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companies for the same drug. However, they still fit the chemistries in the existing
equipment [15, 16], that is, lack of manufacturing technology innovation remains.
This generally happens as it is difficult to justify investment for the new equipment
for the better process. Production volumes also influence the justification [117].
Lack of manufacturing technology innovation begins from the onset of chemistry
development. This happens at the brand as well as generic API producers as no one
challenges the developed chemistry and the processing methods before the process is
considered for sca le-up and commercialization. Unchallenged processes result i n
translation of the developed chemistries to commercial processes even if they are in-
efficient and they will generally have high emissions for every kilo of product.
A chemist or chemical engineer on a scale-up team, after reviewing the chemistry
and the process, assesses the available equipment in their organization and their ca-
pabilities so that the laboratory process after it has been scaled-up and tweaked in
the pilot plant can be commercialized. Tradition of chemistry status quo and using
the available process equipment continues.
The fine/specialty chemical sector from the start of a product commerciali za-
tion uses batch processing as its preferred manufacturing practice until the product
volume warrants a continuous process.
In the fine/specialty chemical industry, a robust process design is essential.
This is due to competitive pressures. Producers cannot tolerate rework and disposal
costs as they lower profitability. Every effort is made to minimize rework and waste.
Process perfection is expected from the onset.
In pharma API, due to stringent product quality requirement, rework is avoided
and the off-spec material is disposed. Repeat quality testing (quality by analysis,
“QbA”) even after a robust design due to batch processing is a normal practice. Test-
ing, rework, and disposal costs are absorbed and passed on to the patients. This is
obvious from the API factory cost and their selling price differentials (Tab. 5.20).
5.12 Innovation opportunities for API manufacturing
Reaction mechanism, physical properties, and chemical properties and their mutual
behavior give us clues about how the reaction takes place. This information can be
used for process design and simplification. Chemists and chemical engineers, as
has been mentioned in earlier chapters, must understand the chemistry, value of
physical and chemical properties of chemicals used and produced in the reaction,
and their mutual behavior. Due to limitations of the available laboratory equipment,
much of the aforementioned cannot be explored prior to pilot or production scale,
although each has to be tested before it can be applied in a commercial process.
Their exploitation can result in using equipment of the appropriate scale and
can improve the profitability of API producers. Such practices have been used in
commercial operations by the fine/specialty chemical industry. With much lower
156 Chapter 5 Manufacturing process development and case studies
profit margins, process optimization is mandatory to remain viable. Process opti-
mization needs to be explored and incorporated in the API manufacturing sector
also. All this has to be done before filing of NDA or abbreviated NDA documentation.
Incorporation of any process changes can be a challenge especially after regulatory
documents have been submitted.
Herein lies a major difference between specialty/fine and API manufacturing.
Regulatory filing is required globally for production and sale of any chemical includ-
ing an API. The cost of regulatory filing for a typical, non-API chemical is a small
fraction of the cost for an API. Any process change in API manufacturing will require
a reexamination of the drug’s performance and efficacy with substantial added cost.
This could also trigger the need to refile regulatory documentation with substantial
added cost and time. Unless there is a large profit driver, API manufacturers will be
reluctant to implement any process changes after an API is approved by government
agencies. Without a profit-driver there is little motivation for innovation.
One of the biggest drawbacks or it could be called hesitation for inclusion of con-
tinuous improvement in API manufacturing is potential change in the performance
and efficacy of the final product which can come about due to the process changes.
Money needed to prove or assure that there is no change in the efficacy could negate
any benefit. Since the API volume at each site is small, the need of process improve-
ment is not considered a necessity. Thus, status quo is acceptable.
5.13 Nondestructive creation [118, 119] in API manufacturing
For innovation in pharma API manufacturing, it is necessary to look at the chemis-
tries and their execution differently from the current practices. They get overlooked
due to smallness of th e needed API volume necessary to fulfill the demand (each
kilogram API on 100% basis produces 1 million tablets at 1 mg). Currently available
equipment gets used even when the equipment is inadequate for the process. Many
companies producing the same API also suggests that inefficient processes are used
for API manufacturing and they are most decidedly profitable.
This presents an opportunity to review the current practices and select the best
alternate. A paradigm shift or some may call it “out of the box thinking” is needed.
Nondestructive creation [118, 119] needs to be considered for A PI manufacturing.
Pharma needs to shed its old ways [120]. If it happens, automatic consolidation of
API manufacturing segment could result.
The concepts outlined here will have to be tested by the API manufacturers. Like
any other change, considerations for alternate manufacturing methods and configura-
tions could meet significant internal resistance [121]. “Not invented here syndrome”
[122] can prevent any suggested change as the chemists and chemical engineers would
be stepping out of their comfort zone. It is possible that companies, in the name of
5.13 Nondestructive creation [118, 119] in API manufacturing 157
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investment and without evaluating their benefits, may shrug from exploring alter-
nate concepts.
Elements for nondestructive creation [118, 119] for the API manufacturing technol-
ogy innovation exist but with the limitations of glassware, they are not recognized, re-
viewed, or tested. Speed to market and profitability of the current manufacturing
methods also hinder. In the suggested methodologies, principles of science and engi-
neering of mutual behavior of chemicals will still be used. They might be applied dif-
ferently. Every change is science and engineering based. Ensuing results will be higher
productivity, profitability, quality, and waste minimization.
A closer review of the reaction chemistry along with the physical properties of
each reactant and intermediates suggest that one can capitalize on them a nd it is
possible to simplify and create excellent manufacturing processes. Discussion here
can be applied to every chemical synthesis. However, there are bottlenecks. They
are the traditions, limitations of the labware to exploit physical and chemical prop-
erties and inability to manipulate the process unit operations. Speed to market and
ready availability of the scale-up equipment are also a hindrance to innovation in
API manufacturing and their formulations. With the exploitation of properties of
the chemicals, it is possible to carry out reactions differently and thereby improve
their productivity.
Unless there is a justification, no company will invest in any new equipment
for every new or existing product. This is due to underutilization of the current as-
sets [19–22] and as a result processes are fitted in the existing equipment [15, 16].
This is a norm in pharma API and fine/specialty chemical manufacturing.
Since the concepts outlined here are different from the current practices, they
will need rigorous evaluation and they can be tested using the existing pilot plant
equipment. Success would lead to adoption across other produ cts and processes.
Testing these alternates is not a waste of time but a learning opportunity for future
use and ensuing value.
Pitfalls of the existing equipment need to be recognized:
– Too large for the process
– Same equipment is used for multiple products
– May not be the right equipment for the unit process and unit operation
– Auxiliary equipment and that includes utilities may not be the right size for the
process
With the equipment that is available in the commercial operations, fitting the labo-
ratory processes is a challenge. However, it is still used even when the equipment
might not be adequate and not have adequate process controls and utilities. Pro-
cesses musts be managed and can pose manufacturing challenges. Every such ef-
fort is not productive and can result in commercialization delays.
158 Chapter 5 Manufacturing process development and case studies
Commonly available equipment commercial equipment in API and fine/specialty
for batch manufacturing can range from 1,500 to 30,000 L. Pilot plant equipment in
API and fine/specialty chemical facilities varies between 100 and 300 L or smaller.
Some nondestructive creation [118, 119] ideas are presented. In the later chap-
ter, how some of the discussed concepts can lead to continuous manufacturing of
APIs are reviewed. They can be exploited and expanded to create simpler and eco-
nomic processes. They can be easily tested in the current process development and
manufacturing environment and applied to simplify commercial-scale manufactur-
ing. Such exploitation might avoid any new investment, dreaded by most companies.
For “nondestructive creation” [118, 119], it is necessary to emphasize the fact
that 1 kg of API can produce 1 million tablets, thus limited quantities of the product
can serve the needs of many. In addition, the current practices besides having the
drawbacks mentioned earlier have additional drawbacks. They are:
– Too much waste is generated and the long-term toxicological impact of the
waste is not known [123, 124]
– Low asset utilization [19–22]
– Lack of manufacturing technology innovation
5.14 Modular plants
Productivity and efficacy of any product c an be impr oved by carryi ng out the re-
action differently. Modular plants offer that “out of the box” opportunity for
pharmaceutical API manufacturing instead of the current sized commercial fixed
equipment needs to be considered [125–129]. Their design is not different than the
conventional plants. These plants would be like the erector sets [130] which can
be assembled for the given process. Companies offer preassembled plants but the
ideal would be that the companies assemble their own from the components. Prin-
ciples of process equipment design that apply to conventional chemical plants
will still apply, except the equipment would be small er in size and can be conve-
niently used in multiple processing situations. Such plants are used in food proc-
essing industry. Modular processes are used in huge scale such as milk collection
from dairy cows: 1 cow + 1 milking fixture = profit; 100 cows + 100 milking fixtures =
more profit; 1 cow + 100 milking fixtures = less profit.
Since the modular plants are not in pharmaceutical companies’ routine vocabu-
lary, pilot plant equipment could be used initially to emulate “modular plants.” An
inventory of the existing pilot plant will assist in initial application and testing of
“modular plant” concept in pharma. Once successful, the concept could be ex-
panded. Every company will have to assess their own needs. Modular plants and
their considerations are discussed in Chapter 6. Furthermore, there is a n array of
available simulation software to test modular concept in silico.
5.14 Modular plants 159
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In this alternate process design, the equipment size would be between labware
and an actual commercial plant currently being used. It may be very much like the
size of pilot plant equipment. Actual size and process will depend on product de-
mand and designer’ s creativity a nd imagination and how they exploit reaction
mechanism and physical and chemical properties. Chemicals would move very
quickly between the reactors and associated equipment. The actual process would
become similar to continuous flow of materials, a continuous process. Schemati-
cally, the process could look like each block of Fig. 5.20.
For such a process to happen, one needs to consider that the chemistry of each
reaction step is being executed separately, each reaction step product is the final
product and that will be used immediately for the next reaction step. There will be
no separation or purification of each product after each reaction.
Solvents used in various patents suggest that there are possibilities to simplify
the process. When the process is scaled up, each reaction step must be reviewed
individually but the solvent selection must be done collectively, limiting to one ad-
ditional solvent besides water. Any solvent, other than water, will have regulatory,
environmental, storage, and disposal concerns and associated costs. Recycling of
solvent must be a necessary selection criterion.
The range of reactor and accessory tank size determination will depend on the pro-
cess designers. Such plants and their quick assembly can give any operation the
needed flexibility and efficiency. Such modular equipment would have ways so that
they can be assembled for flexible manufacturing. Instead of being the fixed equip-
ment dedicated to certain processes, as is the case with the current equipment, the
biggest advantage of such equipment and configuration would be the “right sizing”
of equipment for different products.
The choice of modular reactors of optimum volume and size would have better
mixing along with proper concentration of reactants and could increase the reac-
tion rates. Better temperature control (heating/cooling) will also accelerate process-
ing. Right sized equipment would also lead to reduction in solvent use. Since the
reactants will move quick ly between the reactors, under the right circumstances,
this could lead to continuous manufacturing of APIs. Creativity and imagination of
the chemical engineers and chemists would be put to test to create excellent pro-
cesses. All this could improve throughput.
Static mixers [131] and plate and frame heat exchangers [132] have been used in
the chemical industry to facilitate and improve mixing, augment process design, and
Fig. 5.20: Schematic of a simplified sequential process.
160 Chapter 5 Manufacturing process development and case studies
improve reaction rates and mixing. These have been used for over 50 years in the
fine/specialty chemical industry and can also be used in API manufacturing as the
process equipment designs are same. Piping with static mixers can be part of the pro-
cess design.
Microreactors [133] are also available. They are extremely high priced compared
to static mixers and off-the-shelf available plate and frame heat exchangers or the
electrically heated heat exchangers. Investment in these has to be justified on a
cost/performance basis. In addition, compared to regular reactors their use may be
limited making their justification difficult for across the board use.
The current “QbA” modus operandi to produce quality product could become
history and “quality by design” could finally take hold for API manufacture. It is
well known that continuous processes compared to batch processes have higher
yield, lower cost, and better quality products. It is highly likely that continuous API
manufacturing that has eluded pharma could finally take hold.
All of the above will give the companies advantages of economies of scale and
using the right equipment to minimize excessive solvent use that is predominant in
the current API manufacturing. Waste would also be re duced. Another benefit
would be lower inventory of raw materials, in-process materials, and finished prod-
ucts. These result in significant financial gains from better inventory management,
working capital, and cash flow.
5.14.1 Process design considerations
Modular plants will als o provide the designers an opportunity to exploit the reac-
tion mechanism and mutual behavior of chemicals to create excellent processes. In
the current plants, their exploitation and incorporation can be a challenge. Each
opportunity will have to be tested in the lab and pilot plant.
5.14.1.1 Solvent use/selection
Solvents act as a process facilitator. They function as thermal transfer fluids and by
bringing reactants into reactive proximity. The optimum volume utilization of a typ-
ical reactor is 40–75% for proper mixing and thermal management. In a tradition
inherited from fin e/specialty manufacturing, API manufacturers wil l use existing
reactors that are often too large based on reactant loading. With the 40–75% reactor
filling requirement, this practice results in using more solvent than required.
At times, commercial processes also replicate laboratory experiments. Such sit-
uations, due to the time needed for heating and cooling the volume of liquid, can
prolong the batch cycle time and generate more than necessary waste. If the solvent
volume can be lowered for any reaction, process productivity will be improved.
5.14 Modular plants 161
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Soluble and insoluble solvents along with their density difference and azeotropic
behavior with water are of immense value. They have been reviewed in Chapter 3. It is
necessary to understand the stability of the reaction intermediates. Many intermediates
do not have long shelf life. Thus, their processing of the next reaction becomes timely.
These result in short product cycles, that is, quick turnover of the equipment for better
asset utilization. Every chemist and chemical engineer is familiar with these situations
but their incorporation in a process still requires creativity and imagination.
In many of the API patents, intermediates are isolated at times, dried, and proc-
essed for the next step. Intermediate isolation may be acceptable for the laboratory
but need to be totally eliminated in scale-up and definitely in a commercial process.
Solvent selection should be such that the solid is soluble in the selected solvent. This
will significantly lower the processing time if it is a batch process. For a continuous
process, solid intermediate suspended in a solvent would be used immediately in the
next step. Emphasis is to review and keep in mind how the reaction time can be low-
ered. The purpose of every process is to produce a saleable quality product versus
have a process where intermediates become part of the in-process inventory.
5.14.1.2 Reaction mechanism and order of addition
Attention has to be paid to the reaction mechanisms. Every chemist knows that
each reaction tells us how the reaction proceeds. If the reactants are not added to
the equipment in the sequence suggested by the mechanism, the expected yields/
results will not be achieved. A simple example is: acid added to water versus water
added to acid. Results of addition, acid to water, can be controlled and temperature
maintained versus water added to acid can result in dangerous eruption of the mix-
ture due to an uncontrolled exotherm.
Some of the chemistries are reviewed. No process reviewed uses reaction vessels
that are larger than 500 L. In each process step, physical and chemical properties of
reactants and intermediates are incorporated. Stoichiometry and temperatures are
precisely controlled. Chemical engineers, who are well versed in process design, will
totally understand the value of the processes described.
In diazo reactions, an a mine reacts with hydrochloric acid to produce the
amine hydrochloride that reacts with sodium nitrite to produce the diazonium salt
which is reacted further (Fig. 5.9). In USP ‘203 [45] and USP ‘537 [46], the diazo salt
reacted with sulfur dioxide to produce chloro sulfonyl. This is insoluble in water.
Generally, the suggested practice is to isolate it as solid for further reaction.
Alternate consideration would be to use a suitable solvent that will dissolve the
sulfonyl chloride. The selected solvent should be such that it is water insoluble and
its density is sufficiently different from water. The water phase would be decanted
to reduce the volume of the reaction mass for the subsequent reaction. This works
as it is used in commercial processes. Decantation might look like an extra step and it
is, but is definitely faster than filtration, isolating the solid and subsequent dissolution.
162 Chapter 5 Manufacturing process development and case studies
Solvent can be added to the sulfation reactor and the mix pumped to the decanter.
This significantly lowers the processing time. Figure 5.21 is the process schematic of a
sulfonyl chloride process described above.
The chemistry described above would always be a challenge in conventional batch
reactors due to many limitations, for example, large volume, residence time, and
heat exchange needs. A batch process will also lower the conversion yield. Since the
amine hydrochlorides are water soluble, amines can be slurried in water if they are
not liquid at room temperature. The diazo exotherm can be controlled with proper
heat exchanger design.
Equipment configuration similar to Fig. 5.21 can also be used for the synthesis
of levothyroxine (Fig. 5.19), where 3,5-diiodothyronine is iodized using bleach and
sodium iodide. Bleach can be prepared in line. This would be followed by addition
of sodium iodide to produce levothyroxine. Since the global demand for the product
is not large, a single continuous modular production site could be sufficient for the
global need.
There are alternate methods available but the pharmaceutical industry, being
bound by tradition, has not explored and/or practiced them. Some are reviewed. These
processes do not use reaction vessels that are larger than 500 L. In each process step,
physical and chemical properties of reactants and intermediates are exploited and in-
corporated. Stoichiometry and temperatures are precisely controlled. Chemical engi-
neers who are well versed in process design will totally understand the value of the
processes described.
5.14.2 Dimethyl fumarate
It is necessary to take advantage of methanol, thiourea [36], and maleic anhydride
solubility [134] and temperature relationships (appropriate concentration solutions
can be prepared continuously in a 100 L or smaller feed tank). No specific chemistry
and stoichiometry is suggested as chemists and chemical engineers well versed in
Fig. 5.21: Production of sulfonyl chloride of amine .
5.14 Modular plants 163
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scale-up will understand. Reactors mentioned in Fig. 5.7 can be sized for sufficient
residence time.
Chemical engineers well versed in process design can incorporate process
controls to precisely manage the stoichiometry and temperatures. Global demand
(Tab. 5.2) can be produced at ~ 200 kg /h in a s ing le plant.
5.14.3 Metformin hydrochloride
Reactions like formation of metformin are an excellent opportunity to exercise and
practice chemistry and chemical engineering. They test chemists’ and chemical en-
gineers’ creativity and imagination. Based on review of the various patents related
to metformin hydrochloride, one can conclude that the laboratory processes are
used for commercial manufacturing and most are batch processes. With the needed
volume, it can be produced using a continuous process.
Translation of the two routes (Figs. 5.12 and 5.13) presents us an opportunity to
innovate. Route in Fig. 5.12 can be the route if dimethylamine hydrochloride is not
available as a raw material and has to be produced for metformin synthesis. Raw
material economics and logistics dictate this route. Xylene can assist in the removal
of water using azeotropic property and density difference for the production of di-
methylamine hydrochloride. Xylene can also act as a solvent for the fusion to pro-
duce metformin hydrochloride. Once the product is produced, it can be purified
and a wiped film evaporator can be used to produce the final product. Figure 5.22 is
a process flow diagram for this route.
An all melt fusion process (Fig. 5.13) can also be practiced. In this process, di-
methylamine hydrochloride and cyanoguanidine in stoichiometric ratio can be re-
acted as a melt and processed with xylene as the purification solvent. Each of the
processes would have to be tested, optimized, and scaled-up. One of the most criti-
cal parts of the design would be stoichiometry and temperature controls. Similar
processes are commercially practiced [135, 136].
Fig. 5.22: Metformin route from dimethyl amine and HCl .
164 Chapter 5 Manufacturing process development and case studies
Either of the processes can be commercialized using modular plants. Based on
the global need, continuous operation (~7,200 h/year) is definitely possible. It is very
likely that a single plant would require multiple formulation lines to produce differ-
ent dosage tablets. Technology for their formulations and their subsequent tableting
exists but has not been used [137–139].
Process designers will have to evaluate the technologies themselves and apply
their own creativity and imagination to design formulation and a tableting produc-
tion train.
5.14.4 Omeprazole
Synthesis of omeprazole outlined in Fig. 5.14 is an ideal process design chemistry for
most chemists and chemical engineers. This process design requires excellent appli-
cation of process controls to feed various raw materials in precise ratios. The process
could have inline mixing with back mix plug flow or small reactors with recirculating
loops for the required residence time. Chemical engineers who have designed such
processes would be familiar with the suggested or similar designs [140].
Many alternatives [67–76] are available for the oxidation step. Chemists and chemi-
cal engineers can easily select one that would fit well in their process scheme and
is economic and safe. With advancements in chemistry, they might find other alter-
nate methods. Toluene from the last step would be decanted and azeotroped to
yield wet toluene which facilitates the process [75]. Appropriate and precise process
controls can be incorporated to control the stoichiometry. With the estimated yearly
product demand (Tab. 5.11), a continuous process can produce global needs of
omeprazole at a single site. Currently, it is being produced at multiple sites [81].
Figure 5.23 is a simple schematic flow diagram for omeprazole.
Fig. 5.23: Simplified flow for omeprazole .
5.14 Modular plants 165
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