Continuous Manufacturing of Pharmaceuticals

Disclaimer:

This article has been written and opinions are made in a personal capacity with my 35 plus years of experience/exposure of Generic Product Development, as a former R&D Product Development formulator, responsible for technology transfer to manufacturing sites at various locations in the US for reputed companies.

The term "Continuous Manufacturing" is a misnomer for the pharmaceutical drug products manufacturing. For identity, accountability and in the case of any re-calls, in my opinion, there has to be a batch number. So, this is not exactly continuous endless manufacturing process but an end-to-end production approach that operates in a continuous flow of material through fully integrated components.

As we know in the case of Unit Operation system of manufacture: For example, for oral delivery, solid dosage tablet products by Wet Granulation Process unit operations of: Wet granulation using a High Shear Mixer Granulator, then Drying in a Fluid Bed Processor, then Comminution (size reduction) Milling in a Fitz Mill, then final mixing in a Blender and then compression in a High Speed Multi Station Tablet Press. Mostly are made in intermittent steps that often take place in separate rooms/cubicles in the manufacturing plant of the pharmaceutical firm.

As I understand in the Pharmaceutical Continuous Manufacturing (PCM) they are done in an integrated close system of equipment trains, conveying the material from one unit to the other without involving any operator-based charging & discharging unlike for the unit operation system. The input of the required process CPPs, CQAs are put into a centralized-computerized system by process engineers or IT personnel. Therefore, for a batch of product manufacturing it is in a continuums process. Not on unit operation basis. Hope I have been able to give you a picture of continuous manufacturing operation.

My personal opinion with my fifty years of experience, exposure as a formulator, technology trans person and also as a former FDA product, process and facility reviewer, from the quality perspective there should not be any different for the QbD and cGMP between the Unit Operated Manufacturing System and Continuous Manufacturing System of manufacture.

However, there are Pros and Cons of any system of operation. In the case of the unit operation system, it is laborious, operator dependent time consuming. It needs In-process Testing done by taking sample of each unit operation and sending to either Pharmaceutics or Analytics Lab for analysis, testing for results and waiting. However, there is also advantage with the unit operation system. As unit operation are done in a separate room/cubicle in the production floor and cleaning in place for the equipment, so there is an advantage also. When an operation is going on for a product process, the next operation equipment need not have to be ready at that very moment but being made ready by the other personnel engaged for that purpose in that particular room/cubicle. Also, in the unit operation product to product switch over is easy.

For the continuous manufacturing system, it is very efficient, non-laborious, with many benefits, such as minimizing waste, energy, and raw material use; accelerating new drug development; monitoring drug quality continuously; and improving process reliability and flexibility. It also requires more advanced data analytics and process control to maintain the desired quality by design space. The Process input such as CPPs and CQAs are put into centralized computerized monitor system and results are recorded and printed. The in-process tests are done at the various stages of processing operations and recorded for physical and some analytical by on-line IR, XRPD, & NMR, etc.

However, there are also cons in this system, in the unit operation there is not only assurance and accountability of each steps discharge for the yield and reconciliation. Example in the fluid-bed processing there is chance of adherence of wet-mass or dried mass adhered to the surface area of the processing bowl, expansion chamber or filter assembly in the unit operation operators make it discharged by pounding the equipment with mallets and or other device to get maximum discharge of the batch, which is not possible in a continuous process and there are also left overs on the screens of the milling equipment, under the feed frame of the tablet press or Capsule filling dosator-stations, all of these needs accountability in the BPR. In the continuous process it goes with the final end product results. However, due to very large batch size these process losses are within the acceptable limits. So far, I think switch over from one product to another product would be quite time consuming, since all these equipment just doing cleaning in-place would not provide full cleaning assurance or approval. Besides, other than processing equipment there are parts of conveying system also. All these dismantling and cleaning will take much time and efforts.

Moreover, the Continuous Manufacturing process is feasible for large batch size production of a product be it for the New Drugs or ANDAs where the demand and volume of the product is high. This type of process manufactures most likely would need smaller number of operators but just a very few process and IT engineers. This is not at all feasible for a Pharmaceutical Firm whose supply is small and for the local markets. Specifically in 3rd world developing countries where job availability and opportunities is less, introducing PCM system of manufacture eliminating many normal required process operators, scientific and supervisory positions. This will require less process operators, pharmacists and chemists, which would bring unnecessary un-employment situation, which is not at all desired.

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