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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5716_Библиотеки_им_академика_М_И_Перельмана
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Diluent: acetonitrile:water (40:60, v/v)
Flow rate: 1.0 mL/min
Detection: UV 210 nm
Injection volume: 50 µL
The retention time of dimethyl maleate is about 10.0 min under these conditions.
The present invention provides dimethyl fumarate, a compound of formula I, containing less
than 400 ppm of an anion of a mineral acid.
In one embodiment, the present invention provides dimethyl fumarate, a compound of formula
I, containing less than 400 ppm of chloride ion.
In one preferred embodiment, the present invention provides dimethyl fumarate, a compound
of formula I, containing less than 100 ppm of chloride ion.
The present invention provides dimethyl fumarate, a compound of formula I, containing less
than 400 ppm of an anion of a mineral acid and free of dimethyl sulfate.
In one embodiment, the present invention provides dimethyl fumarate, a compound of formula
I, containing less than 400 ppm of chloride ion and free of dimethyl sulfate.
In one preferred embodiment, the present invention provides dimethyl fumarate, a compound
of formula I, containing less than 100 ppm of chloride ion and free of dimethyl sulfate.
The present invention provides dimethyl fumarate obtained by the above process, having di-
methyl sulfate content, as described, determined by residual solvent analysis using gas chro-
matography (GC), with the conditions described below:
Chromatographic parameters:
Instrument: Gas chromatograph equipped with FID detector and autosampler.
Column: DB-1, 30 m × 0.32 mm, 1.0 µm
Column temperature: 40 °C (hold for 2 min) to 240 ºC
@20 ºC/min, hold at 240 °C for 20 min
Injector/detector: 150 ºC/270 º C
Carrier gas: nitrogen
Linear velocity: 30 cm/s
Split ratio: (2:1)
Injection volume: 5.0 µL
Diluent: dichloromethane (Merck, HPLC grade)
Similar analytical methods need to be included in the manual for the points in the
process, so that quality product is produced. The methods documented and prac-
ticed cannot be changed without testing and authorization.
256 Chapter 7 Process documentation and operating strategies
7.11 Section 10: thermodynamic and physical properties
It is useful to have thermodynamic and physical properties of the reactants and the
reaction intermediates. These are useful in process design. The following are exam-
ples of the information for randomly selected chemicals. Names of some of the
chemicals and reaction products are not shared to protect confidentiality.
7.11.1 Heat of reaction
Heat of reaction of each reaction product is documented. This, again, is of value in
the design of equipment. Table 7.23 lists heat of reaction for different reaction prod-
ucts of a certain synthesis. In order to maintain confidentiality of the reaction and
the chemicals involved, the products are not identified.
Heat of reaction and process production rate are needed for temperature control
and heat exchanger design.
7.11.2 Physical properties
Most of the APIs per site are not large volume products. Thus, it is possible that all
of the necessary physical and thermodynamic property information migh t not be
readily available from different databases. If that is the case, they might have to be
generated internally and/or calculated using mathematical models. Mathematical
data has to be confirmed.
Density, solubility, specific heat, heat of reaction, viscosity, etc. are a must for
each process stream, as they are used and needed for sizing of the reactors, heat ex-
changers, and pumps. It is very likely that these are not readily available. Again, they
might have to be generated in the laboratory.
Tab. 7.23: Example of typical heat of reaction.
Product Kilocalories/kilogram
Amine hydrochloride .
Amine diazo .
Product # .
Product #
Product # .
7.11 Section 10: thermodynamic and physical properties 257
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Having most of these properties might not be considered necessary, but a pro-
cess that is not designed on the basis of science and e ngineering fundamentals
might not produce quality product from the onset. Having detailed knowledge of
the design parameters is also useful for troubleshooting the process.
The following properties for chemical materials are generally available. For the
process described in Tab. 7.20 dimethyl sulfate, sodium hydroxide and sulfuric acid
are used. Their physical properties [Table. 7.24, Table. 7.25 and Table 7.26 respectively]
are included. Their inclusion in every technical manual is a must. Tables 7.8–7.19 list
physical properties of additional chemicals.
7.11.2.1 Dimethyl sulfate: (CH
3
)
2
SO
4
Tab. 7.24: Physical properties of dimethyl sulfate [54].
CAS number –-
Mol. wt .
Melting point (°C) −
Boiling point (°C)
Solubility in water (g/mL @ °C) .
Heat of vaporization (kcal/g mol) .
Sp. heat (kcal/kg °C) .
Temp. (°C) Specific gravity (kg/m
) Viscosity (g/m-s)
. .
. .
. .
. .
. .
. .
Data here is compiled from different source
258 Chapter 7 Process documentation and operating strategies
7.11.2.2 Sodium hydroxide: NaOH (solid)
7.11.2.3 Sulfuric acid: H
2
SO
4
(96%)
Viscosity and density of the raw materials and intermediates can change with tem-
perature. Appropriate charts should be included in the process manual. They are of
value in process design and operations.
7.12 Section 11: final product specifications
Each produced product has its final specifications. Table 7.27 is one of the ways the
final product specifications and its test methods should also be included in the
Technical Manual.
Tab. 7.25: Physical properties of sodium hydroxide [55].
CAS no. --
Mol. wt
Melting point (°C) .
Boiling point (°C)
Solubility in water (g/mL @ °C)
Sp. heat (kcal/kg °C) .
Sp. gr. kg/m
(%) ,.
Tab. 7.26: Physical properties of sulfuric acid [56].
CAS no. --
Mol. wt
Melting point (°C)
Boiling point(°C) decomposes
Solubility in water (kg/m
@ °C) In all proportions
Sp. heat (kcal/kg °C) .
Sp. gr. kg/m
(%) ,.
7.12 Section 11: final product specifications 259
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Tab. 7.27: Product specification of a drug product.
Material
code
Customer name XYZ
Batch no ABNH Date of manufacture /
Batch
quality
. kg Expiry date /
A.R. no. FP Date of analysis ---:
ReferenceUSP/in-house Specification number S--MO-USP/
Specifications
S. no. Test Specification Result
Description Slightly yellow to yellow Slightly yellow
Solubility
. In . N sodium hydroxide Soluble in . N sodium
hydroxide
Soluble in . N sodium
hydroxide
. In water Sparingly soluble in water Sparingly soluble in water
. Methanol Sparingly soluble in
methanol
Sparingly soluble in
methanol
Identification
. By IR To match with the working
standard
Matches with the working
standard
. By HPLC The retention time of the
major peak in the
chromatogram of the assay
preparation corresponds to
that in the chromatogram of
the standard preparation, as
obtained in the assay
The retention time of the
major peak in the
chromatogram of the assay
preparation corresponds to
that in the chromatogram of
the standard preparation, as
obtained in the assay
. Chloride Responds to the test for
chloride
Responds to the test for
chloride
Specific rotation of ° Between – °C and –
°C
−°
Hydrochloride content Should be between .%
w//w and .% w/w
.% w/w
pH (. in ) Between . and . in a
solution
.
Water Not >.% .%
Residue on ignition Not >.% .%
260 Chapter 7 Process documentation and operating strategies
Tab. 7.27 (continued)
Material
code
Customer name XYZ
Sulfate Not >.% w/w <.% w/w
Related substance by HPLC
. Moxifloxacin-related
compound A
Not >.% Not detected
.,-Dimethoxy
(moxifloxacin-related
compound B)
Not >.% Not detected
.-Ethoxy (moxifloxacin-
related compound C)
Not >.% Not detected
.-Methoxy--fluoro
(moxifloxacin-related
compound d)
Not >.% Not detected
.-Hydroxy (-hydroxy
moxifloxacin-related
compound e)
Not >.% Not detected
. N-Methyl piperazine
derivative of moxifloxacin
Not >.% Not detected
.-Hydroxy quinolinic acid Not >.% Not detected
.-Methoxy of quinolinic acid Not >.% Not detected
. Ethyl quinolinic ester Not >.% Not detected
. Other invalid impurity Not >.% .%
. Total impurity Not >.% .%
RR isomer content Not >.% Less than LOQ (LOQ: .)
Assay by HPLC (on
anhydrous basics)
Not <.% w/w and not
>.% w/w
.% w/w
X-ray powder diffraction
pattern
To match with moxifloxacin
hydrochloride working
standard
Matches with HCl working
standard
Method I
. Pet ether Not > ppm Not detected
. Ethyl acetate Not > ppm Not detected
. Methanol Not > ppm Not detected
.-Propanol Not > ppm Not detected
7.12 Section 11: final product specifications 261
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7.13 Section 12: cleaning and cGMP practices
7.13.1 Cleaning
API manufacturing has to adhere to very strict manufacturing and cleaning practi-
ces. Strictness is necessary because of the batch manufacturing practice in which
Tab. 7.27 (continued)
Material
code
Customer name XYZ
. Toluene Not > ppm Below the limit of detection
(LOD:)
. Dimethyl formamide Not > ppm Not detected
Method II Not > ppm Not detected
. Ethanol Not > ppm Not detected
. Acetonitrile Not > ppm Not detected
. Dichloromethane Not > ppm Not detected
. Methyl isobutyl ketone Not >, ppm , ppm
Microbial count
. Total aerobic microbial count Not >, cfu/g Nil cfu/g
. Total yeast and mold count Not > cfu/g Nil cfu/g
Specified microorganisms
. Bile-tolerant Gram-negative
bacteria
Should be absent Absent
. Escherichia coli Should be absent Absent
. Salmonella species Should be absent Absent
. Staphylococcus aureus Should be absent Absent
. Pseudomonas aeruginosa Should be absent Absent
Endotoxins *S--MF-IH-* Not >. EU/mg <. EU/mg
Additional comments, if any: Store conditions: preserve in tight containers and protect from
moisture. Store at controlled room temperature 20–25 °C (excursions allowed between 15 and 30 °C).
Always replenish with fresh silica gel whenever opened, purge with nitrogen, and seal the triple
laminated bag. Packing condition: materials are packed in a clear polybag filled with nitrogen and tie
with nylon strap. Keep this in triple laminated bag along with silica gel bag, insert the vacuum hose
pipe into the triple laminated bag, apply vacuum to the bag, evacuate and fill with nitrogen, and seal
it with heat sealer. Then keep this in HDPE container.
262 Chapter 7 Process documentation and operating strategies
different active pharmaceutical ingredients (API) can be produced in the same
equipment. This is the case not only at the contract manufacturing organizations
[57], but also true in the captive brand and/or generic API manufacturing firms as
they do not have dedicated equipment for every product. If they did, it would add
to the current excess of idle equipment [58].
Equipment cleaning between product changeovers is a must. Cleaning proce-
dures have to be validated [59]. Established cleaning practices that have been ap-
proved cannot be changed without testing, validation, and authorization. It is
necessary to understand these requirements, and if they are not followed, can result
in financial losses.
Cleaning methodology of the continuous process equipment [60] will be differ-
ent from the cleaning of the batch processes. Batch cleaning is intermittent and
often between batches. However, continuous process [3, 4] not being stop-and-go
may not require rigors of batch cleaning. Most likely, such process would require
limited cleanings per year during their planned maintenance. They have to be
thought through and validated.
Equipment cleaning rationale for continuous manufacturing operations, most
likely, would be based on batch cleaning methodology but would be different and
may not be as detailed as batch cleaning. This would be because the equipment is
only exposed to chemicals that are part of the chemistry being executed in the dedi-
cated equipment. Cleaning of continuous process equipment would have to be
tested and validated.
Since APIs are manufactured using conventional batch processes, their clean-
ing solvent volume between products requires at least one turnover of the equip-
ment volume. If the used solvent volume is large, even after recovery and recycling,
it can be a significant volume. Multiple cleanings of different equipment used for
batch processing per year will add to the operating company’s environmental factor,
“E-factor” [7]. This presents an opportunity for alternate manufacturing processes.
Modular plants, which are not part of the API manufacturing vocabulary, as
has been reviewed in earlier chapters, if used, will change the operating landscape.
With longer API runs, their in-between cleaning will be less frequent than batch pro-
cess scenario cleanings. This, in turn, could mean significantly lower the “E-factor”
[7] for each of the API operating sites.
7.13.2 cGMP
Chemists and chemical engineers are taught, from the onset, to create, design, and
commercialize a process for a product that will produce repeatable quality product.
Properly written “Process Technical Manual” covers the suggested cGMP [5] guid-
ance that are needed for a batch [1, 2] or a continuous process [3, 4]. They are a live
document for every process.
7.13 Section 12: cleaning and cGMP practices 263
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Regulators have proposed guidelines that they consider “good manufacturing
practices,” which should be commonly practiced for every manufacturing process.
Actually, chemists and chemical engineers use them as the building blocks of every
process. Thus, they should be easy to practice and should not be circumvented.
7.14 Section 13: safety, MSDS (now called SDS), and material
handling
Safety is extremely important while handling chemicals. In the last one hundred
years, there has been evolution of the safe handling of chemicals. Concept of mate-
rial safety data sheets (MSDS) was introduced in the last century. They used to be
two pages per chemical. Now, they are about seven pages each, suggesting that
safety has become increasingly more important. Information contained in SDS
(safety Data Sheets) is extremely valuable for safe handling of chemicals. However,
still, it is up to the users of chemicals to take extra steps to respect and handle them
carefully.
What was considered safe chemical yesterday could be considered as or is toxic
today. Toxicology [61] is in its adolescence and will continue to evolve. In addition,
development of better drugs over the years have led to use of exotic chemistries.
Environmental impact of many APIs, their reaction intermediates, and by-products
are not completely known and understood. Many of these are showing up in efflu-
ent streams and impacting soil, aquatic, bird, and animal life.
Studies [62–65] have been and are being done to understand the health effects
of land, animal, and aquatic life after the ill-health effects were noticed. However,
even with the knowledge of potential dangers and hazards of the chemicals, safety
and safe handling, at times, slip through, resulting in significant and serious conse-
quences. Thus, safe and proper handling of every chemical is extremely important.
Every “Process Technical Manual” should include material safety data sheets of
raw materials, every process intermediate, and the finished product. This is critical
especially for the batch processes, the preferred method of producing APIs, because
the intermediates are generally isolated and stored for further processing. This in-
formation can be of value in reactor cleaning also.
Table 7.20 is the first page of safety data sheet for Pyrmetazole (omeprazole sul-
fide) [66], an intermediate in omeprazole synthesis. It needs to be noted that some
information on the data sheets may not be complete as the information might not
be available. Thus, it is necessary to take protective safety measures. Tab. 7.28 and
Tab. 7.29 are safety data sheet [66] and product information sheets [67] for omepra-
zole sulfide.
Since the APIs can be used at their own site or could be transported out of man-
ufacturer’s site, they should have their respective safety data sheets e.g. metfromin
hydrochloride Tab. 7.30 [68].
264 Chapter 7 Process documentation and operating strategies
Tab. 7.28: Safety data sheet for pyrmetazole (omeprazole sulfide) [66].
7.14 Section 13: safety, MSDS (now called SDS), and material handling 265
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