RAW MATERIALS AND MANUFACTURING PROCESS
Final bulk substances from the bulk manufacturing processes are used in
formulation operations, along with other raw materials or ingredients. The raw
materials / chemicals for the proposed enhancement will be similar to the existing
operations. A list of major raw materials is given below:
Sr. No. Item Description kg/month
1 10-METHOXI IMIN 12299
2 9-DEXO-9A-AZA-H 6100
3 Iminodibenzyl 25200
4 N-[2-CYANOBIPHE 11000
5 OXIME BASE 1500
6 5-METHOXY-2(4-M 2600
7 5-CYANAPTHALANE 1300
8 Meta bromoanis 8100
9 (-)-4-(4-Dimeth 500
10 2-BUTYL-1-3 DIA 2100
11 DIETHYL D-(-)-T 2300
12 2,3 Di Chloro B 2950
13 3 Dimethyl Amin 3700
14 5 - CyanoPthal 1400
15 4-BROMO METHYL2 3100
16 SODIUM AZIDE 5800
17 Benzoic Acid 23523
18 METHYL ETHYL KE 28335
19 2-Bromo-4, 5-Di 1327
20 2-CLOROMETHYL-3 672
21 5-6-DIMETHOXY I 390
22 3-CLORO PROPIOP 1755
23 Pyridine-4-Alde 200
24 Valerylchlorid 5067
25 Acetic Acid 42872
26 LNZ-IV(5R-3-(3-Fluro-4-Morphol 45
27 Amine-sidechani ATS-9 105
28 Sodium Hydroxide Flakes 37685
29 5[Diflourometho 650
30 POTASSIUM HYDRO 15949
31 BROMO DERIVATIVE BPR1 IIIparty 2475
32 3-(4-PIPERIDYL) 115
33 Triethylamine 8166
34 Sodium Cyanate 19566
35 5-Methly-2-(-2N 490
36 Hydronopol 667
37 (-)-TRANS-4R-(4 76
38 Dimethyl Sulpho 10707
39 2-BUTYL4-CHLORO 542
40 Lyophilized Enz 2
41 Dibenzo[b-f] [1] LACTUM 355
42 PRIDINE-4-ALDEH - FOR EU 88
43 5% Palladium on Carban 12
44 TERTIARY-BUTYL 2925
45 IPA HCL 6779
46 10% Palladium on Carbon 6
47 Di Isopropyl et 5493
Sr. No. Item Description kg/month
48 Cyclo Hexane 11250
49 4 Bromofluro Be 1621
50 Sodium borohydride (NaBH4) 459
51 NAR2 563
52 Therminol (V-Th 2000
53 Sodium Hydroxide (Caustic Lye) 18844
54 BL Type Activat 4713
55 Amino Guanidine 3167
56 BLS(Trlfluorome 8
57 3R-(-)QUINUCLID 8
58 5-CYANAPTHALANE TOL 1334
59 MonochloroAcet 10958
60 1-[2-(2-HYDROXY [QTB-3] HEP 330
61 CYCLOHEXANONE 4785
62 2(1H)-QUINOLINONE,7-HYDROXY, 88
63 CUMENE HYDROPER 1667
64 N- 4-CHLOROBENZ 322
65 Oxindole 22
66 TRIETHYLAMINE H 2500
67 NAR-5 (III party) 113
68 Urea 16702
69 POT. FERRICCYAN 932
70 POTASSIUM CARBO 4358
71 (1S)-1-PHENYL-1 10
72 N-METHYL PIPERA 760
73 3 methly benzyl 129
74 NOPOL 234
75 Methylene Di Ch 187711
76 METHANOL 200000
77 Toluene(Benzene 50 ppm) 60000
78 Iso Propyl Alco 58334
79 ETHYLE ACETATE 43620
80 Tetra Hydrofura 16630
81 ACETONE 46516
82 Acetonitrile 9572
83 ACETIC ANHYDRID 17281
Manufacturing Process
The manufacture of pharmaceutical products can be divided into three main
stages:
Research & Development;
Conversion of organic and natural substances into bulk pharmaceutical
substances or ingredients through fermentation, extraction, and/or chemical
synthesis; and
Formulation of the final pharmaceutical product.
Research and Development
Pre-Clinical Research and Development begins after a promising compound has
been discovered and isolated in the laboratory. During this phase, the compound
is subjected to extensive laboratory and animal tests to determine whether the
compound is biologically active and safe. The average time taken to complete this
phase is six years.
After completing the Pre-Clinical Research and Development and before testing
the drug in humans, an application is filed with FDA known as an Investigational
New Drug Application (IND). The application must show the results of the pre-
clinical testing and detail the plans for human clinical tests. It must also contain
information about the chemical structure of the compound and a general
description as to how the compound is manufactured.
Clinical Research and Development is typically conducted in three phases, with
each phase involving progressively more people. The first phase, which typically
lasts about a year, is aimed at establishing the drug’s safety and involves a small
number of healthy volunteers. The second phase, which lasts about two years,
helps the scientists determine the drug’s effectiveness. In the third phase, the
drug is used in clinics and hospitals, and scientists must confirm the results of
earlier tests and identify any adverse reactions. Altogether the three phases of
Clinical Research & Development takes about six years.
Production of Bulk Pharmaceutical Substances
Most pharmaceutical substances are manufactured utilizing ‘batch’ processes. In
a batch process, a particular substance or ‘intermediate’ is manufactured in a
‘campaign’ for periods ranging from a few days to several months until sufficient
material is manufactured to satisfy the projected sales demand. At the end of the
manufacturing campaign, another pharmaceutical intermediate or substance is
made. The same equipment with potentially different configurations and the same
operating personnel are often used to make a different intermediate or
substance, utilizing different raw materials, executing different processes, and
generating different waste streams.
Bulk pharmaceutical substances typically consist of structurally complex organic
chemical compounds which are manufactured via a series of intermediate steps
and reactions under precise conditions. These substances are used in the
manufacture of the dosage form of a formulated pharmaceutical product and are
manufactured by:
Chemical synthesis;
Isolation/recovery from natural sources; and/or
Combination of above.
In the present project, bulk drugs are manufactured using Chemical synthesis
technology and the technology is described below:
Chemical Synthesis
Most of the compounds used today as pharmaceutical products are prepared by
chemical synthesis, generally by a batch process. Cardiovascular agents, central
nervous system agents, vitamins, antibiotics, and antihistamines are just a few
examples of the bulk pharmaceutical substances made by this process.
The manufacture of pharmaceutical compounds using chemical synthesis involves
a complex series of processes including many intermediate stage and chemical
reactions performed in a step-by-step fashion. Depending on the process, the
operator (or a programmed computer) adds reagents, increases or decreases the
flow rate of chilled water or steam, and starts and stops pumps to draw the
reactor contents into another vessel. At other stages in the process, solutions
may be pumped through filters or centrifuges, recycled within the process, or
pumped to recycling or disposal facilities. Co-products, such as salts, may be sold
to potential buyers for reuse. Spent acids, metals, and catalysts may be
recovered and reused onsite or given to authorized vendors.
The material from each intermediate step may be isolated and transferred to the
next step of the process for continued processing until the final compounds are
derived. These steps may be all conducted at the same manufacturing site, or if
the intermediate is isolated, it may be transferred to another site for further
processing.
It is impossible to provide a single process flow diagram for this industry since
each bulk pharmaceutical substance is different in its manufacture and several
intermediates may be produced in a step-wise fashion prior to the manufacture of
the final active ingredient.
Reactors
The most common type of reaction vessel is the kettle-type reactor. These
reactors typically range in capacity from 50-litre to several thousand litres. The
vessels are made of either stainless steel or glass-lined carbon steel. Reactors are
equipped to provide a range of capabilities that may be required during the batch
reaction step. This equipment may include: A jacket for heating and cooling,
hook-ups for charging raw materials and for discharging the contents of the
reactor, an agitation and recycle line for mixing, control systems for temperature
and pressure, a condenser system for controlling vent losses, return line for
refluxing condensable, a steam ejector for vacuum operation, a nitrogen supply
for padding and purging the reactor, and a man way for taking samples and
adding solid catalysts, reactants, and other solid materials to the reactor.
Raw materials or ingredients, including solvents, used to produce the
intermediate or bulk substances are charged into the reactor vessel. Liquid
ingredients are drawn into the reactor either by pumping or through vacuum from
drums and storage tanks. Solids may be charged manually or via mechanical
means such as through a vacuum system.
Once the reactor vessels are charged with the raw materials, the reaction takes
place. The reactor can be operated at atmospheric pressure, elevated pressure,
or under vacuum. Because of their flexibility, reactors may be used in a variety of
ways. Besides hosting chemical reactions, they can act as mixers, heaters,
holding tanks, crystallizers, and evaporators. Typical reactions performed include
alkylation’s, hydrogenations, brominations etc. Temperature, pressure and the
degree of mixing are carefully monitored to achieve the desired product and to
ensure worker safety.
Separation
Several separation mechanisms are employed by the pharmaceutical industry
including extraction, decanting, centrifugation and filtration. These mechanisms
may be employed jointly or individually, in multiple stages, to separate the
intermediate or bulk substance from the reaction solution and to remove
impurities.
Extraction
Extraction is used to separate liquid mixtures by taking advantage of differences
in the solubility of the mixture components. Absolvent that preferentially
combines with only one of the components is added to the mixture.
Decanting
Decanting is a simple process used to separate mixtures of liquid and insoluble
solid that has settled to the bottom of a reactor or settling vessel. The liquid over
the solid is either pumped out of the vessel or poured from the vessel leaving
behind the insoluble solid and a certain amount of liquid.
Centrifugation
Centrifuges are used to remove the intermediate or product solids from a liquid
stream. Centrifuges work on the principle of centrifugal force, in which an
outward force is exerted on rotating object. Centrifuges with rotating baskets
within them. The sides of the basket are perforated and covered with filter
medium such as woven fabric.
Filtration
Filtration is the separation of fluid-solids mixture-involving passage of most of the
fluid through a porous barrier (the filter medium), which retains most of the solid
particulates, contained in the mixture. In the pharmaceutical industry, filtration is
used to remove solids from a liquid, whether these solids be product, process
intermediates, catalysts or carbon particulates (e.g., from a discolouring step).
Crystallization
After the reaction takes place, the intermediate or final bulk substance (which is
usually in solid form) can be separated from the reaction solution by
crystallization. Crystallization is one of the most common separation techniques
and is often used alone or in combination with one or more of the separation
techniques described above. In crystallization, a supersaturated solution is
created in which crystals of the desired compound are formed. Super saturation
depends on the solubility of the desired compound.
Purification
Once the intermediate or the bulk substance has been separated, it may need to
be purified. Depending on the intermediate or the bulk substance produced, there
may be several purification steps involved to produce the desired active
ingredient. In vitamin production, for example, there are at least three to four
purification steps. Purification typically is achieved through additional separation
steps such as those described above. Purification is often achieved through
re-crystallization. Washing with additional solvents and filtration may also be
used.
Drying
The final step in the chemical synthesis process is drying of the intermediate or
final bulk substance. Drying is done by evaporating the solvents from the solids.
Solvents released from drying operations may be condensed for reuse or
disposal.
There are various types of dryers used by the pharmaceutical industry including
tray dryers, rotary dryers, drum or tumble dryers, or pressure filter dryers. The
selection of the dryer type depends primarily on the characteristics of the solid.
Bulk Manufacturing
Wide variation in bulk manufacturing makes prediction of typical or annual
average emissions difficult. This is because emissions generated are predicated
based on type of bulk substance or intermediate manufactured, duration of
manufacturing time, type of equipment used and raw materials used.
Dryers are one of the largest sources of VOC emissions in bulk manufacturing. In
addition to the loss of solvent during drying, manual loading and unloading of
dryers can release solvent vapours into ambient air, especially when tray dryers
are used. VOCs are also emitted from reaction and separation steps via reactor
vents and man ways. Centrifuges may be source of VOC emissions, especially in
top loading types, where solids are manually scooped out.
Typical controls for these emission sources, excluding storage and transfer
operations, include condensers, scrubbers, carbon absorbers and occasionally
incinerators. Storage and transfer emissions can be controlled by vapor return
lines, vent condensers, conservation vents, vent scrubbers, pressure tanks and
carbon absorbers. Floating roofs may be feasible controls for large vertical
storage tanks.
QUANTITIES OF EXISTING AND PROPOSED
PRODUCTS THERAPEUTIC GROUPS
Sr. No. Products Qty in KGPA
Anti IBS
1
Tegaserod 50
SUB TOTAL 50
Alpha/Beta Adrenergic Agonists
2
Droxidopa 300
SUB TOTAL 300
Anesthetic
3 Ropivacaine 15
SUB TOTAL 15
Anti anginals
4 Ranolazine 10000
SUB TOTAL 10000
Anti Convulsant/Antiepileptics
5 Lacosamide 4000
SUB TOTAL 4000
Anti hypertension
6 Macitentan 50
SUB TOTAL 50
Anti Parkinson's
Sr. No. Products Qty in KGPA
7 Safinamide 50
8 Pimavanserin tartrate 100
SUB TOTAL 150
Antialzheimer
9 Donepezil hydrochloride 7000
10 Galanthamine hydrobromide 250
SUB TOTAL 7250
Anti-androgen
11 Bicalutamide 20
SUB TOTAL 20
Antibacterial
12 Azithromycin 124236
13 Roxithromycin 50
14 Telithromycin 50
15 Gemifloxacin 50
16 Linazolid tetracycline 6000
17 Halogenated aromatic heterocyclic aliphetic derivatives (e.g. Ro 4935028, Oxazolidinone etc)
500
SUB TOTAL 130886
Anticancer
18 Anastrozole 10
19 Docetaxel / Paclitaxel 10
20 Gemcitabine 10
21 Temozolomide 10
22 Pemetrexed 30
23 Letrozole 10
24 Oxaliplatin 10
25 Fulvestrant 20
26 Irinotecan/Topotecan 20
27 Azacitidine 10
28 other Nische API like Imatinib , Erlotinib, Necarabine, etc.
70
SUB TOTAL 210
Anticholinergic bronchodilator
29 Tiotropium Bromide 50
SUB TOTAL 50
Anticoagulant
30 Dabigatran etexilate Mesylate 1250
31 Rivaroxaban 40
32 Apixaban 20
33 Betrixaban 50
SUB TOTAL 1360
Anticonvulsant/Antiepiliptic
34 Oxcarbazepine 167564
35 Carbamazepine 250000
36 Tiagabine 50
37 Lamotrigine 38467
38 Levetiracetam 30000
39 Eslicarbazepine 3000
Sr. No. Products Qty in KGPA
40 Brivaracetam 500
41 Pregabalin 50
SUB TOTAL 489631
Antidepressant
42 Citalopram Hydrobromide 34474
43 Escitalopram oxalate 5292
44 Paroxetine HCl Hemihydrate 5250
45 Bupropion hydrochloride 75616
46 Duloxetine hydrochloride 9500
47 Atomoxetine hydrochloride 50
48 Vilazodone 75
49 Perphenazine 16
SUB TOTAL 130273
Antidiabetic
50 Repaglinide 50
51 Saxagliptin 16
52 Sitagliptin 150
53 VILDAGLIPTIN 3600
54 Canagliflozin 500
55 Empagliflozin 50
56 Dapagliflozin propanediol hydrate 50
SUB TOTAL 4416
Antiemetic
57 Aprepitant 800
58 Dronabinol 10
59 Rolapitant 90
60 Netupitant 300
SUB TOTAL 1200
Antifibrotic agent
61 Pirfenidone 50
SUB TOTAL 50
Antifungal
62 Voriconazole 425
SUB TOTAL 425
Antigout
63 Febuxostat 4500
SUB TOTAL 4500
Antihistamine
64 Cetirizine dihydrochloride 500
65 Levocetirizine 200
66 Meclizine hydrochloride 4140
67 Fexofenadine hydrochloride 100
SUB TOTAL 4940
Antihypertensive
68 Losartan potassium 26670
69 Valsartan 135697
70 Irbesartan 38396
71 Eprosartan mesylate 50
72 Telmisartan 14388
Sr. No. Products Qty in KGPA
73 Candesartan cilexetil 5000
74 Olmesartan medoxomil 11067
75 Lisinopril 50
76 Bosentan 160
77 Guanfacine 10
78 Labetalol 7000
79 Sacubitril 100
SUB TOTAL 238588
Antilipemic
80 Simvastatin 50
81 Atorvastatin calcium 850
82 Ezetimibe 50
83 Fluvastatin sodium 50
84 Rosuvastatin calcium 12000
85 Niacin 75000
SUB TOTAL 88000
Antimigraine
86 Rizatriptan benzoate 100
87 Zolmitriptan 30
88 Eletriptan 30
89 Naratriptan 10
90 Almotriptan 10
SUB TOTAL 180
Antimuscarinic
91 Solifenacin 1628
92 Darifenacin 261
SUB TOTAL 1889
Antiparkinsonian
93 Rivastigmine 708
94 Entacapone 50
95 Cabergoline 50
SUB TOTAL 808
Antiplatelet
96 Clopidogrel 50500
SUB TOTAL 50500
Antipsychotic
97 Risperidone 1322
98 Quetiapine fumarate 18570
99 Olanzapine 2931
100 Ziprasidone HCl Monohydrate 2063
101 Lurasidone 200
102 Paliperidone 80
103 Brezpiprazole 40
104 Aripiprazole 1508
SUB TOTAL 26714
Antiulcerative
105 Rabeprazole sodium 543
106 Pantoprazole sodium 13831
107 Lansoprazole 3950
Sr. No. Products Qty in KGPA
108 Esomeprazole magnesium 28075
109 Dexlansoprazole 10
SUB TOTAL 46409
Antiviral
110 Valacyclovir hydrochloride 31397
111 Adefovir 50
112 Emtricitabine 50
SUB TOTAL 31497
Smoking cessation
113 Varenicline tartate 50
SUB TOTAL 50
Bone resorption inhibitor
114 Zoledronic Acid 50
115 Residronate sodium 464
116 Alendronate sodium 3300
117 Ibandronate sodium 50
SUB TOTAL 3864
Calcimimetic
118 Cinacalcet hydrochloride 50
SUB TOTAL 50
Anti-Multiple sclerosis
119 Fampridine 120
SUB TOTAL 120
Chelating agent
120 Deferasirox 4247
SUB TOTAL 4247
CNS Stimulant
121 Dex Methylphenidate 50
SUB TOTAL 50
Estrogen for harmone replacement therapy
122 Equilin 50
SUB TOTAL 50
Gastrointestinal disorders
123 Pinaverium bromide 21050
SUB TOTAL 21050
Immunosuppressant
124 Mycophenalate mofetil 20
SUB TOTAL 20
Intravenous MR Contrast agent for CNS
125 BOPTA 40
SUB TOTAL 40
Iron Chilating agent
126 Pentataic acid 800
SUB TOTAL 800
Antipsoriasis
127 Apremilast 130
SUB TOTAL 130
Opioid Analgesic
128 Tramadol hydrochloride 82000
Sr. No. Products Qty in KGPA
SUB TOTAL 82000
Oral Contraceptive
129 Drospirenone 50
SUB TOTAL 50
PDE5 inhibitor
130 Tadalfil / Vardenifil 1780
SUB TOTAL 1780
Phosphate binder
131 Lanthum Carbonate 200
SUB TOTAL 200
Platelet Aggregation Inhibitor
132 Ticagrelor 274
SUB TOTAL 274
Sedative-Hypnotic Drugs
133 Zopiclone 100
SUB TOTAL 100
Selective alpha-1 antagonist
134 Terazosin 50
SUB TOTAL 50
Tetracycline Antibiotic
135 Minocycline 50
SUB TOTAL 50
Urinary antispasmodics
136 MIRABEGRON 530
SUB TOTAL 530
OTHERS
137 Aldehyde ketone aromatic heterocyclic aliphatic derivatives (e.g. Sergeant etc) 500
138 Aminated hydroxy nitro aromatic heterocyclic aliphatic derivatives (e.g. Amino alcohol etc) 500
139 New products for Devlopement and Validations 5000
SUB TOTAL 6000
GRAND TOTAL in KGPA 1395866
GRAND TOTAL in MTPA 1396
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