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b) Paroxetine-free base The reaction vessel was charged with 16 kg of potassium hydroxide and
45 L of 1-butanol, and the mixture was heated under s tirring to 80 °C. The solution from the
preceding step was mixed with 33 L of 1-butanol and the combined solution was added to the
above mixture under stirring. In approx. 20 min, the exothermic reaction brought the mixture
spontaneously to reflux. Next, the supply vessels and pipes were rinsed with 5 L of butanol,
which was combined with the reaction mixture. The reaction mixture was stirred under reflux for
2 h. Then, the mixture was cooled to approx. 95 °C and 45 L of water was added under stirring.
The mixture was allowed to stand for phase separation and the lower phase was discarded. The
upper phase was diluted with 13 L of toluene, and the combined solution was washed with
19 kg of 30% aqueous NaOH solution and 18 kg of 16% aqueous NaCl. The solvent was removed
by distillation at reduced pressure, at 50 °C.
The crude product was dissolved in 70 L of toluene. 0.3 kg of Tonsil was added and the reac-
tion mixture was filtered. Next, the reactor and the filter were rinsed with 5 L of toluene. The
combined toluene solution was washed twice with 35 L of water and evaporated at reduced
pressure, at 50–60 °C.
c) Paroxetine mesylate The product from step b) was mixed with 58 L of ethanol and heated to
60 °C. Methane sulfonic acid (4.9 kg) was added to the resulted solution under stirring. The
solution was cooled to 25 °C and inoculated with a seed crystal. The mixture was cooled to 0 °C,
stirred for 30 min, and the obtained solid was filtered. The filter cake was washed 2 times with
6 kg of cold ethanol. About 19.6 kg of wet paroxetine mesylate was obtained. After recrystalliza-
tion from ethanol and drying, 14.5 kg of the dried product was obtained.
Analysis of the laboratory process:
Like paroxetine hydrochloride process, this process uses multiple solvents. Excess toluene is used
as a solvent, thereby diluting the process. Butanol and ethanol are the two additional solvents
used. Patent suggests removal of water from N-methyl paroxetine. This needs to be reviewed, as
water has to be removed from the reaction mass before the phenyl chloroformate reaction.
Washing with 30% NaOH and 16% NaCl may be acceptable for a lab exercise, but their adoption
in commercial process will suggest that the mutual physical properties have not been understood
and exploited. For process simplification, it is necessary that the physical properties be exploited.
In both syntheses of paroxetine salts, excessive amounts of multiple solvents are
used. That may be acceptable to prove the chemistry in the laboratory, but if they
are to be commercialized, they will have excessive waste. They also add to the com-
plexity of the whole process.
Table 8.5 is an estimate of global paroxetine hydrochloride needed. It is being
produced at about 36 plants [31]. Since there are multiple plants, their “E-factor” [1]
emissions will be high, and every potential benefit of economies of scale is completely
lost. Like other APIs, it also presents an opportunity to lower its “E-factor” [1].
Tab. 8.5: Global paroxetine hydrochloride need.
Global population Percent
use
Use, global
population
Dose mg @
days/year
Total kg/year Plants producing []
,,, ,, ,
286 Chapter 8 Road Map
8.5 Why innovation is needed in pharma?
Discussion about innovation and simplification in API manufacturing has been
going on for quite some time [32, 33] at FDA [34]. FDA’s report in 2004 explained
the current and the “desired state” of manufacturing very clearly.
Excerpt of the Current State: Pharmaceutical manufa cturing operations are inefficient and
costly. Compared to other industrial sectors, the rate of introduction of modern engineering
process design principles, new measurement and control technologies, and knowledge man-
agement systems is low. Opportunities for improving efficiency and quality assurance through
an improved focus on design and control, from an engineering perspective, are not generally
well recognized. For example, when discussions at the FDA Science Board and Advisory Com-
mittee for Pharmaceutical Science shed light on the current low efficiency and its cost impli-
cations (e.g., costs associated with manufacturi ng can far exceed those for research and
development operations in innovator pharmaceutical firms) many at FDA had difficulty under-
standing this and common reactions were “how could this be possible?” or “this can ’ tbe
true.” Regulators and many in manufacturing operations express their frustration by suggest-
ing that manufacturing is a “step-child” in this industry, and that there is no economic motiva-
tion (e.g., cost and price difference) for improvement. Other suggestions include a general lack
of systems perspe ctive, organizational barriers that inhibit exchange of knowledge, and the
attitude that much of pharmaceutical formulation and process development is an “art.” Some
in pharmaceutical development suggest that there are very limited opportunities (“develop-
ment time crunch”) to realize and/or demonstrate the level of science underlying current for-
mulation and process development efforts.
Excerpt of the Desired State:
Improving the foundation of manufacturing science in our current manufacturing practices
should be the primary basis for moving away from the corrective action “crisis” to continuous
improvement. The “desired state” for pharmaceutical manufacturing in the 21st Century there-
fore emphasizes and aims to improve knowledge on design and understanding of product and
processes. The “desired state” for pharmaceutical manufacturing in the 21st Century therefore
emphasizes and aims to improve knowledge on design and understanding of product and
processes.
Chemists and chemical engineers, who are development specialists for the API pro-
cesses, need to put themselves in the operator’s shoes and need to ask themselves:
“If I had to operate the process in a manufacturing environment, how would I feel? Is
this really the best that I can do?” [32]. Many of the answers become obvious. They
would want each process to hum as a well-oiled machine and produce a quality prod-
uct all the time. Unfortunately, batch processes, especially most API processes, fall
short of that expectation.
It is interesting that not much progress in manufacturing innovation, to achieve
what USFDA calls the “ desired state”, has taken place since 2004. All of the com-
ponents (science and engineering) to significantly lower the “E-factor” [1] and
manufacturing are taught and are available to all of the practitioners, but the indus-
try, being tradition bound, has not exploited the methods to achieve what is possible.
8.5 Why innovation is needed in pharma? 287
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Pharma manufacturing (API and their formulations) have not made much prog-
ress towards manufacturing technology innovation. It seems that the industry, in
general, is going around in circles and will not have much of impact on process
simplification. Regulators and equipment vendors, who might have relevant equip-
ment for synthesis, have been pushing the API manufacturers and their formulators
to adopt “continuous processing methods”. However, neither, especially the regula-
tors, have ever developed, designed, financially justified, or commercialized such
processes for pharmaceuticals. With respect to equipment, API manufacturers have
to justify the investment for any new equipment. With excess equipment capacity
[21–26], it is going to be extremely difficult to justify any investment, if the equip-
ment is not going to be producing a single product for about 7,000–8,000 h/year.
If pharma’s most recent patents are any indication, they do not reflect much of
“solvent conservation” as part of their API synthesis development process. It is very
likely that the laboratory process development practices of excessive and multiple
solvent use will continue, but a change in their scale-up and commercialization
practices is definitely needed if pharma is to lower its “E-factor” [1] emissions.
Pharma has resisted any change in their manufacturing practices, once their
product and process have been approved. Regulators have acknowledged that this
resistance is due to regulatory uncertainty.
Unfortunately, the pharmaceutical industry, generally, has been hesitant to introduce innova-
tive systems into the manufacturing sector, for a number of reasons. One reason often cited is
regulatory uncertainty, which may result from the perception that our existing regulatory sys-
tem is rigi d and unfavorable to the introduction of innovative systems. For example, many
manufacturing procedures are treated as being frozen, and many process changes are man-
aged through regulatory submissions. In addition, other scientific and technical issues have
been raised as possible reasons for this hesitancy. Nonetheless, industry’s hesitancy to broadly
embrace innovation in pharmaceutical manufacturing is undesirable from a public health per-
spective. Efficient pharmaceutical manufact uring is a critical part of an effective U.S. health
care system. The health of our citizens (and animals in their care) depends on the availability
of safe, effective, and affordable medicine. [35]
Regulators claim that pharma’s hesitancy toward “continuous improvement [36]” is
unacceptable, but on the other hand, they have not done much to alleviate its own
“red-tape” [37] practices, which could placate this hesitancy on the part of API man-
ufacturers and their formulators. Their bureaucracy, which prolongs filings, ap-
proval, and making updates expensive and difficult, is well-known. Regulators
need to practice what they preach and they have not done so. This is obvious from
the prolonged time they take in approving new drug (NDA) and abbreviated new
drug (ANDA) application filings. FDA does not publish the average time it takes to
approve any “single” application, but publishes what they do in a fiscal year, which
camouflages the real time per application. Regulators have to establish and improve
their own current practices [38].
288 Chapter 8 Road Map
It would be beneficial for the pharmaceutical industry if the regulators practiced
their current NDA (new drug application) and ANDA (abbreviated new drug applica-
tion) filing requirements and processes in-house, to get a feel for what the industry
has to follow for the respective approval. These would be reviewed by the fellow FDA
employees as if they were filed by a company. These have to be blind tests. The time
for each such process has to be published and used by FDA to simplify and reduce
their current filing and approval times. They can use such work to set benchmark
goals. Benefits of these will be faster introduction of brand and generic drugs to the
market, which pharma companies would like to have, and it would be a global win.
When regulators make suggesti ons to the industry to improve manufacturing
technologies, it seems they forget that for the adoption of any new manufacturing
technology/methods, companies have to justify the investment. They have been
pushing companies to innovate their manufacturing practices, but have not shown
any leadership in innovating their own practices which will facilitate industry inno-
vation [39, 40].
Every industry has innovated and many new ones have evolved through innova-
tion. Cellular phones are an excellent example. However, pharma has been very pas-
sive with its manufacturing practices and needs a total “rethink” if it wants to lower its
“E-factor” [1] emissions, make drugs affordable to a larger population, and, further, im-
prove its profits. Pharma has an opportunity to innovate. It needs to shed its addiction
to the old ways of manufacturing and implement improved methods [40, 41]. Pharma
can choose “speed and curiosity” of the startup communities or Silicon Valley, or
chose either of the following two ways to innovate manufacturing technologies. It has
to make a selection. Continuous manufacturing of API and their formulations is very
doable. All of the necessary fundamentals (science and engineering) and equipment
are available and commercially used, except in the manufacture of API [9, 42–53].
In the continuous processes, none of the reaction process intermediates are iso-
lated or purified for the subsequent reaction step. If they are, then the process is
not a continuous process but a batch process. If the FDA and other regulators de-
mand that the intermediates in a process be isolated and tested for defined charac-
teristics and purity, then the process is no different from a batch process.
8.6 Transformational innovation/creative destruction
Transformational innovation [54] entails transition from the mode of operating that
is known and secure, to one that is unknown and potentially chaotic. This requires
doing something fundamentally different; a metamorphosis most organizati ons
don’t excel at. Pharma manufacturing has become extremely comfortable with its
ways over the last one hundred y ears. For it to move away from “what it is” to
“what it can be”, it is going to be a challenge, as it has not faced any threat.
8.6 Transformational innovation/creative destruction 289
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Innovation via “creative destruction” [55], which is similar to transformational
innovation, is disruptive, because it introduces products and services that change
the business landscape by providing a dramatically different value proposition.
Championing innovation via “transformati onal inn ovation” or “creative de-
struction” involves going to war with all of the elements inside an organization that
benefit from t he status quo. Within the orga nization, it may involve persuading
managers and staff to turn their working lives upside down and inside out, and not
to do so slowly and grudgingly but quickly and ent husiastically. Such a shift will
never be easy because it puts in question the existing strategies, jobs, careers, pro-
cesses, brands, customers, and culture. For API manufacturing companies to con-
sider such an innovation method will be difficult, as it has not faced any external
threat.
Current Status
Chocked Innovation
Regulators
Manufacturing
Technology
Innovation
Fig. 8.2: Pharma’s current state of manufacturing technology innovation.
290 Chapter 8 Road Map
8.7 Nondestructive creation
According to Edmund Phelps, a Nobel Laureate, “creative destruction” and “trans-
formational innovation,” in which free and uncoordinated contest of ideas generate
growth, lead to chaos. Either of the above routes may not be suitable for pharma, as
it would not be creating anything new, but causing more disruption. With either
route, it is possible that the regulatory interference might also increase.
The concept of “nondestructive creation” [56, 57], introduced by Phelps, is an-
other way for innovation. It takes the “whole village” for an improvement to be devel-
oped, adopted, and launched. It is “all inclusive” and would be the least disruptive
way for any business to innovate. Team members, “the village” at a pharmaceutical
manufacturing, would include chemists and chemical engineers, marketing, financial
analysts, supply chain professionals, quality control, regulators, maintenance, and
manufacturing, to think about and commercialize manufacturing processes [58].
The likelihood of success through “nondestructive creation” is the highest, and
would be the least disruptive option, as all of the elements and components for its
realization are part of every existing manufacturing and business process. Since it
will be a collective effort and an extension of the current methods practiced differ-
ently, it will deliver results quickly and would be beneficial for the organization .
With the success of this methodology, it is very likely that the current business
model will improve significantly. It could influence and lessen the current migra-
tion of API manufacturing to, CMOs. It will bring the philosophies of “continuous
improvement” [36] home to API manufacturing. A pride of creating excellent and
innovative manufacturing processes, which is being lost as manufacturing is being
outsourced, will come back. Like every initial effort for change, skeptics will be
there and will have to be convinced of the values. Equipment vendors could resist
and detest internalization of process design, as they could lose their current clout.
It is necessary to review the reasons for the current high solvent use landscape.
Handling of solid raw materials, intermediates, and use of the available equipment
size are the major causes. Solvents facilitate fitting of most unit processes and unit
operations in the existing equipment, even if they are inefficient. In addition, since
they can be recovered and recycled, methods to lower the solvent use are not
a priority or explored. The current API costs are based on excessive solvent use. If
the solvent changes from the current use levels, it does not impact much the drug
selling price. The cost impact of the solvent on the selling price of the API or the
selling price of the drug is in single-digit percentage (Tab. 8.2). Customers will not
feel the impact of a ny conservatio n. The current API costs are based on excessive
solvent use.
As reviewed earlier in this chapter and other chapters, solvents are process fa-
cilitators. Even though they are recycled, it does not mean that they can be and
should be used in large quantities. In reality, the chemists and chemical engineers,
due to the tradition of using the available processing equipment that is routinely
8.7 Nondestructive creation 291
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used for chemical processing, are forced into using excessive amount of solvent. As
a result, alternate processing options are not considered.
There are reasons and rationale for the high solvent use. A recap of the existing
practices is necessary. It was, and still is, that with the h elp of solvent/s, organic
synthesis reactions can be fitted in the existing equipment. This minimizes any in-
vestment for products. This practice continues:
1. Solvents are used as the medium to transfer the raw materials and intermedi-
ates, to and between the reactors. This allows fitting the process in the existing
equipment.
2. Even if a solid raw material has a low melting point and is not a liquid at room
temperature, it will be slurried to feed the reaction system. If the intermediates
or a raw material to be added later in the reaction are solid, again they are slur-
ried to make sure that the slurries can be pumped and easily ag itate d in the
subsequent steps.
3. Excess solvent use also facilitates mixing and heat transfer in the current
equipment.
4. Some raw materials could be fed as a melt. However, due to the low API annual
productio n volume, a dedicated melt feed system would be expensive at any
commercial plant. If it is used, it would have to comply with the cGMP cleaning
requirements and may end up using additional solvent, thereby creating more
solvent waste. Using a supplier provided molten liquid feed carrier would also
be subject to FDA regulations and, in certain cases, that could be a challenge.
5. If any solid intermediate of the process is isolated, purified, and re-solubilized
or re-slurried in a solvent for further processing, it will create additional waste.
For a continuous process, such isolation would not be needed.
Chemists and chemical engineers by, their training, are seekers and experimenters
who, by nature, create the simplest processes. They experiment and extrapolate the
physical and chemical properties of the chemicals used and produced along with
unit operations to create processes that are viable and safe.
Chapter 3 discusses value of the physical properties of raw materials, intermedi-
ates, understanding their solubilities, melting and boiling points, azeotropic behav-
ior, mutual miscibility, and density differences. They are the crux of “nondestructive
creation” [56, 57] and can be exploited to create excellent processes.
There are considerable ways and opportunities to improve batch and continu-
ous API manufacturing. Companies will have to “think differently” [58–66] if they
want to significantly lower their “E-factor” emissions. For API manufacturing sim-
plification, it is time to exploit every possible opportunity.
The process of “nondestructive creation” [56, 57] in API process development
has to start as soon as the efficacy of a molecule is acknowledged. The mission of
all involved has to be to create an efficient process that will produce a quality prod-
uct of the lowest cost, from the onset, with the lowest “E-factor” [1] emissions. The
292 Chapter 8 Road Map
inclusion of lowest “E-factor” [1] emissions is a new or different value proposition
for an organic synthesis process. This is an important consideration for each or-
ganic molecule synthesis in an effort to lower pharma’s high organic emissions
[67]. With the understanding of the root cause of high “E-factor” [1], it is distinctly
possible to address the related issues and take the necessary remedial steps.
8.8 Why excess solvent is used?
Solvent use in large quantities, as has been discussed in earlier chapters, also
begins at the first development step i n the laboratory. A review of every patent
indicates that if any of the reactants is a solid, a large excess of solvent will be
used to produce a slurry or solution and, in general, the solid concentration
would be about 15 to 50%. High use of s olvent continues for most API for multiple
reasons. The mortar and pestle philosophy persists in every step of API chemical
synthesis.
If the chemists and the chemical engineers are constrained about the solvent
use and given the freedom to exploit, they can create excellent processes with all
the tools that are available. Their creativity and imagination have to be let loose.
The methodology, techn ology, and knowledge to lower pharma’s “E-factor” [1]
have existed from the inception of chemical processing, but they have never been
truly considered and applied to lower the solvent use. The requirement of using the
existing equipment has stood in their way. API manufacturers will have to give
away their deep-rooted and imbedded traditions [65]. Just the consideration or re-
striction of using smaller-sized equipment will set the path to reduce the amount of
solvent use.
Another major benefit of such a restriction would be that many of the APIs that
are produced using batch processes at multiple sites could be produced by continuous
processes. In reality, the API manufacturing landscape could totally change. Many
APIs that do not have the product demand for continuous production could be cam-
paigned using modular plants for long production runs, emulating continuous
processes. Chemists and chemical engineers ha ve the necessary knowledge and
background. These modular plants will be like the erectors sets that have been
discussed earlier in Chapter 6. Pilot plant equipment can be used.
8.9 Continuous processing
The tradition in chemical process development has been that the development work
starts in the laboratory. After the proof of safe and viable chemistry and all justifica-
tions, the process gets scaled-up and commercialized. In pharma manufacturing, due
to the speed to commercialize the products, a totally different process development
8.9 Continuous processing 293
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and commercialization tact has to be taken if continuous manufacturing has to be con-
sidered, even when the eventual volume of the product is not finalized. Learnings from
the outlined process could also be applied to batch processes to reduce the product
commercialization time. Process development for API manufacturing will have to
be done differently.
Instead of the current practice of sequential process development and a need
for the speed in product introduction, development has to be done in parallel, as
described in Tab. 8.6. This can be modified to suit needs. This process will acceler-
ate speed for product introduction. Compared to a batch process, the “E-factor” [1]
for the same product produced by continuous process will be significantly lower.
The basic premise for every API development has to be that every laboratory pro-
cess will be commercialized and each company has the necessary expertise for the
required work. Parallel effort (proposed method, Tab. 8.6) could cut the commer-
cialization time by as much as 50%. Such a development process will be a realign-
ment of the current practices, and will be fast-paced. It is necessary to emphasize
that the parallel process will significantly reduce the total process development and
Tab. 8.6: Current and proposed method of process development.
Current method:
A sequential process: Each process is followed after the first
Lab work →Pilot plant → Commercial
Proposed method:
Each of the steps to be done simultaneously.
Lab work
Knowledge of chemistry
Knowledge of the chemicals
used and intermediates formed
How the physical and chemical
properties can be capitalized
on to create a simple process
in the low-volume pilot plant
equipment?
Pilot plant testing
Testing of the sequential
addition/removal of different
raw materials/intermediates
using different small-volume
processing vessels. This would
simulate a continuous process.
If and when the volume
increases, the equipment used
to test the process can become
the dedicated process
equipment for the product. This
method can be ramped up and
down to meet the global
product is a brand product
under patent or a generic when
out of patent.
Commercialization
The smaller equipment could be
considered as modular
equipment that will not only be
efficient, if properly designed,
but also lower “E-factor”
emissions and change the API
manufacturing landscape.
294 Chapter 8 Road Map
commercialization time. Such a pathway will also be a training ground for newbies.
There will be naysayers within the companies.
The International Council for Harmonization of Technical Requirement s for
Pharmaceuticals, with its recent FDA Q7 [68], ICH Q11 [69] and ICH Q12 [70] guidan-
ces, make simplification of process development and commercialization, extremely
difficult. These guidance s can be considered as a hindrances. FDA will frown on
such a connotation. Their focus needs to be on a quality product of a desired effi-
cacy and characteristics, and not the details of who supplies the starting materials.
For batch processes, there could be multiple suppliers for the same raw material.
The FDA’s connotation implies that the API manufacturers are ignorant of their raw
material purchases and their impact on the product quality.
Process chemistries indicate the natural reaction mechanism for the highest
yield. Developers have to define these conditions. In the laboratory synthesis, every
reaction is conducted in sequential addition of various raw materials. If this is not
followed and the reactants do not react properly, the end product will not have the
desired yield and purity profile. Sequential addition of raw materials is the main-
stay of every continuous process. Chemists and chemical engineers, by taking ad-
vantage of the mutual behavior of chemicals and the manipulation of operating
conditions, can improve process yields. These, along with the manipulation of reac-
tion kinetics and thermodynamics, result in creating an excellent manufacturing
process.
Table 8.7 is the stoichiometric balance for Paroxetine hydrochloride [27]. Prepa-
ration of tables similar to Tab. 8.7 is necessary and a must if the process designers
want to have control of the raw materials, solvent and raw material use, and the
process and its operating parameters. If the yield is not as expected, effort needs to
be made to improve the process. Such an analysis assists in developing and com-
mercializing economic processes with low “E-fa ctor” [1] emissions. Table 8.7 indi-
cates that the yield is about 81.3% (=80/98.3) [29]. Compared to its theoretical yield,
this presents opportunities.
Based on Tab. 8.7 one can conclude that the process uses an excess of toluene
so that it can be processed in the laboratory flask. This will have to be evaluated
and optimized for a commercial operation. The mole ratio of other chemicals (Phe-
nyl chloroformate, KOH, and NaOH) indicates an opportunity to improve the stoi-
chiometry of the process.
Figure 8.3 Is a schematic of the first step pf the paroxetine hydrochloride [29]
process. Chemical engineers and chemists will quite understand the process. They
would have to optimize it. Based on the total global demand, Tab. 8.5, a continuous
process can be easily designed for a rate of about 30 kg/h.
8.9 Continuous processing 295
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