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. The 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:
The 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?
Throughout the 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:
In the current pharmaceutical 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
- Shreve,
R. Norris: Unit Process In Chemical Processing, Ind.
Eng. Chem., 1954, 46 (4),
pp. 672–672
- Unit Operation, https://en.wikipedia.org/wiki/Unit_operation,
Accessed July 11, 2017
- McGraw Hill Chemical engineering series, https://www.librarything.com/tag/McGraw+Hill+Chemical+engineering+series,
Accessed July 6, 2017
- Chemical
process control, https://www.librarything.com/subject/Chemical+process+control,
Accessed July 6, 2017
- Batch Production Wikipedia, https://en.wikipedia.org/wiki/Batch_production
Accessed July 6, 2017
- Malhotra, Girish: Square Plug In A
Round Hole: Does This Scenario Exist in Pharmaceuticals? Profitability
through Simplicity, August 17, 2010 Accessed July 11, 2017
- Benchmarking
Shows Need to Improve Uptime, Capacity Utilization, Pharmaceutical
Manufacturing, Sep 20, 2007
Accessed July 7, 2017
- Malhotra, Girish: A Blueprint for Improved Pharma
Competitiveness, Contract Pharma, September 2014, pp. 46-49
- Continuous Production, https://en.wikipedia.org/wiki/Continuous
production, Accessed July 14, 2017
- Malhotra, Girish: Strategies for Improving Batch or Creating
Continuous Active Pharmaceutical Ingredients Manufacturing Processes, Profitability
through Simplicity, March 20, 2017, Accessed July 17, 2017
- Drug Making Email exchange with Dr. Janet Woodcock,
FDA July 13, 2016
- Breaks Away From Its Old Ways, The
Wall Street Journal, February 8, 2015, Accessed July 17, 2017
- Jerry
Maguire, Accessed July 18, 2017
