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Thursday, July 20, 2017

Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing


Use of “Fake and/or False” in our vocabulary has become very pervasive since 2016. I thought it would be useful and helpful if we re-visit definitions of Batch and Continuous production processes and try to see do either of them fit in the realm of False or Fake “B or C” process. My observations are based on my education, experiences in chemistry and chemical engineering and the prevailing practices established more than 100 years ago. They are also based on actual process design and development, scale up of developed processes and management of manufacturing processes and operations in fine/specialty chemicals, coatings, resins that were produced using organic chemicals. Many of the products were produced by reacting chemicals and others were formulated by blending different chemicals.

In recent months certain pharmaceutical processes have been labeled as continuous process but no process information has been shared. However, based on public information about the products their viability of being operated as a continuous process is extremely doubtful. Additional details are shared later.

Established batch and continuous process definitions and examples are reviewed after a brief overview of what chemical engineers are taught. I do not want to go in details but the following are part of the Ch.E. curriculum.  

Fundamentals taught in Chemical Engineering:

Chemical engineers are taught that every process should be safe, sustainable, and economic and should produce quality product first time and all the time. If a product has to be reworked or its stoichiometry has to be adjusted during the process to produce a quality product, its cost goes up and the profitability of the company is lowered.

It is well known and practiced in every manufacturing industry that the market size demand influences the type of process used. Irrespective of the process used product quality is a must for the market success of every product. These expectations are most stringent for the pharmaceuticals as they influence human life.

Chemical reactive processes are called Unit Processes (1) that produce a product that could be the final saleable product or could be an intermediate for another reactive or formulated product. Unit operations (2) involve a physical change or chemical transformation that are used in the chemical and allied industry to facilitate unit processes to produce the desired products. Combination of these makes a process and depending on demand it could be a batch or continuous process. 

McGraw-Hill has published series (3) of books that cover unit processes, unit operations and the economic considerations that allow chemical engineers and chemists to develop, design and commercialize processes that are economic and profitable to any individual or company. Besides these books there are many other books that have been written on the subject. Excellent books have been written about process control methods and strategies (4). Most of these books have been written by what I would call “Hall of Famers” of Chemical Engineering and are considered Bibles of Chemical Engineering profession. None of these books are recommended or sponsored. There is no affiliation or financial relationship with the author.

Batch production:

Wikipedia’s (5) definition for batch production: Batch production is a technique used in manufacturing, in which the object in question is created stage by stage over a series of workstations (steps), and different batches of product/s are made. Batch production is most common in bakeries and in the manufacture of sports shoes, specialty/fine chemicals, resins, pharmaceutical ingredients (APIs), purifying water, inks, paints and adhesives. There are other formulated products and most prominent are finished pharmaceutical drug dosages.    
Batch production processes generally require much lower investment and have an advantage because several products can be produced in the same equipment. However, if the same equipment is to be used for different products, productivity will be significantly lower (6) compared to a process where the equipment is dedicated to produce a single product. If different products are to be produced in the same equipment, cleanliness becomes critical, especially for the APIs and their formulations. Idle (down) time can be high. Down time in the pharmaceutical industry is extremely high (7).  
For the pharmaceutical industry batch processes are the main stay in the manufacture of active ingredients (API) and their formulations. This is due to two inherent reasons. Micrograms to milligrams of API are needed in every dose. One kilogram of an active produces ONE million tablets of one milligram each. Thus, not a large quantity of the API is needed to satisfy the need. Table 1 is an illustration of the needed API and potential production methods for different dosages and number of patients. Additional analysis (8) is available elsewhere.

Dose, mg
Patients    Millions
API Kilograms needed/ year @ one tablet per day per year
API Production
Preferred Process Type
Number of plants
1
500
182,500
Batch
One or More
200
0.1
7,300
Batch
One
10
100
365,000
Batch
One or More

100
50
1,825,000
Batch or Continuous
Could be a single continuous plant but most likely batch
500
20
3,650,000
Continuous

Could be a single continuous plant but generally batch due to multiple sites

Table 1: Typical API need, Number of Patients and API Production Process
Process economics, chemistry and execution method will determine type of process used. Typical available hours for production at any plant are about 8,400 (24x7x50) hours per year. How many of these available hours are used for the production of a single product define the production process. If less than 8,400 hours are used to produce a product such process according to the established norms (5) will be a batch process. This holds true for API production and their formulations.
Table 2 is an illustration of how many hours per year are needed to produce at @200,000 tablets per hour at different doses. Production equipment of higher tableting rates are commercial and available. It is most likely most of the products would be formulated using batch processes even when they could be operated continuously.     

Dose, mg
Patients Millions
Tablets Used per day
Tablets, Millions/ year
Run Time Needed, hours @200,000 tablets/hr.
Number of plants
operating 7,140 hours per year
Preferred Formulation Process
1
50
1
18,250
91,250
13
Continuous but will be multiple batch plants
10
20
2
14,600
73,000
10
Continuous but will be multiple batch plants
100
15
3
16,425
82,125
12
Continuous but will be multiple batch plants
500
10
4
14,600
73,000
10
Continuous but will be multiple batch plants
200
0.1
1
36.5
183
1 (Run time less than 200 hours
BATCH ONLY
Table 2: Tablets Needed, Tablet Run time, Number of Plants and Patients Served
Continuous production:

Definition of continuous (9) production has been long established. Continuous usually means operating 24 hours per day, seven days per week with infrequent maintenance shutdowns, such as semi-annual or annual. Time could be allocated for unexpected shutdowns. Any process that does not meet the defined and established definition and is operated fewer hours than the established definition would be difficult to be justified as a continuous process. Excellent examples of continuous process are Earth’s rotation and our heartbeat. Can we imagine “stop and go” movement of earth and human heart? 

On pharma landscape most likely there are ten or less APIs that are being produced by continuous processes. There are additional APIs that could be produced continuously (10) but effort is needed to develop and commercialize such processes. Different business model would be needed. Alternate business model and consolidation can convert batch processes to continuous processes. There is a downside of the continuous processes. It will result in consolidation of operations especially among the contract API producers and formulators.

McNeil, a Johnson and Johnson subsidiary, due to the formulation volume of Tylenol could have built a continuous process but they did not, a missed opportunity. It seems that chemical engineers and chemists at some companies forgotten FRUGAL SCIENCE and FRUGAL ENGINEERING.


Fake/False Continuous processes:

Somehow on pharmac landscape, processes that are in reality batch processes are being called continuous by the chemical engineers working in public and private sectors. We all need to understand and recognize that if multiple products can be processed in the same calendar year in the same equipment by re-arranging the reactive chemistry or the formulations, their processes would not be called “continuous manufacturing”. Any process that has a wide spot in the manufacturing line [material is held for any time period], the process is a batch process. Processing step before such hold can be called by any name but if it is different from established definition, we have are making fun of science and engineering.

FDA (11) does not have an established definition and I am told one would be forthcoming. I wonder how different it would be from what is established and practiced methods.  Even the press (12) has chimed in. Numerous articles have been written that include “continuous manufacturing” but no one has put forth its definition or names of the product or their production rates. I am sure many, me included, want to see the proof. I am sure many of us remember movie Jerry Maguire (13).

API Example:

Analyzing Table 1, we have an example of a drug that has 100,000 patients. They have to take 200 mg dose every day of the year. Total API needed is about 7,300 Kg. per year. This product would and should be produced using a batch process in the available equipment. If each batch reaction produced about 250 kilos per batch and about 30 batches per year would be needed. If each batch took 30 hours per batch all of the API would be produced in about eight weeks. If they campaigned the whole production for first two months of every year, this would not make their process a continuous process. If this campaign run was called a “continuous process” then it would be an incorrect characterization and I will label this process “fake/false continuous process”.  

Formulation Example:

If the example of API above was to be formulated and tableted, the product can be produced at single plant in less than 200 hours at 200,000 tablets per hour. However, if the tableting were done at 10,000 tablets per hour, it would take them six months to produce the total demand. It still does not make the process continuous, as the equipment would be sitting idle for six months every year. It would be a wasted investment earning no return if every reader of this post had to invest his or her own money. Again if the process is called a continuous process, it again would be an incorrect characterization and I will label this process “fake/false continuous process”.

Vertex (8) has claimed to have a continuous process for their cystic fibrosis (CF) drug. With less than 80,000 patients worldwide, they do not have large enough global patient (~80,000) base for all of their CF drugs and cannot operate their equipment for 8,400 hours per year per drug. Similar situation exists for Janssen Pharma drug Prezista.

To me, an incorrect characterization of established definitions seems to have become a new fashion especially in the pharma landscape. Is it because the US FDA is mentioning continuous manufacturing in their communications and the industry wants to look good by calling a naturally batch process as a “continuous process”? Thus, if we accept an incorrect definition then we should be also ready to accept 2+2=6, Sun can rise from the West and a mammal can be half pregnant (my apologies to all readers). If that were the case basic laws of science, math and anatomy would be defied.
Quality Assurance in Batch and Continuous Processes:
Meeting quality standards in batch as well as continuous processes have different rigors. Command of the processes is a must whether it is a batch or a continuous process. If command and understanding of the processing steps are lacking, invariably there could be a batch-to-batch and/or a lot-to-lot quality variation. Efforts to rework or bring the material to quality can and often results in waste i.e. higher product costs.
In batch processes due to their stop and go nature quality can be sometimes managed and the process adjusted to achieve the established quality benchmarks. Thus an absolute command of the batch process is less stressful but still is necessary. Batch processes are based on in-process quality checks and adjustments. This practice extends cycle time and adds to inventory [raw material, in-process, work in process and finished goods] challenges. If the batch process cannot be adjusted to correct process deviation, significant waste can result. In the simplest terms, batch processes have economic value for products that do not require continuous production but their quality testing can be an aggravation. Batch process = quality by aggravation (QbA) unless the process repeatability is strictly controlled.  

Compared to batch processes, continuous processes have much higher process control demand. Since the process is running with minimal/no stop time, it is extremely critical that process operating parameters do not deviate outside the established process operating control limits. If process deviates outside the established control limits, significant quantities of waste and financial loss can result. Continuous processes demand that the quality be established through robust process design when the process is developed, designed and commercialized. This would be a case of quality by desire (QbD).

I am sure the debate on what is a continuous or a fake/false continuous process will go on till the economic realities of investment that have been well established are understood by most. Chemical engineers and Chemists are taught everything, values and virtues, of batch and continuous processes there is to know about such processes but one thing is sure unless one has not justified, developed, designed or commercialized a process, it is difficult to discern value of the developed process. I know no investment would be made for namesake unless it can be justified and meets established norms of the science, economics and engineering.

As I said earlier a batch process cannot be continuous and vise versa. If we accept it otherwise then we have a case of “false/fake” science, engineering, economics and human intelligence.  


Girish Malhotra, PE
EPCOT International

  1. Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem.195446 (4), pp. 672–672
  2. Unit Operation, https://en.wikipedia.org/wiki/Unit_operation, Accessed July 11, 2017
  3. McGraw Hill Chemical engineering series, https://www.librarything.com/tag/McGraw+Hill+Chemical+engineering+series, Accessed July 6, 2017
  4. Chemical process control, https://www.librarything.com/subject/Chemical+process+control, Accessed July 6, 2017
  5. Batch Production Wikipedia, https://en.wikipedia.org/wiki/Batch_production Accessed July 6, 2017
  6. Malhotra, Girish: Square Plug In A Round Hole: Does This Scenario Exist in Pharmaceuticals? Profitability through Simplicity, August 17, 2010 Accessed July 11, 2017
  7. Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharmaceutical Manufacturing, Sep 20, 2007 Accessed July 7, 2017
  8. Malhotra, Girish: A Blueprint for Improved Pharma Competitiveness, Contract Pharma, September 2014, pp. 46-49
  9. Continuous Production, https://en.wikipedia.org/wiki/Continuous production, Accessed July 14, 2017
  10. Malhotra, Girish: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredients Manufacturing Processes, Profitability through Simplicity, March 20, 2017, Accessed July 17, 2017
  11. Drug Making Email exchange with Dr. Janet Woodcock, FDA July 13, 2016
  12. Breaks Away From Its Old Ways, The Wall Street Journal, February 8, 2015, Accessed July 17, 2017
  13. Jerry Maguire, Accessed July 18, 2017