Industrial Training Report Introduction

Plethico Pharmaceuticals Limited, kalaria, Indore

Company Owner :
Mr. Shashikant Patel (Chairman & M.D.) Mr. Chirag S. Patel (Director & CEO) Ms. Gauravi Parikh (Executive Director) Mr. Hemant Modi (GM & COO) Mr. Rajiv Bedi (GM Export) Mr. Sharad Kumar (GM Production)

Location:
Site Address: Plethico Pharmaceuticals limited. Place: Kalaria village dharawara Indore (M.P.)

1. HISTORY
PLETHICO PHARMACEUTICALS LIMITED is a group of companies engaged in the manufacturing of ethical Pharmaceuticals for more than 40 years. On implementation of the new Industrial Policy in 1963, for Indian entrepreneurs, by the Government of India, a small pharmaceutical company M/s. Plazma Laboratories Pvt. Ltd. was founded in 1963, in partnership by our Chairman, Shri Bhaskar A. Patel, a Pharmacy graduate and young entrepreneur. The company was initially engaged in the manufacturing and marketing of products required by Government Stores, Hospitals and Nursing Homes. In 1967-68 under their expansion programme, another new partnership concern under the name of M/s. Ethico Drugs & Chemicals Mfg. Co. was started under the guidance & supervision of a young technocrat, Shri Shashikant A. Patel for manufacturing and marketing of patent & proprietary medicines. Among the few products produced & marketed First Time in India by this company were Minicycline Capsules (Doxycycline), Timizol range of products, namely tablets, capsules & suspension, etc. (Timizol is Co-trimoxazole) & Anti T. B. range of products containing Rifampicin, Isoniazid, Ethambutol & Pyraziramide under the trade name of Montonex Forte & Montorip etc.

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In 1983-84 a new and modern manufacturing unit was established in Manglia a place about 16 Km away from Indore city on Mumbai Agra road. This company was named as M/s. PLETHICO PHARMACEUTICALS (A Partnership concern) for manufacturing of tablets, capsules & dry syrup etc. as per the Good Manufacturing Practices. In 1996-97, this partnership concern was converted into a Public Limited Company under the name M/s PLETHICO PHARMACEUTICALS LIMITED. Looking into the progress of the company, a new world-class manufacturing facility is created on Indore-Ahmedabad road, about 16 Km from Indore city at a place called Dharavara. The plant is designed to meet Indian, WHO, MHRA, MCC, TGA, MCA & US FDA requirements. The new Pharmaceutical plant at Dharavara has manufacturing facilities for tablets, capsules, injections, liquid oral preparations, ointments and neutraceuticals. It also has full - fledged Quality Control laboratory. This new plant also has a dedicated herbal product division along with a completely automatic Lozenges manufacturing plant using latest German technology & a PET bottle-manufacturing unit using a latest state of art Direct Heat Conditioning Stretch-Blow Molding Machine. In addition to India in the OTC segment, Plethico is also a leading player in the Commonwealth of Independent States (CIS), Africa, South East Asia, and Latin America and in the GCC for its Travisil range of products. With the recent acquisition of Natrol a leading manufacturer and marketer of branded nutritional products in the United States, Plethico has now expanded its global footprint to the regulated markets of the United States and Europe.

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2. MILESTONES
1963-70 The beginning of the group activity This decade saw the establishment of the company's first formulation plant, manufacturing tablets, Capsules and Liquid Orals, at Indore, Madhya Pradesh, India. 1971-80 Up-gradation and expansion of Manufacturing Facilities Establishment of a nationwide marketing and distribution network. Introduction of branded formulations in various categories. 1981-90 An ultra modern formulation plant was established at Manglia, near Indore, to manufacture a wide range of allopathic formulations. Innovative branded formulations were introduced and established in Anti-malarials, Anti-tubercular, Cardiovascular & Cough & Cold segments. The company pioneered the launch of Doxycycline and Cotrimoxazole in the Indian market. 1991-2000 Diversification into Herbal & Natural formulations with scientific and modern manufacturing plant for Herbals set up at Indore. Introduction of novel herbal products for Hepatocare, Diabetes and Syndrome X developed with in-house research and clinical evidence. Major thrust into International Marketing. Travisil, an indigenously developed herbal Cough & Cold product became a star performer in the entire CIS market. 2000-2005 Commissioning of the state of the art formulation manufacturing plant at Kalaria, Indore, as per the requirements of WHO GMP, UK MHRA and US FDA.Plethico brand topped the Anti-Malarial segment of quinines. (AC Neilson 2002). Plethico, ranked amongst the TOP 5 Anti-TB companies in India, with its revolutionary 3/4 drug fixed dose Anti-TB combinations. The company re-oriented its business strategy and launched its Consumer Healthcare Division in India. Ultra modern fully integrated plants set up for manufacture of PET bottle (AOKI, Japan) and hard boiled candies (Klockner Hansel GmBH, Germany).The company acquired a marketing and distribution chain in the CIS, with subsidiaries in Russia, Ukraine, Kazakhstan, Moldova, Azerbaijan and Kyrgyzstan. Marketing and Distribution Joint

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Ventures formed in South East Asia, Africa and Latin-America. Establishment of Plethico Africa Limited (Kenya), a manufacturing Joint Venture to cater to the East African market. 2006 - 2008 Plethico raises Rs 110 crore from IPO to part finance: The up-gradation of its Kalaria plant to make it UK MHRA compliant. Setting up a WHO GMP (World Health Organisation Good Manufacturing Practices)compliant plant in Jammu & Kashmir and land to be used for organic farming of importan herbs. Setting up a R&D and formulation and development centre. Acquiring stake in domestic herbal/OTC/nutraceutical company or a brand. Setting up its corporate office in Mumbai.

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3. PRODUCT PROFILE
This site manufactures Pharmaceutical Products like: Tablets Capsules Oral Liquids Injectables Ointments and Creams Herbal Products Neutraceuticals Table: 1 Category of drugs are manufactured in the location Name of the Drug Product Name Chloroquine Phosphate Paraquin P-Quin Quinine sulphate RezQ Tablets/ Suspension Antimalaria / Injection Tablets/ Suspension / Injection Arteether Paracetamol Nimesulide Diclofenac Sodium Ciprofloxacine HCl Ofloxacine Co-trimoxazole Gentamycine Rezart-E Pletin Nimez Maxi Cebect Gonocin timizol Zentotic80 Amlodipine besylate Amlodipine besylate &atenolol Amlodipine &lisinopril Diltiazem HCl Ranitidine HCl
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Dosage Forms

Category

Injection Tablets/ Suspension Tablets/ Suspension Tablets/ Injection Tablets Tablet Tablets/ Suspension Injection Antipyretic, Analgesic,Antiinflamatory Antibiotic/antibacterial

amloz Amloz-at Amloz-L Diitiaz Aciran

Tablets Tablets Tablets Tablets Tablets

Cardiovascular

Antiulcer / antacid
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Omeprazole Pantaprazole Dried aluminium Pleom Pantoz hydroxide,Mg. Coolz Capsules Tablets Tablets/ Suspension

trisilicate,Mg. hydroxide,simethicone Paracetamol,triplodine&pseudoepedrine Recofast plus Codiene mallaite B-complex with vitamin-c&zinc Folic acid Mebendazole Metronidazole Delirek Plelic Bendam Emigyl Capsules Tablets Tablets/ Suspension Tablets/ Suspension Anti-diarrheal,anti amoebic helmintics Herbal hepato protective agent Herbal hepato protective agent Mometasome furoate Terbinafine 1% octogen Previl Metacort Capsules/suspension Herbal Capsules/suspension Cream Dermatological &anti Vitamins&minerals phosphate &cholrpinramin planokuf Syrup Tablets Cough&cold

Dermafine Cream

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4. DEPARTMENTS
Research and development Formulation & Development Quality Assurance Quality Control Stores (RM/PM) Distribution Production Engineering Personnel & Adm. Security 4.1 FORMULATION & DEVELOPMENT Plethico takes pride in a team of dedicated scientists with expertise in botany, pharmacognosy, phytochemistry, analytics and pharmacology, as well as consultants having a long association with the herbal drug industry. Procuring authentic plant material, pharmacological evaluation in laboratory models, formulation development and modern clinical trials are an integral part of the herbal product development activities. Herbal Research unit focuses on developing standardized, clinically proven and safe herbal products for therapeutic and cosmetic use. They are engaged in various activities that enable us to bring out the most efficacious herbal products to consume. Some of the activities are: Research on new herbs/ existing herb ingredients for better therapeutic usage, dosage form/ Novel Drug delivery system (NDDS). Spearheading improvements in existing formulations to meet growing regulatory demands. Stabilizing of existing dosage forms based on stability studies as per International Guidelines. Development of marker based standardized dosage forms. Methods of extraction

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Commercially herbal crude materials are extracted by water as the extraction medium, which is achieved at Plethico by following methods: Cold maceration, Hot percolation, Hot extraction, Distillation, etc. based on the type of material to be extracted Supercritical or Liquid CO2 extraction 4.2 QUALITY ASSURANCE Quality assurance is a major challenge, particularly in light of growing regulatory stringency and the international dimensions of trade, rightly so, since manufacturing of substandard medicines result in prolonged treatment for patients, drug resistance and increased incidence of adverse effects. The self-implied stringent quality standards are followed to ensure that all the products being manufactured are consistently safe, effective and of good quality. While the general principles of GMP apply for all types of pharmaceutical products, herbal products differ from conventional pharmaceutical products in that they are prepared from herbal substances, which include materials derived from leaves, seeds, bark, essential oils and resins. Because of their unique origin, herbal products often require procedures for their processing; manufacturing and storage that differ from those used for conventional pharmaceuticals, and therefore present a degree of complexity. In Plethico, I took pride in stringent following of specially developed protocols for hygiene; sanitation and processing that are specific to herbal products. Some of these are: Storage facilities with quarantining of incoming herbal matter to prevent the spread of microorganisms, Maintenance of segregated areas for different herbal materials and of appropriate environmental conditions. Production areas controlled for dust, fumes and vapors generated by the processing of these substances, Cleanliness of equipment to avoid microbiological contamination as per US FDA GMP norms.

At Plethico, I learned that each major stage of the manufacturing process is validated to

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ascertain that the finished products comply with all quality and design protocols, and consistently meet their specifications.

4.3 QUALITY CONTROL

Standardization is done to ensure that every batch of a product is consistent with respect to quality and results in beneficial therapeutic effect, i.e., to ensure total Quality, Safety and Efficacy of each and every herbal product. Standardization of herbal products at Plethico includes the following steps: Authentication of the plant material Determination of Foreign matter Organoleptic evaluation Macroscopy and Microscopy Determination of extractive values Group analysis Chromatographic profile matching Marker compound analysis Contaminant analysis Few of advanced instruments used for the herbal products apart from pilot scale batch size machines are: High Pressure Liquid Chromatography (HPLC) from Waters Atomic Absorption Spectroscopy for analysis of Heavy metals Gas Liquid Chromatography (GLC) for analysis of Pesticides Thin Layer Chromatography (TLC) for detection and chemical analysis of certain phytochemicals such as Alkaloids, Tannins, etc. The Quality Control and Assurance Laboratories have following facilities. Chemical Analytical Laboratory Microbiological Laboratory Instrumental Analysis Laboratory Sterility Testing Section Control sample and record room Other supporting facilities.

Well-equipped shop floor IPQC Laboratories. 4.4. BRIEF DESCRIPTION OF MICROBIOLOGICAL ACTIVITY:
Bacterial endotoxin test
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Principle: There are two types of techniques for this test: the gel-clot techniques, which is based on gel formation, and the photometric techniques. This MOA is based on gel clot technique. In gel clot technique, equal volume of LAL & diluted test specimen are mixed in tubes and incubated at 37+1C for 60 + 2 min. The tubes are then observed for gel clot formation. A positive response in the gel clot test indicates the Endotoxin in the sample, which equals or exceeds the reagent labelled sensitivity represented by the symbol lambda (). Reconstitution of LAL reagent: Remove Aluminium seal of the Lysate vial without opening the rubber stopper. Tap on the rubber stopper to collect the LAL powder in the bottom of the vial. Carefully remove the stopper. Keep the stopper in a clean surface without touching the inner portion of the stopper. Reconstitute the lyophilized LAL reagent with LRW as per the COA. Stop the re-constituted vial. Do not shake, mix gently avoiding formation of air bubbles and keep aside till clear solution is not visible. Storage: Lyophilized LAL reagent should be stored at 2-8C. Reconstituted LAL reagent ideally should be stored in a refrigerator at 2-8C during intermittent use for up to 24 hours, otherwise, store LAL reagent in freezer upto 28 days. LAL reagent can be frozen and thawed only once. Testing Procedure: Take 2 depyrogenated test tubes for each negative and positive control. Arrange TT of negative and positive controls in separate rows of the stand. Take depyrogenated tubes in duplicate for sample and mark them as 1, 2, 3 or with batch no. of the sample. Add the reagents as mentioned below in the table 04. In case of water sample (Water for Injection and Pure Steam Condensate), transfer 100l of water sample in 2 depyrogenated TT and add 100l Lysate to them (when testing at EL = 0.125 EU/ml). When testing at EL = 0.25 EU/ml, take 50l of water sample to be tested, 50l of LRW and add 100l Lysate. Record the results in the respective formats. Mix gently and incubate the tubes in heating block at 37 C 1 for 60 + 2 min.

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After incubation remove the tubes gently from the heating block and slowly invert through 180C and note the observations. If a firm gel has formed that remains in place after inversion, record the results as positive. A result is negative, if an intact gel is not formed. Record the results and other details in respective format. Microbial Limit Test Pour plate method Add 10gm of sample/10ml of sample in 90ml of SCDM media Place it on the shaker at 35-37c for -1 hour transfer 1ml into the petridish in duplicate T.B.C T.F.C 1st p.d +20-25 ml of SCDA 2nd p.d +20-25ml of SCA Mix & incubate it for 5 days at 30-35c Mix & incubate it for 7 days at 20-25c Incubate it for 24 hour at 37c

E. coli salmonella S.aureus p. aurigenosa Transfer 1ml in M.B media Directly streaked it on Directly streaked it on M.S.A media C.A media Incubate it for 48 hours at 42-44c transfer 1.0 ml in R.V.S.E.B media Then streaked it on M.A media Then streaked it on X.L.D.A media Incubate it for 72 hrs at 30-37c Incubate it for 48 hrs incubate it for 72 hrs at 30-37c at 30-37c Incubate it for 48 hrs At 30-37c

Flow Diagram of Microbial Limit Test 4.5. BRIEF DESCRIPTION OF MAJOR PRODUCTION EQUIPMENT
Major production equipments are as follow: Mechanical vibrating sifters
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Rapid Mixer Granulator Fluidized Bed drier Tray driers Size reduction mills Tablet compression machines Tablet coaters Tablet polishers Liquid manufacturing tanks Bottle washers Bottle fillers & sealers Bottle labelers Ampoule washer Sterilizing tunnels Dry heat sterilizer Autoclaves Ampoule filler & sealer Ampoule inspection machine Ampoule labelers Strip sealing m/c Blister packing m/c Shrink wrappers, etc. Vial washers Vial filler & Sealer PET bottle mfg. unit (Stretch blow moulding) Lozenges Forming Line Ointment/Cream Line 4.6. BRIEF DESCRIPTION OF LABORATORY EQUIPMENTS: Major Analytical instruments in Quality Control Department are as follows: H. P.L. C. With Auto Sampler U.V. -- Visible Spectrophotometer. F. T. I. R. Spectrophotometer.

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Gas Chromatograph. Dissolution Apparatus. K. F. apparatus for Water determination. pH Meter. Potentiometric Titrator Incubators. Humidity control ovens. Autoclave Refractometer Atomic Absorption Spectrophotometer H. P. T. L. C With Photo Documentation System T. O. C. Analyzer Laser diffraction particle size analyzer BOD Incubators Incubator LAL testing Equipments Sterility Testing related equipments Zone reader

4.7. BRIEF DESCRIPTION OF WATER SYSTEM

As we consider water as the most important ingredient of our process, whether it remains in the product or not we use raw water, soft water, drinking water, purified water & water for injection in this plant. Source of raw water is underground natural water. Raw water is treated using water softening plants and converted into soft water, which is used in the boiler, chillers, cooling towers, etc. Potable water is passed through either a two pass ReverseOsmosis System (Capacity 3000 Ltr. Per hour) with Electro Deionising Unit, or Demineralization plant followed by mix bed unit to prepare purified water.

4.8. Table: 2 PRODUCTION EQUIPMENT LIST

Equipment Name Lifting & Tippling device Equipment ID MAKE DTB 03 Tapasya MODEL -

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Sifter Planetary Mixer Blister packing m/c Conveyor Belt Shrink Machine Carton coding M/c Stirrer Rapid Mixer Granulator Fluid Bed Dryer Blister packing m/c Sifter RMG Lifting Positioning Device FBD Tippler Planetary Mixer Conta blender Conta blender Lifting Positioning Device Lifting Positioning Device Coating m/c Coating m/c Lifting Positioning Device Compression m/c DTB 05 DTB 07 DTB 23 DTB -25 DTB -27 DTB -31 DTB 41 DTB-56 DTB-57 DTB-62 DTB-64 DTB-65 DTB-66 DTB-67 DTB-69 DTB-70 DTB-71 DTB-72 DTB-73 DTB-74 DTB-75 DTB-76 DTB-77 DTB-78 Pharmac Tapasya P.G. Pharmac Shrink packing Nimach Pharmac Anchor mark Anchor mark P.G. Anchor mark Anchor mark Anchor mark Anchor mark Anchor mark Anchor mark Anchor mark Anchor mark Anchor mark Anchor mark Gansons Gansons Anchor mark Cadmach machinery Cadmach machinery Cadmach machinery Anchor mark Fabtech Fabtech 240 CH HS-115X RMG 600 FBD 250 PG Ecostar VFST RMG-250 LPU FBD100 LTU PLM100 CB250 CB600+250L -

Compression m/c

DTB-79

Compression m/c Lifting Positioning Device Static Pass Box Static Pass Box

DTB-80 DTB-81 DTB-82 DTB-83

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Vacuum Tray Drier DTB-84 Grovers VTD-48

(Production equipment list continue) Empty capsule sorter Sorter elevator Minifilled capsule sorter Air displacement unit Metal detector Punch polish M/c Balance Balance Balance Balance Balance Balance Balance Capsule filling machine Compact air displacement unit DTB-88 DTB-89 DTB-90 DTB-91 DTB-92 DTB-93 DTB-94 DTB-95 DTB-96 DTB-97 DTB-98 DTB-99 DTB-100 DTB-85 DTB-86 PAM PAM PAM PAM Technofour ACG Mettler Toledo Mettler Toledo Mettler Toledo Mettler Toledo Mettler Toledo Mettler Toledo Mettler Toledo PAM PAM ECS100 SE100 MCS100 ADU100 MD2000 Minicat-S2 Minicat-S2 Minicat-S2 Minicat-S2 Minicat-S2 IND225 AF40T CADU100

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Fig.1:F.B.D

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Fig.2: Disintegration Test Apparatus

Fig.3: Tablet Punching Machine

Fig.4: Capsule Filling Machine

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Fig.5: Blister Packing Machine

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PROCESS FLOW CHARTS
5. PROCESS FLOW CHART FOR TABLETS MANUFACTURING 1.Approved Raw Material Issue from R. M. Stores Weigh Approved Materials as per Batch 2.Wet Granulation Mixing Pulverization and Sifting Slugging 3.Fluidized Bed Drying Sieving 4.Tray Drying 5.Lubrication 6.Tablet Compression 7.De-dusting 8.For Uncoated For Coated QC Approval Tablets Tablets 1.Tablet Quarantine Visual Inspection Tablet Coating 2.Approved Tablets Approved P. M. Issue From P. M. Stores

3.BottlePacking Strip / Blister packing Labeling Strip checking 4.Induction Sealing Label / Carton Carton Packing 5.Coding 6.Shrink packing 7.Shipper Packing 8.QC Approval Finish Goods Store Dispatch 5.1. PROCESS FLOW CHART FOR CAPSULES MANUFACTURING 1.Approved Raw Material Issue From R. M. Stores Weigh Approved Materials As per Batch 2.Non-Aqueous Coating Mixing Shifting 3.Compactin 4.Tray Drying Sieving (At room temperature) 5.Blending 6.Capsule Filling 7.Polishing
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8.Visual Inspection 9.Capsule Quarantine 10.QC Approval 11.Approved P. M. Issue From P. M. Stores Approved Capsules Bottle Packing Strip / Blister packing 12.Labeling Strip checking 13.Induction sealing Label / Carton Carton Packing 14.Coding 15.Shipper packing 16.QC Approval 17.Finish goods Store 18.Dispatch 5.2. PROCESS FLOW CHART FOR INJECTION MANUFACTURING (AMPOULE) 1.Approved Raw Material issue Weigh Approved Materials As per Batch 2.From R. M. stores 3.Bulk preparation Approved W.F.I 4.QC Approval 5.Prefilteration 6.Approved P. M. from Aseptic Filtration 7.P. M. stores Ampoules 8.Approved In-process Checks 9.Purified WaterAmpoule Washing 10.Sterilization Filling & Sealing In Aseptic Area 11.Leak Test 12.Visual Checking 13.Ampoule Ampoule Label Ampoule Labeling Label Coding Roundo Tray Roundo Tray / PVC Tray / PVC Tray Packing Carton Carton Carton & Insert Coding Insert Packing Shipper Shipper Packing BOPP Tape BOPP Taping QC Approval Finish Goods Store Dispatch
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6. CONCLUSIONS
Involving the class at all stages of industrial training motivates the students and helps to take full advantage of all learning opportunities presented. It also brings dimension to students education, which cannot be gained in the class room as well as helping to make connection between the different aspects of educational experience. During my training schedule, I have gone through various department of the company and find that company follow the latest CGMP and also meet the environment norms. During my industrial training in Plethico, I learned different things about the pharmaceutical industry. I came to know about functioning of different instruments used in the pharmaceutical company. Every task is performed in scientific manner. Target are presented and achieved within the time limit. The one thing that impresses every visitor is the discipline and the maintenance of the company. The understanding between the employee and the management is very precise and the cooperation between the departments is very good. In very concise words I would say that this kind of training help us to know about the actual situation inside the pharmaceutical industries so that we get familiarize with that and work in a proper and systematic way.

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