the bottom line of the enterprise is only indirect are over. The coming era is when the PW, Present Worth of chemical plants are better for having an army of engineers and Ph.D scholars who perform process dynamics studies, develop process control block diagrams, instrument the chemical plant with sensors hooked with data acquisition to the desktop computer.

GlaxoSmithKline, Novartis, DSM, Lonza are developing continuous process technogies for pharmaceutical production. Over $ 1 billion has been invested in continuous process for pharmaceutical production. Glaxo is building a $ 50 million plant in Singapore in order to manufacture asthma and allergy drug fluticasone propionate. Contract manufacturing can be used in order to perform flow hydrogenations that are catalyzed in packed bed configuration, distillation, extraction, crystallization from the tube to manufacturing. SK Life Sciences sill run 60-70% of the chemistries in batch mode. The operators need to be trained in the PFD, process flow diagram. This can also be shown to the customers. Material and Energy balance can lead to cost savings for the enterprise. Spreadsheets can be used for this purpose. It does not come as a surprise that the high attrition rate in pharmaceutical industry can be decreased when continuous process is adopted. Several unit operations have to be made to work in consonance with each other. It is hard to miss the efficient conversion of raw materials to product using continuous process in large scale. Scale-up principles such as L/D, length over diameter ratio of the reactors, distillation columns, adsorption towers, agitator speed and power draw used, pre-treatment of raw materials can be augmented using reliable mathematical models for mixing, heat transfer, mass transfer for a given pharmaceutical chemistry.Waste heat recovery and energy audit can lead to a more optimcal operation. For new products the continuous processes are readily adapted. The cost of over the counter drugs may decrease. Value addition during development of pharmaceutical products are high. It is not hard to break down the value addition along the sequence of unit operations used from raw material pre-treatment to post-treatment of the drug capsule steps.

Industrial scale flow processes can be developed for a step identified in the bench scale. One example here is the nitation step developed by DSM. DSM manufactured API, active pharmaceutical ingredient at a capacity of few hundreds of tons per year. They ran hundreds of microscale reactors in parallel. Usually PFR, plug flow reactor is more efficient. Utility costs will be high in the parallel configuration. The cost of recovery of the unreacted materials and recycling back to the reactors will consume the money budgeted. This is because of the low conversion in the microreactors and high conversion in the case of the PFR. In cases where the yield of the reaction is low in the bench scale attempts have to made in order to improve the yield. Advances have been made in the downstream processing methods used in pharmaceutical industry. Implementation of these changes can result in higher overall yield of the product. Research in continuous manufacturing has lead to the development of a pilot effort to make the API in Tekturna a cardiovascular drug, i.e., AliskirneHemifumarate. The number of operations in the batch mode was 21. The unit operations used in the continuous process is 14. Novartis is spending $ 65 million for more R & D over a 10 year period. Some steps used in continuous manufacturing of pharmaceuticals are reactions, separations, purification, crystallization, drying, formulation, tableting. 3 million tablets a year can be made at a reactor output of 41 g/hr. Portable units are possible.

Nutritional supplement, NBMI was developed by University of Kentucky in 6 years with the help of contract manufacturing. The drug is intended for use as antioxidant and can be used for reversing ageing. Clinical trials are being conducted. It works by mercury chelation. PCI the contract manufacturer eliminated chloroform used as solvent, increased the yield to 98%, isolated the material in powder form and made into capsules.

Last Updated (Friday, 25 July 2014 02:29)