Is Continuous Processing in Pharma’s Future?

The answer to the question is “May be and depends”. This is not the answer everyone would be expecting from anyone who is proponent of “continuous processing”. “May be or depends” needs further explanation. I describe pharmaceutical manufacturing processes as follows.

    API (drug) + Formulation processing/packaging = Dispensable drug dose

We all know that each component and the resulting product must meet the established performance and quality standards and that is a must. Annual volume, process design and equipment are some of the factors that direct us to the right process selection.

Table 1 illustrates the amounts of API (active pharmaceutical ingredient) needed for various dosages to serve variable population size. This table directs us to the answer to the “May be and depends” question between batch and continuous processing in pharmaceutical manufacturing. Breaking down the overall manufacturing process described above assists in rationalization. 

Dose Milligram	Tablets per day	Doses per year	Patients, Millions	Tablets/yr. Millions (1)	Tablet Process		API needed,  Kg./ yr.	API Process
					Batch	Continuous		Batch	Continuous
					Number of plants			Number of plants
0.1	1	365	10	365	*	**	456	1		No
0.1	1	365	100	3650	*	**	4,563	1		No
0.5	1	365	500	91,250	*	**	114,063	1		**
10	1	365	100	365,000	*	**	456,250	*		**
10	1	365	500	1,825,000	*	**	2,281,125	*		1-2
50	1	365	10	182,500	*	**	228,125	*		**
250	1	365	500	45,625,000	*	**	57,031,250	*		5-7
500	1	365	500	91,250,000	*	**	114,062,500	*		10-14
* Multiple batch plants would be needed to meet the global demand. ** Potential continuous process. (1) 80% formulation and packaging yield.

                                                               Table 1

A quick review of the table suggests that between API manufacture and formulation/packaging later has the highest potential to be a continuous process. This observation is based on annual volume of the tablets needed. It is expected that the formulation and packaging process steps are adequately designed. Quality by Design (QbD) will be the rule for such processes.

To serve 10 million population using 0.1 milligram dose tablet, API volume is not large enough to have a continuous process. If the equipment used to produce the APIs is going to stay the same as currently used, less than optimum processes will stay in place. Since the companies with the current manufacturing practices are able to achieve their profit margins they do not have any incentive/justification to change their manufacturing practices even if the methods are inefficient and highly un-sustainable. Such operations present an excellent opportunity to improve yield, create sustainable processes, lower manufacturing costs and improve profitability.

For continuous process to become a reality for APIs while using the current equipment technologies, production volumes have to be about 750,000 pounds or higher per year per site or the size of equipment used has to change to produce for lower volumes i.e. a complete paradigm shift is needed. A single plant operating continuously (24/7/50) producing (750,000 pounds per year) would produce about 110 pounds product per hour. Such plants, if they become a reality, could significantly reduce the regulatory load significantly and would produce highest quality product.

To serve 10 million people taking 0.1 milligram tablet per day per year about 3.65 billion tablets would be needed. This is producing about 8500 tablets per minute (80% operating rate) from a single manufacturing train. A single continuous train that takes the API to a finished tablet is very feasible provided the equipment is properly designed. Depending on the size of the tablet, commercially available equipment can produce up to one million tablets per hour. Through campaigns this particular train could also be used to produce other drugs following cGMP practices. Multiple tableting and packaging trains can be used to fulfill higher tablet needs.

As the dose and frequency needs increase, the needed API volume increases and manufacturing trends toward continuous processes. Increased per site production volume and process technologies can justify better manufacturing methods that have higher yield and are sustainable. It is possible that the companies might still use batch processing even if the total API production volume could justify continuous manufacturing. This can happen if the companies do not want to invest in better process technologies. If the companies do not change their methods competition will force the change.

Based on the above review one can conclude that better than 70-80% of the APIs needed would be produced by batch process using existing type of reactors, heat exchangers and other processing equipment unless the existing equipment can be used creatively to develop continuous processes. This is definitely possible. On the other hand better than 85-95% of the formulations can be produced using continuous processes.

Above quick review demystifies “May be or depends” mystery and shows us a clear path. The choice is ours to act.

Girish Malhotra, PE

EPCOT International

Is the New Terminology Going to Make the Pharmaceutical Processes Environmentally Friendly and Economic?

Reading two recent articles in Organic Process Research & Development magazine ^(1,2) had me wondering about my chemistry and chemical engineering education and practices. They created a doubt in my mind and raised a question “would the fundamentals that we had learnt and are the building blocks of the chemical industry where chemicals are either reacted or blended to produce useful products not work anymore?”

These articles also eluded that the pharmaceutical manufacturing is different and cut above the chemical industry. A new terminology rather than the fundamentals of chemical engineering and chemistry (simple heat/energy and mass balance, improving process productivity and having an economic process) are more important and necessary to design and create an economic and sustainable process. If that is the case then things have changed dramatically and many others and I could be oblivious to the change. The new terms are process mass intensity (PMI), reaction mass efficiency, E factor, Eutrophication Potential, atom economy and space-time yield etc.

During my undergraduate degree in chemical engineering, we were taught the fundamentals of heat/energy and mass balance, organic, physical and inorganic chemistry along with unit operations and unit processes, thermodynamics, chemical reaction kinetics and economics to develop processes that when commercialized using properly designed and appropriate equipment produced quality product, had minimal impact on environment and were economical. As the time progressed environmental laws encouraged us to improve processes to minimize the ecological impact.

Based on end application of the products, the manufacturing processes were labeled differently e.g. products covering surfaces were called coatings, chemicals that have disease curing value were called pharmaceuticals, chemicals that did not have disease curing value but were used as additives were classified as fine/specialty chemicals and products from crude oil were categorized as petrochemicals and so on. However, the fundamentals that were/are applied for the process design and development have not changed much.

I am not sure how many practicing chemical engineers or chemists understand what the new terminology discussed above means or are they just fancy expressions for the fundamentals that many will not understand. Due to diverse chemistries and processes of active pharmaceutical ingredients and formulations being produced in existing equipment that is not designed and/or optimized for their production, I am not sure if these factors truly on their own can deliver a green process.

There are ninety-nine references in these articles. One is from 1994 and two are from 1999. Does the lack of prior references suggest that the chemists and chemical engineers before 1990 were totally naïve and oblivious to good process development, design and engineering practices and did not use the fundamentals to develop, design and commercialize sustainable chemical processes? Or is there a latent message that the pharmaceutical development and manufacturing is elite, complex and chemistry and chemical engineering principles apply differently to them or some other principles apply?

I hope that is not the case. If it is, then it is suggests that the manufacturing will have occasional problems. This will be manifested by our lack of command of the processing steps forcing us to rely on QbA (Quality by Analysis) methods to ensure quality of active pharmaceutical ingredients and their formulations. Occasional recalls and increasing citations are suggestive of our lack of command and control of the manufacturing practices. 

To have robust, economic and sustainable processes I strongly believe that we need to have understanding and command of the processes. That can only happen by application of fundamentals that we learn in our chemistry and chemical engineering curricula along with our creativity and imagination ^(3,4). The products produced using such processes will produce the desired quality products. Quality by Design (QbD) will prevail and the environmental impact will be minimized. 

Girish Malhotra, PE

EPCOT International

1. Jimenez-Gonzales, C. etal, Using the Right Green Yardstick: Why Process Mass Intensity is Used in the Pharmaceutical Industry to Drive More Sustainable Processes, Organic Process Research and Development, Org. Process Res. Dev., 2011, 15, pgs. 912–917
2.  Jimenez-Gonzales, C. etal, Key Green Engineering Research Areas for Sustainable Manufacturing: A Perspective from Pharmaceutical and Fine Chemicals Manufacturers, Org. Process Res. Dev., 2011, 15, pgs. 900–911
3. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability, February 2011, John Wiley & Sons Inc.
4. Malhotra, Girish: Focus on Physical Properties To Improve Processes, Chemical Engineering, Vol. 119, No. 4, April 2012, pgs. 63-66