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About 8,400 h/year represents 100% manufacturing operation, with no downtime.
Generally, 15% downtime is allocated for planned maintenance and unexpected
downtime. Downtime allocation is each company’s choice and is used in standard
product cost calculation.
Even as demand for omeprazole, dimethyl fumarate and metoprolol are high
and could be well suited for continuous production, based on the current operating
philosophies, they are still produced using batch processes [8, 9] in multiple plants.
Each such process will have high “E-factor” emissions [7].
7.1.2 Process documentation
Since processes for many API are fitted in existing equipment [8, 9], pharma
manufacturing companies need to have excellent documentation of the process and its
operating rationale, chemistry, process equipment design and selection basis, physical
and chemical properties of the reactants and intermediates, and their mutual behavior.
It is necessary and even critical to know the impact of every process operating
condition and method of addition of reactants, as each deviation from a prescribed
process could produce a product that necessarily does not meet the desired quality
from the onset. Impact of each process deviation on the product quality can be sig-
nificant. Thus, it is necessary to document impact of each deviation and its remedy.
This is not only necessary for every regulatory filing but can also significantly
reduce commercialization time. This information can be extremely useful in transi-
tion, if the product manufacturing is going to be outsourced.
A road map of what can result in quality products without repeated analysis is
reviewed. Readers can tailor the knowledge base for their products. Not only such
information that facilitates operations but also information for continuous improve-
ment and to expand, if need be, are given. For lack of a better term, this document
“Process Design and Technical Manual” can be modified to suit needs. Such a doc-
ument would include all of the process design rationale, justification, and calcula-
tions. This manual is an excellent tool to understand the design rationale for the
equipment, process controls, and the whole operating philosophy for the process.
Process design considerations and parameters assist in troubleshooting and replac-
ing the equipment.
Documentation is also an excellent tool for internal training. It could be used
for regulatory filings. Since the same equipment is used for multiple products, it is
necessary to emphasize that a detailed documentation of the equipment related to a
given product is essential.
If modular processing equipment or other configurations, discussed in earlier
chapters, are used in the manufacture of APIs, such documentation will be ex-
tremely valuable, as it will detail the rationale and logic related to every product
and process. High product quality will be sustained, and there will be no errors.
216 Chapter 7 Process documentation and operating strategies
Table 7.2 lists the “table of contents” that should be part of documentation for
each product and its process. This information is each designer’s thinking, justification,
and rationale for the process. It is also each company’s documentation of the process.
This is an excellent tool for speedier commercialization and technology transfer, if the
product is to be outsourced. It can also be used for most regulatory filings, trouble-
shooting the process, and expansion. This document has to be a live document and
needs to be updated continuously.
Each company can edit/tailor “table of contents” to suit its needs. Some camps
within each company might consider such a document difficult to produce, cumber-
some, or having all of the confidential information in one place as a security risk.
This compilation also may not be considered necessary or c ritical by many. How-
ever, having it provides an extraordinary value to the companies. In the long run,
its value is incalculable. All of the rationale and the information that is needed for
the process, troubleshooting, and de-bottlenecking are easily accessible, as it is cre-
ated by each company. It just has to be compiled. In real business situations, even
the early naysayers, who have seen its usefulness, have been convinced of its
value.
Examples for each section of “table of content s” are reviewed to explain their
value. As indicated earlier, practitioners can add/expand to include content to suit
their manufacturing, safety, and regulatory needs. To illustrate usefulness, informa-
tion discussed is for different chemistries and processes.
The focus, here, is to share the value of the information and let the chemists
and chemical engineers document their rationale and creativity, so that it can be
used to exploit and resolve any adverse situation and “continuously improve” the
manufacturing process. It is hoped that all involved will see the value of improve-
ment to lower the product’s “E-factor” [7] and improve quality. It is also expected
that information compiled will be helpful in process development and commerciali-
zation of the company’s additional products.
Tab. 7.2: Table of contents: process design and technical manual.
Section Table of contents
Process and its description
Process charge and recovery
Raw material specifications
Process chemistry
Heat and mass balance
7.1 Operating strategies and process documentation 217
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7.2 Section 1: process and its description
Omeprazole and metformin hydrochloride chemistries and processes [17] are used
as illustrations for this section. Theoretical stoichiometry is the mass balance at
100% yield. Its inclusion is helpful, as it identifies the by-products that are pro-
duced in the reaction.
7.2.1 Omeprazole
Omeprazole is produced by reacting pyrmethyl alcohol with thionyl chloride to pro-
duce pyrmethyl chloride. Wet toluene is used as a solvent. Wet toluene not only
improves the yield, but also simplifies the process by not having to dry it [18]. Pyr-
methyl chloride is reacted with metmercazole and caustic to produce pyrmetazole,
which is oxidized using m-chloroperoxybenzoic acid. The resulting omepra zole is
processed and used for further processing using traditional methods.
Tab. 7.2 (continued)
Section Table of contents
Process equipment, description, and their design criterion and details
This section should include the necessary design calculations for each process
equipment and process controller. Necessary process control parameters should also be
included.
Process conditions and effect of variables
Suggested operating instructions
Laboratory synthesis procedure
Analytical methods
Thermodynamic and physical properties of raw materials, intermediates, and final
products
Final product specifications
cGMP and cleaning practices
Safety
Material safety data sheets
Methods and instructions of safe handling
US Pharmacopeia Standards
218 Chapter 7 Process documentation and operating strategies
Figure 7.1 presents the theoretical stoichiometry.
As reviewed in earlier chapters, using the best yearly product demand and the com-
pany’s business model, the manufacturing process (batch or continuous) gets de-
fined. Process designers have to know and understand the process parameters,
operating conditions, and their impact on the product quality, so that the produced
product will meet the established quality specifications.
Batch and continuous processes will be different, as illustrated in Figs. 7.2 and
7.3. Based on process (batch or continuous) selected, raw material addition and han-
dling will influence the economics.
Volume of solvent and the sequence of reactant addition for each chemical have
to be defined for each processing step. Solubility will influence how the process is
designed. The amount of toluene used as a solvent in the process is not identified. It
has to be the lowest volume to ensure that the reaction mass can be pumped. To this
end, knowledge of solubilities of various reactants and reaction products in the reac-
tion is necessary. Companies have to create their solubility data. The value of solvent
minimization has been explained in Chapter 6.
7.2.1.1 Batch process
In the batch process, each reaction step would be carried out in individual reactors,
and after the reaction is complete, the mass will be transferred to the next reactor
for further processing. Each processing company could select and carry out their
batch reactions based on its preference.
Omeprazole’s batch process, if conducted in reactors that range from 1,500 lit-
ers and up, would be similar to the laboratory process, as the process would not
have dedicated equipme nt. This would also mean extra solvent use and cleaning
time. Batch process could also be done in the same reactor but would be a complex
process.
Pyrmethyl alcohol + Thionyl chloride
Pyrmethyl chloride + SO
2
+ Metmercazole + 3NaOH
Pyrmetazole + 2 NaCl + 2 H
2
O
+NaHSO
3
+ m-Chloroperoxybenzoic acid
Omeprazole + m-chlorobenzoic
acid
Fig. 7.1: Theoretical omeprazole chemistry.
7.2 Section 1: process and its description 219
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7.2.1.2 Continuous process
Pyrmethyl alcoh ol is a liquid at room temperature. Toluene, alcohol, and thionyl
chloride can be metered to react to produce pyrmethyl chloride slurry in toluene.
Metmercazole is a solid at room temperature and would have to be slurried in caus-
tic solution. Toluene is used in the process and, thus, could be used as the solvent.
Reactions can be done in a circulating plug flow or similar reactor with proper
mechanism to control the heat of reaction. Reaction temperatures can be higher than
the temperatures suggested in the patent. This can be advantageous, as the higher
reaction temperature accelerates the reaction rate and minimal impurities would be
formed. No intermediate sampling would be necessary. Pyrmetazole and omeprazole
of the subsequent steps can be similarly produced, using circulating plug flow or sim-
ilar reactors. Reaction rates can be precisely controlled.
If omeprazole is produced using a continuous process, equipme nt size, com-
pared to the conventional equipment, would be considerably reduced. Compan ies
would require investment for a dedicated process. Since continuous process equip-
ment is smaller in size compared to conventional process equipment, com panies
can use pilot plant and associated equipment as an alternate, or other modular
equipment, as discussed in earlier chapters, as a distinct possibility.
Fig. 7.2: Batch omeprazole process.
Fig. 7.3: Continuous omeprazole process.
220 Chapter 7 Process documentation and operating strategies
7.2.2 Metformin hydrochloride
Theoretical metformin hydrochloride chemistry is outlined in Fig. 7.4.
Withitsglobaldemand(Table7.1),onewouldexpectitwouldbemanufactured
using a continuous process. However, there are about 81 API supplier companies [19].
Most likely, the majority of their production uses the batch process. Fundamental
chemistry is per Fig. 7.4, but how it is executed (reaction, purification, and drying)
to produce the dry API can be different, and that makes it a batch or a continuous
process.
7.2.2.1 Batch/continuous process
Metformin chemistry can be practiced in three different ways. Each is described.
Companies selecting either route have to review the economics of each route and
select the one that suits their needs.
Process #1
Use molten dimethyl amine hy drochloride and dicy andiamide (2-cyanoguanidine)
in stoichiometric quantities to produce metformin hydrochloride, which will be
purified and dried. Schematics of an all-melt process could be similar to Fig. 7.5.
Dimethyl amine + Hydrochloric acid
HCl
Dimethylamine hydrochloride
+
Dicyandiamide (2-cyanoguanidine)
Metformin hydrochloride
+ HCl
Fig. 7.4: Theoretical metformin hydrochloride chemistry.
7.2 Section 1: process and its description 221
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An all-melt process necessitates that each raw material is available as a solid or
can be melted. If molten raw materials are available, each producer will have to ac-
quire necessary melt equipment. Most likely, this process would only work for a con-
tinuous process. Economic justification for investment in the melt equipment would
be difficult for a batch process.
Process #2
Figure 7.6 is a batch metformin process that uses dimethyl amine (DMA), liquefied
gas, and commer cially available hydrochloric acid. Hyd rochloride is centrifuged
and further reacted with dicyandiamide to produce metformin hydrochloride.
Commercial bulk availability of DMA would dictate this process route. Normal pro-
cesses to decolorize and drying follow. Most of the chemists and chemical engineers
are familiar with such processes, and they are not reviewed. This process is being
Fig. 7.6: Metformin batch process.
Fig. 7.5: Metformin all-melt process.
222 Chapter 7 Process documentation and operating strategies
commercially followed [20]. Process charge for this process is reviewed later in this
chapter.
Process #3
Process described in Fig. 7.6 can be a continuous process and is schematically
described in Fig. 7.7. Every chemist and/or chemical engineer understands that
continuous processes are more economical and produce less waste, compared to
batch processes [21].
In this process, DMA can be used as liquid or as a 40% solution. All of the physical
and chemical properties of each raw material and reaction product can be exploited to
design and commercialize this process. Heat and mass balance would assist in the pro-
cess design. Heat of exotherm of DMA and hydrochloric acid can be used to raise the
reaction at the water/xylene azeotropic temperature. If any additional heat is needed,
it can be provided after DMA addition to drive the reaction to completion. Xylene
would be separated using a decanter and recycled. Water from the decanter can be
treated.
Any additionally needed xylene would be used to slurry dicyandiami de. This
process uses 40% commercially available dimethyl amine hydrochloride. If DMA is
to be used as gas, water mass balance would have to be carefully reviewed. Again the
economics of the process would have to be justified.
7.3 Section 2: process charge and recovery
Process charge and recovery for the metformin process schematically shown in
Fig. 7.6 is included. The referenced company [20] chose to explain different stages
of the process as illustrated in Figs. 7.8–7.11. Tab. 7.3, Tab. 7.4, Tab. 7.5, Tab 7.6
Tab. 7.7 are the mass balances of processes illustrated in Fig. 7.8, Fig. 7.9, Fig. 7.10
and Fig. 7.11.
These figures are also the process and instrumentation diagrams of various
steps of metformin hydrochloride process [20].
Metformin hydrochloride 1,200 tons per month
7.3 Section 2: process charge and recovery 223
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Fig. 7.7: Metformin continuous process.
224 Chapter 7 Process documentation and operating strategies
Tab. 7.3: Stage 1 dimethyl hydrochloride [20].
Stage DMA HCl No. of batches: per day
Input (kg) Output (kg)
DMA DMA HCl
HCl % Loss on drying
Evaporation loss
Total , ,
Fig. 7.8: Production of DMA hydrochloride for metformin process [20].
7.3 Section 2: process charge and recovery 225
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