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