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Fig. 7.16: Centrifugal pump data sheet [48].
246 Chapter 7 Process documentation and operating strategies
Fig. 7.17: Centrifugal pump data sheet [48].
7.6 Section 5: process equipment 247
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Fig. 7.18: Centrifugal pump data sheet (API-610) [49].
248 Chapter 7 Process documentation and operating strategies
Fig. 7.19: Agitated vessel process data sheet [50].
7.6 Section 5: process equipment 249
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7.7 Section 6: process conditions and effect of variables
It is important to document the cause and effect of every deviation of the process
condition. This is critical as the majority of API manufacturing processes are batch
operations. In addition, if different equipment, on the same or other site is used to
produce the API, significant process variability can be introduced in the API
manufacturing process, as the behavior of every process equipment can be differ-
ent, even when the design crite rion a nd fa bri cati on ar e the same.
Reaction mechanisms, generally, give excellent clues about the sequence of addi-
tion of chemicals for most reactions. One of the simplest examples is the formation of
a diazo salt of an aromatic amine. If hydrochloric acid is to be used in the reaction,
addition of acid to amine (it could be dissolved in water or appropriate solvent) will
produce the amine hydrochloride, which, in turn, reacts with sodium nitrite to form
the diazo salt that is used in subsequent reaction. However, if the hydrochloric acid is
added to amine and sodium nitrite mix, NO
x
will be formed, which is not desirable. In
addition, impurity formation can lower the yield.
Process stoichiometry has to be precisely controlled. It is necessary to understand
and document the influence of stoichiometry variation on the process yield and the
impurity profile. The same applies to temperature operating parameters, feed rates
and raw material addition methods, and the points of addition. Any and every devia-
tion will be manifested by change in overall reaction profile, and that can change the
process yield and impurity profile. Mole ratios of process streams cannot deviate out-
side the established control limits. “What if” analy sis and understanding of each
processing step and stoichiometry are important and have to be documented.
Chemists and chemical engineers can use some of the following to create their
own guidelines for each process. It is critical that the changes to a commercial pro-
cess are not made without authorization. If changes are to be made, they need to be
tested and authenticated.
As has been suggested in earlier chapters, changes to the process and equip-
ment can influence process dynamics and costs.
7.7.1 Liquid/solid feeds
It is extremely critical that the liquid and solid feed systems are the same for the
designated API manufacture. Not only the feed mechanism, but also the location
and method of feed in the reaction scheme can influence the process. The rationale
for this is that the raw materials react with each other to produce a different prod-
uct. Variations between equipment on the same site or other sites can influence the
process stoichiometry and the outcome. Metering systems for the solids and liquids
have to be calibrated respectively on a routine basis for the liquid and the solid that
will be used in the process. Optimum performance is critical.
250 Chapter 7 Process documentation and operating strategies
7.7.2 Batch process
In majority of batch processes, a solvent is used to facilitate the reaction. The sol-
vent is generally heated to a prescribed temperature. If the amount of solvent use is
changed without testing and authorization, process results can be different from
the approved process. Reactants are added in the predetermined order to complete
the reaction. It is necessary that the temperature profiles (heating and cooling), agi-
tation, and feed methods are the same for each batch of the API. This is critical. Not
having the same heating and cooling profile and the residence time can greatly in-
fluence the process yield and the impurity profile. Since the equipment size change
is not translational, processing conditions change and care is needed to understand
the influence on operating conditions.
Batch stoichiometry has to be controlled well within the design parameters. If
the product can be or has to be reworked to an acceptable and saleable product, it
can cost as much as 25% of the standard factory API cost [51].
In many of the API processes, gaseous raw materials are used. They are used as
a liquid because the liquid feed rate can be precisely controlled. Operating condi-
tions have to be precisely defined. Since the gas will evaporate and need heat for
evaporation, any reaction exotherm can be easily absorbed. Calibration of gaseous
raw materials can be a challenge but can be done.
7.7.3 Continuous process
Continuous processes are very different from batch processes; so are their operating
philosophies. Per established definitions [3, 4], they are supposed to operate 24 ×7 ×
50 = 8,400 h/year. Each operating company, based on their established practices,
allocates a certain time for maintenance and unexpected shutdowns. Unlike batch
processes, the liquid and solid intermediate materials are not held in any sto rage
facility.
Since the liquids are added in an established sequence to capitalize on their
mutual properties and reactivity, it is necessary that the same sequence and stoichi-
ometry are also followed in a commercial operation. Temperature and pressure pro-
files have to be precisely followed.
In continuous processes, stoichiometry has to be controlled extremely well. De-
viations outside the established parameters will result in off-spec product and
lower-than-expected yield, resulting in significant financial loss through nonsalable
product, cleanup, and disposal costs. Rework of the reactive in-process materials is
difficult, if not impossible. If the cause of deviation is not remedied quickly, equip-
ment will be idle until the cause of error is figured and remedied. All this can hap-
pen as the flow of the materials is time-independent.
7.7 Section 6: process conditions and effect of variables 251
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Most companies understand the impact of batch vs. continuous processes and
have to make sure every cause and effect of process deviation from the set parame-
ters is understood well. Technology and methodology of precise process control has
been, and, is being, practiced every day, in the fine/specialty chemical industry,
the older cousin of the pharmaceutical industry, which includes API manufacturing
and their formulations. Thus, precise controls are not a new art or technology.
In each type of manufacturing process manual, the chemist or the chemical en-
gineer should include the influence of stoichiometry, temperature, and feed rate
variation in the product yield and quality. Documentation of impact of these varia-
bles is extremely useful in troubleshooting the product quality and yield variation.
7.8 Section 7: suggested operating conditions
Operating conditions for a batch or a continuous process have to be defined pre-
cisely and documented. They need to be strictly followed and cannot be changed
without testing and authorization.
For a batch process, the raw materials have to be charged in the predetermined
sequence, at the defined weights, and heated/reacted at the operating temperatures.
For a continuous process, process operating manual has to have a startup and
a shutdown procedure. Once the process is operating, the feed rate of each reacting
process raw material has to be at the established process feed controllers/meters
settings. Heating and cooling parameters have to be monitored and controlled.
Cleaning procedures and their sequence have to be defined well.
7.9 Section 8: laboratory synthesis procedure
Process development starts with writing the chemistry on paper and progressing to
visualize its commercialization. It may sound or look to be simple and is a simple
exercise. However, on the contrary, it is the most difficult task that needs to be per-
fected, as it is the first brick of the process foundation.
Different process schemes and methods are imagined and tested in the labora-
tory. The process selected is the most viable, safe, economical, and has to be easily
executable on commercial scale. If we review the processes that are outlined in the
patents, they are based on the traits of the chemicals used and can produce the de-
sired product. However, generally, the methodology outlined in the patent is for
batch processes, is based on laboratory equipment, and may not be the one that is
used in the commercial process.
The following example is for the diazonium salt formation of methyl anthrani-
late. The synthesis for a batch process is outlined in USP 4464537 [52]:
RNH
2
+ 2HCl + NaNO
2
=RN
2
Cl + 2H
2
0 +NaCl Eq. 7.1
252 Chapter 7 Process documentation and operating strategies
About 76 g (0.5 mol) of methyl anthranilate and 135 g of an aqueous sodium
nitrite solution (containing 0.5 mol of NaNO
2
) were added gradually in the course of
30 min to 196 gm. of 30% strength by weight aqueous hydrochloric acid (=1.61 mol
of HCl) at from − 5.0 to + 10 °C. The diazonium salt solution is processed further.
The laboratory continuous process is as follows. Table 7.22 is the stoichiometry
for the laboratory process.
Synthesis for the same synthesis emulating a continuous process is as follows:
Place 50 mL of HCl (37%) in 250 mL beaker equipped with stirrer and a ther-
mometer. Add 5 mL of water and cool to 0–5 °C using suitable ice bath. Dissolve
sodium nitrite in 30 mL of water and place in an addition funnel with a long tube.
Charge about 4 mL of methyl anthranilate with a dropper into the stirred acid fol-
lowed by dropwise addition of sodium nitrite, below the acid surface, Continue al-
ternate addition of the amine and the nitrite. The appearance of brown fume (NO
x
)
should be avoided by controlling the addition of nitrite. With all of the amine in,
the remaining nitrite solution should be added to starch-iodide end point. The color
of anthranilate diazo is golden yellow, and it is a clear solution.
Process design for the batch process will be different from that for the continu-
ous process.
7.10 Section 9: analytical methods
It is necessary to document each analytical method used to measure and correct
every stoichiometric and process deviation. In the batch processes, any process de-
viation due to stoichiometry imbalance or temperature deviation within limits can
be corrected and the manufacturing process controlled to produce a product that
meets its specifications. However, in a continuous proce ss, deviation from estab-
lished stoichiometry and temperature parameters can result in significant financial
loss, because the incorrect chemistry or process operating parameters can produce
significant quantities of off-spec material that might have to be disposed.
Tab. 7.22: Laboratory synthesis of diazonium salt methyl anthranilate.
Raw material Mol. wt Mole ratio g/g of MA-T Unit charge (g/test)
Methyl anthranilate .. . .
Water . . .
HCl (%) use % .. . . ( mL)
Sodium nitrite . . .
7.10 Section 9: analytical methods 253
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Analytical methods for every process step that is considered necessary for the
manufacture of the product should be detailed. An HPLC (high-performance liquid)
analysis method for dimethyl fumarate [53] is detailed below.
HPLC analysis of dimethyl fumarate [53]
Reagents, solvents, and standards:
Water (Milli Q or equivalent)
Perchloric acid 70% (AR grade)
Acetonitrile (HPLC grade)
Chromatographic conditions:
Apparatus: A high-performance liquid chromatograph equipped with quaternary gradient pumps,
variable wavelength UV detector attached with data recorder, and integrator software.
Column: GL Science, Inertsil ODS 3 V, 250 × 4.6 mm, 5 µ
Column temperature: 30 °C
Sample cooler temperature: 15 °C
Mobile phase:
Mobile phase A = buffer
Buffer: 0.5 mL of perchloric acid dissolve in 1,000 mL of water (0.05% perchloric acid in water)
Mobile phase B = acetonitrile
Diluent: acetonitrile:water (20:80, v/v)
Flow rate: 1.0 mL/min
Detection: UV 210 nm
Injection volume: 20 µL
The retention time of dimethyl fumarate is about 20.0 min under these conditions. Relative re-
tention time for fumaric acid is about 0.23 and for monomethyl fumarate is about 0.57, with
respect to dimethyl fumarate under these conditions.
The present invention provides dimethyl fumarate, obtained by the above process, wherein the
amount of an anion of a mineral acid is determined by analytical techniques; for example, chlo-
ride ion content can be monitored by ion chromatography, potentiometric titration with silver
nitrate, turbidimetric method; sulfate ion content can monitored by ion chromatography, turbi-
dimetric method.
Time (min) % mobile phase A % mobile phase B
.
254 Chapter 7 Process documentation and operating strategies
The present invention provides dimethyl fumarate, obtained by the above process, wherein the
chloride ion content was determined by USP method as described below:
Preparation of standard solution:
Take 0.2 mL of 0.02 N hydrochloride acid solution in 30–40 mL of water and mix. Filter this solu-
tion through 0.45 µ Nylon filter. Add 1 mL each of nitric acid and 0.1 N silver nitrate TS and suffi-
cient water to make 50 mL. Mix and allow to stand for 5 min protected from direct sunlight.
Preparation of test solution:
Take 0.35 g sample in suitable test tube. Add 30–40 mL of water and sonicate for 3–4 min and
filter through 0.45 µ Nylon filter. Add 1 mL each of nitric acid and 0.1 N silver nitrate TS and
sufficient water to make 50 mL. Mix and allow to stand for 5 min protected from direct sunlight.
Then, compare the turbidity of test and standard solution.
The present invention provides dimethyl fumarate obtained by the above process, having di-
methyl maleate content, as described, analyzed by using high performance liquid chromatogra-
phy (HPLC), with the conditions described below:
Reagents, solvents, and standards:
Water (Milli Q or equivalent)
Potassium dihydrogen phosphate (AR grade)
Acetonitrile (HPLC grade)
o-Phosphoric acid (AR grade)
Chromatographic conditions:
Apparatus: A high-performance liquid chromatograph equipped with quaternary gradient pumps,
variable wavelength UV detector attached with data recorder, and integrator software.
Column: GL-Science, Inertsil ODS 3 V, 250 × 4.6 mm, 5 mu
Column temperature: 30 °C
Sample cooler temperature: 15 °C
Mobile phase:
Mobile phase A = buffer
Buffer: 0.01 M potassium dihydrogen phosphate. Adjust pH 4.0 with o-phosphoric acid.
Mobile phase B = acetonitrile
Time (min) % mobile phase A % mobile phase B
.
7.10 Section 9: analytical methods 255
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