Cadila Industrial Training Report

Training Report | Cadila Pharmaceutical Limited Anas Haruna Indabawa BARCHALOR OF PHARMACY ADDRESS: Naini, Allahabad, U.P, INDIA. 211007. ID NUMBER: 13BPH053 JUNE- 2016

Training Report | Cadila Pharmaceutical Limited CERTIFICATION

ndabawa, a, a student from Depart ment ment of This is to certify that M r. Anas H arun a I ndabaw from the Depart Phar maceuti maceuti cal Scie Science nces s, Sam Hi gginbottom I nstitute of Agri cultu re, Techn Techn ology & Science Sciences s Allahabad has Completed his Industrial Training from

to at Cadila Pharmaceuticals Limited, Samba, State of Jammu & Kashmir in integration of B.Pharm degree Course.

We wish him all the success in life Seal of the company

Signature of the competent authority Of the institute/organisation

Place: Date:

Sam Higginbottom Institute of Agriculture, Technology & Sciences (SHIATS) Allahabad.

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Training Report | Cadila Pharmaceutical Limited ACKNOWLEDGEMENT I consider it a great privilege & honor to have had the opportunity to undergo the industrial training program in Cadila Pharmaceutical Limited , Samba (Jammu & Kashmir). I hereby wish to take the opportunity to express my gratitude to all members of Human Resource Department (HR), especially Mr. K. S Chauhan (General Manager HR), Mr. Ranbir Singh (Assistant Manager HR), and Sourabh bhattr . I express my special thanks and gratitude to Mr. Ranbir for taking care of all our official requirements. I convey my heartiest thanks to Mr. G.P Chaurashia (Vice presedentcadila pharma. & Plant Head Gen. Manager Cadila, Samba.),Mr. Dinesh Jain (Deputy General Manager& Production Head)Mr. ManojChaurashia (Senior Manager – Production Dept. Line C), Mr. Anil kumarsaini (Head of Dept. QA/QC), Mr. Mohan S. Pundik (Asst. H.O.D QA/QC) for guiding, and encouraging me to carry out my industrial training successfully. Aspecial regards to Mr. G.P Churashia for allowing me to undertake my summer training at this great and reputed organization like Cadila pharma. Ltd. Ltd. I owe deepest gratitude to Dr. Himanshu Pandey (Department of Pharmaceutics) Sam Higginbotom Institute of Agriculture, Technology & Sciences (SHIATS) who work tirelessly to make this training program possible. I also extend my thanks to Prof. (Dr.) Arvind Dayal (Dean faculty of Health science SHIATS), Prof. (Dr.) G.S Shukla (Associate Dean), Dr. AmitaVerma (Head of Dept., Pharmaceutical Science, FHS, SHIATS) for their help. I extend my regards to all Nigerian students in (SHIATS), especially Abdulsalam M. Uba, Isah Hassan Abubakar and Yusuf Baba Dala whom we undergo the training together at cadila pharma. My very special thanks to my parent for giving me a good background that helps me benefits many achievements of my life. Finally, I wish to convey my deep thanks to all staffs in different departments for their kind cooperation, guides, supports, encouragements for me to get vast knowledge and ideas regarding many sectors to improve my educational carrier and to have excellent training practice. Special regard to Anupam Rai (production Dept. line C); Rano Yadav, Mohini sharma, Diguijay Rai, Sanjay Yadav, Ranveer singh (QA/QC); Nisha Tickoo (Microbiology Dept.); Vidushisharma, Rhythm parghal, Aditya Verma (Packaging Dept); Ramandanjha (Raw material store); Rahul sharma, Rajesh sharma (sofgel Dept.) for their kindness during the tenure of my training program.I also extend my regard to Mr. Raul kashaf (Engineering (Engineering Dept).


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Training Report | Cadila Pharmaceutical Limited PREFACE

Pharmacy is the Art and Science of preparing and dispensing drug. It is the health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs.So it is a fully technical profession where practical knowledge is much more important along with theoretical knowledge. According to curriculum of a four year integrated degree course of BACHELOR BACHELOR OF PHARMACY each student has to undergo practical training for a periods of four four week in various various pharmaceutical pharmaceutical industries in India. I was directed to undergo my industrial training at CADILA PHARMACEUTICAL PHARMACEUTICAL LIMITED LIMITED and this report contains a brief description of the above pharmaceutical industry which was observed during the training program.


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Training Report | Cadila Pharmaceutical Limited TABLE OF CONTENT S/N CONTENT 1 Profile of Organisation - About Cadila - Vision - Mission - Our Inspiration - Research - Approved patents - Formulations

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2

8-15

3

4

5

6

7

Production Section - General Instructions and Precautions - Granulation - Compression - Coating - Packaging and Labelling - Encapsulation Soft Gelatin and Hospicon Section - Soft gelatin - Hospicon Quality Control & Quality Assurance Section - Size and Shape - Organoleptic Property - Hardness and friability - Weight Variation Microbiology Section - Microbiological Microbiological Testing of Non-sterile product - Sterility Testing - Validation Engineering Section - Electricity Unit - Water Treatment System - Water Softening Unit - Chilling/Steam Unit - Air Handling Unit (AHU) - Effluent Treatment Plant (ETP) Raw Material and Finished Goods Section

16

17-19

20-23

24-27

28-30


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Training Report | Cadila Pharmaceutical Limited

8

Raw material Receiving Sampling Storing Dispensing - Finished goods Conclusion

31

9

Bibliography

32

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Training Report | Cadila Pharmaceutical Limited PROFILE OF ORGANIZATION ABOUT CADILA

Cadila Pharmaceuticals Ltd. is one of the largest privately held pharmaceutical companies in India, headquartered at Ahmedabad, in the State of Gujarat. Over the last six decades, the company has been developing and manufacturing pharmaceutical products in India and selling and distributing these in over eig hty-five other countries around the world. Focused strongly on Innovation and Research, the company is present in more than fortyfive therapeutic areas spread across twelve specialities, including cardiovascular, gastrointestinal, analgesics, haematinics, anti-infectives and antibiotics, respiratory agents, antidiabetics and immunologicals. At Cadila Pharmaceuticals, Research and Development is at the core of all its initiatives, be it Biotechnology, APIs, Formulations, Plant Tissue Culture or Phytochemistry. More than 300 scientists in its various Research and Development setups reinforce the competitiveness of research in the therapeutic areas which have high unmet medical needs.Cadila Pharmaceuticals Excellence in manufacturing facilities is central to Cadila Pharmaceuticals. The company’s formulations formulations manufacturing plant at Dholka near Ahmedabad, Gujarat is spread over hundred acres of land. This state-of-the- art facility is not only impressive in size, but is also USFDA approved. The second formulations manufacturing facility is located at Samba in Jammu and Kashmir. The facility meets most of the stringent quality standards across the globe to produce tablets, capsules, soft and hard gelatin capsules, liquids and orals.Two Active Pharmaceutical Ingredient (API) manufacturing units at Ankleshwar, Gujarat manufacture a wide range of APIs and intermediates including many USFDA-certified products. The company has strong foothold in the African continent through its formulation manufacturing facility at Addis Ababa in Ethiopia. VISION

“Our vision is to be a leading pharmaceutical company in India and to become a significant global player by providing high quality, affordable and innovative solutions in medicine and treatment.” MISSION

“We will discover, develop and successfully market pharmaceutical products to prevent, diagnose, alleviate and cure diseases. We shall provide total customer satisfaction and achieve leadership in chosen markets, products and services across the globe, through excellence in technology, based on world-class research and development. We are responsible to the society. We shall be good corporate citizens and will be driven by high ethical standards in our practices.”


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Training Report | Cadila Pharmaceutical Limited OUR INSPIRATION Mr. I A Modi is the Founder Chairman of Cadila Pharmaceuticals Ltd.

Born in a small village of Hansot of Bharuch district in South Gujarat on February 18, 1926, Mr. Modi has left a long lasting impact on Indian Pharmaceuticals industry. Mr. Modi is revered in the Indian Pharmaceutical Industry as the Champion of Indian Patents Act, 1970 which helped the Indian Pharmaceuticals Industry in attaining its present global status. He played a major role in giving shape to the 1986 Drug Policy of Government of India.His contributions are widely acclaimed in the industry circles. Mr. Modi represented the National Working Group on Patent Laws, India (NWGPL) and Indian Drug Manufacturers’ Association (IDMA) on the subject “Patent Regime” proposed in the the Uruguay Round at Delhi 1993. He effectively championed the cause of national sector of the pharma industry and became a rallying point against the new patent regime during its consideration stages. Under his leadership Cadila Pharmaceuticals achieved new milestones and offered many innovative and ‘firsts in the world’ medicines to the mankind including Rabeprazole in IV form for upper GI bleeding, Polycap for prevention of cardiovascular diseases, Risorine with booted Rifampicin for the treatment of Tuberculosis etc. He also has the credit to bring cutting edge technology VPL Virus Like particles) for vaccine manufacturing in India. Following in his vision, Cadila Pharmaceuticals continues to innovate and bring affordable medicines for the end users.Mr. Modi has been a champion of Corporate Social Responsibility long before the concept became popular. In 1985, he established Kaka-Ba hospital with ultramodern facilities at a remote village to serve the needy poor patients. RESEARCH

Spread over more than 1,05,000 sq. ft. area, Cadila Pharmaceuticals’ Pharmaceuticals’ R & D facilities, recognized by the Department of Science & Technology, Government of India, are manned by more than 300 scientists. A centralized Quality Control & Analytical Research Laboratory has been set up to meet the domestic and international quality standards. The Company has expanded operations by building further on already existing set-up by investing in new premises, to include modern, state-of-the-art amenities. One of the few companies in the country carrying out collaborative research, Cadila Pharmaceuticals taps the best scientific talent in the country and has collaborations with more than 30 leading Research and Development centers in India.   

1177 Formulations registered worldwide 148 API Drug Master Files (DMFs) submitted 52 patents granted and 405 patent applications filed globally

APPROVED PATENTS   

Intravenous composition of Rabeprazole Solid oral composition contain five actives in one capsule Pharmaceutical composition of novel vaccine adjuvants and its method of treatment


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Training Report | Cadila Pharmaceutical Limited 

New molecular entity on diabetes

FORMULATIONS

Our extensive range of finished dosage formulations covers every aspect of human life. Our basket of formulations contain more than 850 products in several forms belonging to 45 therapeutic segments and 12 specialities including cardiovascular, gastrointestinal, analgesics, haematinics, anti-infectives and antibiotics, respiratory agents, antidiabetics, immunogicals and oncology. The manufacturing expertise is available for almost all dosage forms including sterile as well as non-sterile products. Formulations have three manufacturing facility in the state of Gujarat, Jammu (India) and Ethiopia. All of which are approved by all prominent international regulatory bodies, including USFDA


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Training Report | Cadila Pharmaceutical Limited PRODUCTION SECTION GENERAL INSTRUCTIONS AND PRECAUSIONS  

Ensure area and equipment cleanliness before starting the manufacturing o perations. Check and ensure that all manufacturing equipment and other required accessories are clean ready for use.

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Wear gloves and nose mask during all manufacturing process.

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Counter check the weights of all ingredients before u sing in the batch

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Get line clearance from QA for manufacturing.

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Air handling unit (AHU) system should be kept ON throughout the manufacturing process. Temperature should be kept between 25ºC ±2ºC and relative humidity should be kept between 50±10%.

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Ensure that only QC approval purified water is being used for manufacturing purpose

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Always transfer solution to the manufacturing vessels through 20 meshes.

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During the preparation of this product, no other product processing should be done in the same area. Whenever sifting through SS mesh is involved; check the mesh integrity before and after use. All critical aspects during manufacturing like temperature, duration of mixing, weight, etc. must be checked and recorded by the supervisor. Supervisor to ensure completion of all in-process records during various stages of manufacturing operations till completion of the batch. Release from QA should be taken from all in-process tests mentioned in batch manufacturing record No over writing is allowed in batch manufacturing record. If initial data is wrong entered, cancel the data by single stroke arrow and put initials. Record reasons for change as footnote on the same page. All the details whatever is necessary should be recorded in batch manufacturing record (BMR). Send a test request form to QC after manufacturing is completed Check all polyethylene bags before and after material loading for black particles and sealing. Check calibration of respective equipment/machine before use.

Tablet component and Additives Active Ingredients: Aceclofenac,olmesartan, montelukast, loperamide, paracetamol, chlozoxazole, seratiopeptidase, sesquihydrate AF, domperidone, pantoprazole, ranitidne,


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Training Report | Cadila Pharmaceutical Limited amiodorone, fexofenadine, amikacin, dexamethasone, ciprofloxacin, fluconazole, vitamin B3 granule etc. Non-active Ingredients a. Diluents: starch, lactose, mannitol, sorbitol b. Binders: acacia, gelatin, Tragacanth, Calcium lactate trihydrate granular N.F, Starch paste, polyvinyl pyrollidone, sodium alginate c. Lubricant: Stearic acid, Magnesium stearate, Calcium stearate and Talk d. Disintegrates: Starches and most common disintegrants e. Colous: D&C and FD&C Dyes and lacquers

GRANULATION Departments 

Line A : for tablets preparation

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Line B : for tablets preparation

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Line C : for tablets preparation

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Line D : for tablets and capsule

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Line E : for tablets preparation (Dexamethasone)

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Line L : for liquid preparation

Unit Operation

There are three methods of preparing Tablets. These are: 

Wet granulation

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Dry granulation (also called slugging) and

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Direct compression

Each of these methods has its advantages and disadvantages. The first two step of milling and mixing of the formulation are identical, but thereafter the processes differ, Each individual operations of the process is known as u nit operation. Step in different methods of manufacture WET GRANULATION o o o o o

Mixing of drugs and excipients Mixing of milled powder Preperation of Binder solution Mixing of binder solution with powder mixture to form wet mass Coarse Screening of wet mass using 6-12 mesh


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Training Report | Cadila Pharmaceutical Limited o o o o

Drying moist granules Screening dry granules with lubricant and disintegrants Mixing screened granules with lubricant and disintegrants Tablet compression

DRY GRANULATION o o o o o o

Milling of drugs and excipients Mixing of milled powders Compression into large, hard tablets called slugs Screening of slugs Mixing with lubricants and disintegrating agents Tablet compression

DIRECT COMPRESSION o o o

Milling of drugs and excipients Mixing of ingredients Tablet compression

Equipments  Rapid Mixing Granulator (RMG)  Steam Kettle  Fluid Bed Dryer (FBD)  Vibro Sifter with Loader  Tippler and Co-Mill  Rimek Communiting Mill  Conta Blender  Compressor

Rapid Mixing Granulator (RMG)

RMG was developed for pharmaceutical and chemical industry. With the help of MRG wet sifting is generally no longer necessary. After the mix ing of dry components, wet granulation occurs (without transfer of dry mixture) producing loose granules in RMG. RMG is specifically designed to meet the GMP requirements of the pharmaceutical industries. Fluid Bed Dryer (FBD)

In FBD, the fluidized air steam is introduced by a fan or a blower mounted at the top of the apparatus. The air is heated to a required temperature in the air heater and flows upwards through the wet materials, which remains in a drying chamber fitted with a wire mesh supported


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Training Report | Cadila Pharmaceutical Limited at the bottom. By this process, the material is suspended and agitated in a warm air steam while the granulation is maintained in motion. Vibro Sifter with Loader

Sifter is an instrument used to sieve the ingredients of the tablet with a replicable mess ware. In this technique, particles of power mess are placed on a screen made of uniform aperture. The sifter is attached with vibrator that helps in sieving the materials through the meshwork. The mechanism of action is to loosen the parking of particle in contact with screen surface, permitting entrapped sub sieve particles to the screen surface. Communiting Mill

Communiting mill is used for wet and dry granulation, pulverization or dispersion of product or ingredients in pharmaceutical, chemical, bulk drug food and other industries. It consists of stainless steel hopper through which the product slide into the enclosed chamber, where it is milled between beater and reduced to required size and finally collected in a container.

Conta Blender

The Conta blender gives better efficiency as compared to conventional blenders. Tumbling principle in partial void enables the homogeneous mixing of active ingredients, additives and raw materials. The rotation of bunker in a diagonally eccentric plane ensures efficient blending.

COMPRESSION: This step involves consistent flow of an adequately lubricated, uniform blend, into dies where the granules are being compressed into tablets. Compression is to be carried out as per batch manufacturing record. rec ord. Collect the samples at various stages i.e. at start up, high RPM, low RPM, low weight at target speed, high weight at target speed, initial, middle and end of compression and carry out the testing of content uniformity and physical parameters such as hardness, thickness, friability etc.In compression stage three batches i.e. Batch No I, II and III shall be considered for validation. Compression results of all the batches are well within the acceptance criteria results of the compression at different speed, low weight at target speed, high weight at target speed, initial, middle and end of the compression.


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Training Report | Cadila Pharmaceutical Limited Compressor

For increase production, rotary machine offers a great advantage. A head carrying a number of sets of punches and dies revolves continuously while tablet granulation runs from the hopper,through a feed frame and into the dies placed in a large, steel plate revolving under it. This method promotes a uniform fill of the die and therefore an accurate weight for the tablet. Compression takes place as the upper and lower punches passes between a pair of rollers. This action produce a squeezing effect on the material in the die cavity from the top and bottom and so gives a chance for the entrapped air to escape. The lower punch lifts up and ejects tablet. The punches and dies can be removed for inspection, cleaning and inserting different sets to produce a great variety of shapes and sizes.

COATING Tablets may be coated for a variety of reasons, including protection of the ingredients from air, moisture, or light. Tablets are also coated to protect the drug against decomposition or to disguise or minimize the unpleasant taste of certain medicaments. Coating also enhances the appearance of tablets and makes them more readily identifiable. In addition, coatings can be resistant to gastric juices but readily dissolve in the small intestine. These enteric coatings can protect drugs against decomposition in the acid environment of the stomach. Coating is to be carried out as per batch manufacturing record. Samples are collected at the end of coating stage and carried out the testing of content uniformity and identification tests, related substances, individual impurities, and physical parameters such as hardness, thickness, friability, etc. In coating stage three batches i.e. Batch No I, II and III shall be considered for validation. Coating results of all the batches are well within the acceptance criteria. Types of coating include:  Sugar coating  Film coating  Modified coating

Sugar Coating :- The sugarcoating process involves building up layers of coating material on the tablet cores as they are tumbled in a revolving pan by repetitively applying a coating solution or suspension and drying off the solvent. Before sugarcoating, the core is coated with a sealing coat of shellac, PVP*-stabilized types of shellac, or other polymeric materials, such as cellulose acetate phthalate and polyvinyl acetate phthalate. The next stage is to build up a sub coat that will provide a good bridge between the main coating and the sealed core, as well as round off any sharp corners. This step is followed by smoothing or grossing. The finishing stage is accomplished by again applying one or two layers of clear syrup. The tablets are then left for Sam Higginbottom Institute of Agriculture, Technology & Sciences (SHIATS) Allahabad.

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Training Report | Cadila Pharmaceutical Limited several hours before being transferred to the polishing pan. The polish is a dilute wax solution (e.g., carnauba or beeswax in petroleum spirit) applied sparingly until a high luster is produced. Film Coating :- Film coating has increased in popularity for various reasons. The film process is simpler and, therefore, easier to automate. It is also faster than sugarcoating, since weight gains of only 2 to 6% are involved, as opposed to more than 50% with sugarcoating. Two major groups of film coating materials may be distinguished:

(a) Those that are non-enteric and, for the most part, cellulose derivatives, and (b) Those that can provide an enteric effect and are commonly esters of phthalic phth alic acid. Films may contain a plasticizer that prevents the film from becoming brittle with consequent risk of chipping. Until recently, alcohols, esters, chlorinated hydrocarbons, and ketones have been among the most frequently used types of solvents. However, because of increasing regulatory pressures against undesirable solvents, there has been a pronounced trend toward aqueous film coating. Modified-Release Coating: - A coating may be applied to a tablet to modify the release pattern of the active ingredient. Two general categories, enteric coating and controlled-release coating, are distinguished. The former are insoluble in the low pH environment of the stomach but dissolve readily in the small intestine with its elevated pH. They are used to minimize irritation of the gastric mucosa by certain drugs and to protect others that are degraded de graded by gastric juices.

PACKAGING AND LABELLING Packing is the technology of enclosing or protecting product for distribution, storage, sale, and use. Packaging is also refers to the process of designing, evaluating, and producing packages. Packaging P ackaging can c an be b e described as a coordinated system of preparing goods for transport, warehousing, logistics, sale, and end use. It is sometimes convenient to categorize packages by layer or functions. o o o

Primary Packaging Secondary Packaging Tertiary Packaging

PRIMARY PACKAGING: Primary packaging is the material that first envelope the product and holds it. This usually is the smallest unit of distribution or use and is the package which is in direct contact with the content. SECONDARY PACKAGING: Secondary packaging is outside the primary packing, and may be used to prevent pilferage or to group primary packages together.


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Training Report | Cadila Pharmaceutical Limited TERTIARY PACKING: These are used for bulk handling, warehouse storage and transport shipping. The most common form of palletized unit load that packs tightly into containers. TYPES OF PACKAGING

a. Blister Packing : This is useful for packaging of unit dose of pharmaceuticals. This packing mode has been used extensively for several good reasons. It is a packaging configuration capable of providing excellent environmental protection, coupled with an aesthetically pleasing and efficacious appearance. It also provides user functionally in terms of convenience, child resistance and now temperature resistance. The blister package is formed by heat softening a sheet of thermoplastic resin and vacuum drawing d rawing the softened sheets of plastic into a contoured mould. After coming, the sheet is released from the mould and proceeds to the filling station of the packaging machine. The semirigid blister previously formed, is filled with the product and lidded with a heat sealable backing material. The backing material can be either a push through or peelable type. For a push through type of blister, the backing material is usually heat seal coated aluminum foil. b. Strip Packing:The strip packing is done by aluminum foil or glassine poly paper. A strip package is formed by feeding two webs of a heat sealable flexible film through either a heated crimping roller or a heated reciprocating platen. The product is dropped into the pocket formed prior to forming the final set of seals. A continuous set of packets is formed, generally several packets wide depending on the packaging machine’s limitations. The strip of packets is cut to the desired number of packets in length. The strips formed are usually collected and packed into a folding carton. The product sealed between the two sheets of film usually has a seal around each tablet, with perforations usually separating adjacent packets. c. Bulk Packing : The packaging of the final product is done in paper cartons, manually, and is finally sealed using an automatic sealer. Th e machine can seal cartons. PACKING MACHINERIES 

Accumulating and collating machine

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Blister packs, skin packs and vacuum packing machines

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Converting machine

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Filling machine

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Linear vibrator

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Coding, printing, marking, stamping and imprinting machine

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Package filling and closing machine

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Palletizing, depalletizing, unit load assembly

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Packing sealing machine

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Conveyor belts


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Label dispenser: Domino printer

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Weighing machine: check weigher

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Wrapping machine

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Carton machine

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Other specialty machinery: Slitters, perforating, laser cutters, parts attachment, etc.

ENCAPSULATION Encapsulation is the process of manufacture of capsules. Capsules are solid dosage forms in which the drug substance is enclosed en closed in either hard or soft, soluble form of gelatin. TYPES OF CAPSULES  Hard gelatin capsule  Soft gelatin capsule

HARD GELATINE CAPSULE It is referred to as dry filled capsule; consist of two sections, one slipping over the other, thus completely surrounding the drug formulation. SOFT GELATING CAPSULE It is a soft, globular, gelatin shell, somewhat thicker than that of hard gelatin capsules. The gelation is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The hard capsule is also called “two pieces” pieces” as it consists of two pieces two pieces in the form of small cylinders closed at one end, the shorter piece is called the “cap” which fits over the open end of the longer piece, called the “body”. The soft gelatin capsule is also called as “one piece”. Capsules are available in many sizes to provide dosing flexibility. Unpleasant drug tastes and odors can be masked by the tasteless gelatin shell. The administration of liquid and solid drugs enclosed in hard gelatin capsules is one on e of the most frequently utilized dosage forms. Filling of hard gelatin capsules:

a) Removal of caps b) Filling of the bodies, c) Replacement of caps, and d) Ejection of filled capsules


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Training Report | Cadila Pharmaceutical Limited  Capsules are delivered into the perforated capsule filling ring. The ring is rotated on a

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turntable, and a vacuum pulls the bodies into the lower half of the ring, leaving the caps in the upper half of the ring. The top & bottom halves of the filling ring are separated manually, and the cap half of the ring is set aside. The body half of the ring is then moved to another turntable where it is rotated mechanically under a powder hopper. The hopper contains an auger which feeds the powder into the bodies. When the capsule bodies are filled, the cap and body rings are rejoined.

Capsules equipment seen 

Medicament preparation vessel

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Gelatin preparation vessel

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Colloidal mill

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Water storage tank

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Gelatin holding tank

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Encapsulation machine

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Tumbler dryer

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SS trolley

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Auto sorting machine

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Weighing balance

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Bottle filling/ capsule sealing machine

SOFT GELATIN AND HOSPICON SECTION SOFT GELATIN A softgel is an oral dosage form\ for medicine similar to capsules. They consist of a gelatin

based

shell

surrounding

a

liquid

fill.

Softgel

shells

are

a

combination

of gelatin, water, opacifier and a plasticiser such as glycerin or sorbitol. Softgels are produced in a process known as encapsulation using the Rotary Die Encapsulation process invented by Robert Pauli Scherer. The encapsulation process has been described as a form/fill/seal process. Two flat ribbons of shell material are manufactured on the machine and brought together on a twin set of rotating dies. Cadilapharmaceuticals commissioned a modern sophisticated manufacturing facility for soft gelatin capsules at jammu complex. Designed to meet the most stringent international standards, all operations in this plants from encapsulation to packaging, are carried out under class 100,000. All systems are validated to meet international FDA standards, and the present capacity of one million capsules per day can be doubled with marginal investments. Sam Higginbottom Institute of Agriculture, Technology & Sciences (SHIATS) Allahabad.

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Training Report | Cadila Pharmaceutical Limited HOSPICON The wide range covers Orthoset, a leading plaster of paris bandage; Duralite, a fibre glass-based synthetic cast bandage; Glotex examination gloves and Surgitex surgical gloves, both made of high-grade double-centrifuged latex; Opstic adhesive tapes, Dermaporehypoallergic tapes, Dermasilk wound dressing and Castinetguaze bandage. Other specialty products includes Cadi-V infusion sets and Bioflon I.V cannula; and Softcrepe and cotton crepe bandages.Besides these, the company has entered into the agreement to lunch modern wound cares including Hydrogel.

Equipment seen in Hospicon Section  Mass mixer  Bandage making machine  Bandage cutting machine  Bandage coating machine  Dryer / Dehumidifier  Pulling machine  Slitting machine  Conveyor

QUALITY CONTROL AND QUALITY ASSUARANC ASSUARANCE E SECTION Quality control is the part of GMP concerned with sampling, specification and testing and with organization; documentation and release procedures which ensure that necessary and relevant tests are carried out and that materials are not released for sale or supply, until their quality has been judged satisfactory. Quality Control (QC) laboratory ensures that the products are pure, safe and effective and are released only after thorough analysis as per stringent specifications, methods and procedures developed according to international guidelines viz. EU cGMP, MHRA, WHO, TGA, etc. One of the most important elements in QC laboratory programme is the quality and assurance of the standard, which are used. The standard can be broadly defined into two categories 

Reference standard or primary standard

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Working standard or secondary standard

The working standard are those obtained from reliable source and whose purity and strength have been optimized through test, generally compared with the reference standard. The quality control section section performs different control measure measure and test Sam Higginbottom Institute of Agriculture, Technology & Sciences (SHIATS) Allahabad.

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Training Report | Cadila Pharmaceutical Limited procedures to verify the product and material quality. The tests are performed by the QC personnel and the results are matched with a reference standard. Quality control is an essential operation of the pharmaceutical industry. Drugs must be marketed as safe and therapeutically active formulations whose performance is consistent and predictable. New and better medicinal agents are being produced at an accelerated rate. At the same time more exacting and sophisticated analytical methods are being developed for their evaluation Different types of test are performed for different material. The types of test performed for each material are as follows1. 2. 3. 4. 5. 6. 7.

Testing Purified water Assay of different tablet Disintegration Test Dissolution Test In Process Quality Control HPLC – HPLC – High High Pressure Liquid Chromatography Testing Uniformity of Weight of Tablets

EVALUATION 

SIZE AND SHAPE: - Thickness: ±5% of standard value control to facilitate packaging. shaped tablet requires slotted punches because of the non-uniformity force during compression  ORGANOLEPTIC PROPERTY: -Color of product must be uniform. Non uniformity of color on the tablet is called Mottling. Instrument used to measure color uniformity and quantitative measurement includes 

Reflectance spectrophotometer

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Micro reflectance photometer

Tristimulus Collimating  HARDNESS AND FRIABILITY:- Both for tablet strength testing. Force required to break a tablet in a diametric compression test is called hardness, also called tablet crushing strength. 

Friability is the resistance shown by the tablet during packing and transshipment. Friability tester:  Roche friabilator  Revolution at 25 rpm for 4 minutes (100 rev.)  Dropping from 6 inches


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%Friability = (Initial weight- Final weight)/ Initial weight × 100

 WEIGHT VARIATION:- 20 tablets are weighted

Meet USP test: Not more than 2 tablets are outside of limit if no tablet differ more than 2 times the percentage limit. IP Less than 85mg 85mg-250mg Greater than 250mg

% ±10% ±7.5% ±5%

USP Weighing 130mg or less Weighing 130-324mg Weighing 324mg or more

 DISINTEGRATION  6 test tube and 3 inch long  10 mesh screen  1L beaker of water (0.1N HCL) simulated gastric fluid or simulated intestinal

fluid  Temperature 37±2ºC  Up and Down from 5-6 cm  Frequency 28-32 cycle/min Tablet should remain 2.5cm below the surface of liquid on their upward movement and same for downward movement. The potency of tablet is expressed in mg ,g, µg. Official range is not less than 95%. Majority of tablets has their disintegration time of 30 min. Instruments and Devices seen in QA/QC             

Hot Air Oven. Dissolution Test Apparatus. Vacuum Oven. Bulk Density Apparatus. Membrane Filter. Conductivity meter Halogen moisture balance Gas chromatograph Melting point detector Viscometer Muffle Furnace. Centrifuge. Magnetic Stirrer.


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Training Report | Cadila Pharmaceutical Limited         

Ultrasonic Bath. UV Cabinet. Bursting Strength Test Apparatus. UV-VIS Spectrophotometer. (Ultra Violet Visible) FT-IR Spectrophotometer.(Fourier Transform Infrared). Karl Fisher Titration. HPLC system Polarimeter Digital pH meter

MICROBIOLOGY SECTION The Guide to the Inspection of Pharmaceutical Quality Control Laboratories provided very limited guidance on the matter of inspection of microbiological laboratories. While that guide addresses many of the issues associated with the chemical aspect of laboratory analysis of pharmaceuticals, this document will serve as a guide to the inspection of the microbiology analytical process. As with any laboratory inspection, it is recommended that an analyst (microbiologist) who is familiar with the tests being inspected participate in these inspections. Following processes are carried out in microbiology laboratory: 

Sterility Testing



Antimicrobial Efficacy Testing (AET)



Microbial Limits Testing



Bioburden Determination



Endotoxin (LAL) Testing



Environmental Monitoring and Identification



Water Analysis

MICROBIOLOGICAL TESTING OF NON-STERILE PRODUCTS For a variety of reasons, we have seen a number of problems associated with the microbiological contamination of topical drug products, nasal solutions and inhalation products. The USP Microbiological Attributes Chapter <1111> provides little specific guidance other than "The significance of microorganisms in non-sterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential hazard to the user." The USP recommends that certain categories be routinely tested for total counts and specified indicator microbial contaminants. For example natural plant, animal and some mineral products for Salmonella, oral liquids for E. Coli, topical for P. aeruginosa and S. Aureus, and articles Sam Higginbottom Institute of Agriculture, Technology & Sciences (SHIATS) Allahabad.

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Training Report | Cadila Pharmaceutical Limited intended for rectal, urethral, or vaginal administration a dministration for yeasts and molds. A number of specific monographs also include definitive microbial limits Microbiological testing may include an identification of colonies found during the Total Aerobic Plate Count test. Again, the identification should not merely be limited to the USP indicator organisms. The importance of identifying all isolates from either or both Total Plate Count testing and enrichment testing will depend upon the product and its intended use. Obviously, if an oral solid dosage form such as a tablet is tested, it may be acceptable to identify isolates when testing shows high levels. However, for other products such as topical, inhalants or nasal solutions where there is a major concern for microbiological contamination, isolates from plate counts, as well as enrichment testing, should be identified. STERILITY TESTING One of the most important aspects of the inspection of a sterility analytical program is to review records of initial positive sterility test results. Request lists of test failures to facilitate review of production and control records and investigation reports. Particularly, for the high risk aseptically filled product, initial positive sterility test results and investigations should be reviewed. It is difficult for the manufacturer to justify the release of a product filled aseptically that fails an initial sterility test without identifying specific problems associated with the controls used for the sterility test. Examine the use of negative controls. They are particularly important to a high quality sterility test. Good practice for such testing includes the use of known terminally sterilized or irradiated samples as a system control. Alternatively, vials or ampules filled during media fills have also been used.Be especially concerned about the case where a manufacturer of aseptically filled products has never found an initial positive sterility test. While such situations may occur, they are rare. In one case, a manufacturer's records showed that they had never found a positive result; their records had been falsified. Also, the absence of initial positives may indicate that the test has not been validated to demonstrate that there is no carryover of inhibition from the product or preservative. VALIDATION Confirmation, through the provision of objective evidence, that the requirements for a specific intended use or application have been fulfilled. Validation is one of the important steps in achieving and maintaining the quality of the final product. If each step of production process is validated we can assure that the final product is of the best quality. Validation of the individual steps of the processes is called the process validation. Different dosage forms have different validation protocols PROCESS VALIDATION: “Process Validation is establishing documented evidence which

provides a high degree of assurance that a specific process will consistently produce p roduce a product meeting its pre-determined specifications and quality characteristics.”


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Training Report | Cadila Pharmaceutical Limited Types of process validation:

1) Prospective validation 2) Retrospective validation 3) Concurrent validation 4) Revalidation

Instruments and Devices seen in Microbiology Laboratory 

Analytical balance



Incubator



Refrigerator



Biosafety cabinet / Laminar Air Flow



Magnetic stirrer



Deef freezer



Light microscope



PH meter



Autoclave



Hot air oven

Analytical Balance

They are used in precise weighing of small amounts (upto miligrams) of samples and chemicals used for preparing media and stock solutions. Biosafety Cabinet

It is used in microbial inoculation and isolation studies as well as sterile storage of materials. In addition, it is utilized for protection of user, samples and the environment from hazardous contamination. Refrigerator

The device is used for the storage of the stock solutions, chemicals, kits and nutrient media that should be maintained at certain temperatures. Shaker Incubator

In the microbiology laboratories it is among the leading devices which are based on the principle of shaking at different temperatures according to the pu rpose and the work load of the laboratory. Sam Higginbottom Institute of Agriculture, Technology & Sciences (SHIATS) Allahabad.

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Training Report | Cadila Pharmaceutical Limited It is used in cultivating, multiplying and in the characterization tests of microorganisms. This device provides the heat necessary necessar y for the growth of microorganisms. Deep Freezer

It is used to store stock cultures in microbiology. It is a device used to store materials which should be kept at low temperatures te mperatures (cells, tissues, enzymes, proteins, etc.)

Inverted Phase Contrast Light Microscope

Inverted Phase Contrast Light Micros By the help of different refractive properties of the light, Phase Contrast Light Microscope provides visibility to subcellular structures of microorganisms that are examined in a liquid medium without any staining. Fluorescence attachment is used to display objects stained with special fluorescent dyes (DAPI, FITC, Texas Red Etc.) and that cannot be displayed displayed with normal light microscopy techniques. It operates according to the principle of reflective light. Magnetic Stirrer

Magnetic stirrer is a device which provides mixing and keeping the chemical solutions and mixtures at a certain time and temperature by the help of a magnetic bar. Vortex agitates the solutions in the tube, flask and so on in certain speed and duration. Incubator

In the microbiology laboratories it is among the leading devices which work at different temperatures according to the purpose and the work load of the laboratory. It is used in cultivating, multiplying and in the characterization tests of microorganisms. This device provides the heat necessary for the growth of microorganisms. PH meter

It is used to determine the pH of the media prior to experiments and to monitor pH value during experiments. The device is used especially in the preparation of stock solutions and the culture media used for the growth of microorganisms. Autoclave

The main purpose of this device is to sterilize materials and media under pressure and steam.


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Training Report | Cadila Pharmaceutical Limited ENGINEERING SECTION 

Electricity unit



Water treatment system



Water softening unit



Chilling/ steam unit



Air Handling Unit (AHU)



Effluent Treatment Plant

ELECTRICITY UNIT: Generation of electricity in cadila is from three sub-station red, yellow and blue (RYB) 





Light arrester: - A lightning arrester is a device used on electrical power systems systems and systems to protect the insulation and insulation and conductors of the system from the damaging effects of lightning. lightning. The typical lightning arrester has a high-voltage terminal and a ground terminal. Transformer:- Step-down unit, this transformer converts high-voltage, low-current power into low-voltage, high-current power. The larger-gauge wire used in the secondary winding is necessary due to the increase in current. The primary winding, which doesn’t have to conduct as much current, may be made of smaller-gauge wire. Cadila has two step-down transformers, one which convert voltage from 66kv to 11kv and the other one which convert the voltage from 11kv to 440 volt for the industrial use.

:-A A circuit an automatically Vacuum Circuit Breaker :breaker is operated electrical switch designed to protect an electrical circuit from damage caused by over current or overload or short circuit. Its basic function is to interrupt current flow after protective relays detect a fault.

WATER TREATMENT SYSTEM:

Water treatment is used to optimize most water-based industrial processes, such as: heating, cooling, processing, cleaning, and rinsing so that operating costs and risks are reduced. Poor water treatment lets water interact with the surfaces of pipes and vessels which contain it. Steam boilers Steam boilers can can scale up or corrode, and these deposits will mean more fuel is needed to heat the same amount of water. Cooling towers can towers can also scale up and corrode, but left untreated, the warm, dirty water they can contain will encourage bacteria to grow, and Legionnaire’s Disease can be the fatal consequence. Also, water treatment is used to improve the quality of water contacting the manufactured product e.g. semiconductors, and/or can be part of the product e.g. beverages, pharmaceuticals, etc. In these instances, poor water treatment can cause defective products. Domestic water can become unsafe to drink if proper hygiene measures are neglected.


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

Water softening: - Water softening is the removal of calcium, magnesium, and certain other metal cat ionsin hard water. The resulting soft water is more compatible with soap and extends the lifetime of plumbing. Water softening is usually achieved using lime softening or ion-exchange resins. Chilling/Steam unit :  Chiller A chiller is a machine that removes heat from a liquid via a vaporcompressionor absorption refrigeration cycle. This liquid can then be circulated through a heat exchanger to cool equipment, or another process stream (such as air or process water). As a necessary byproduct, refrigeration creates waste heat that must be exhausted to ambient or, for greater efficiency, recovered for heating purposes. Concerns in design and selection of chillers include performance, efficiency, maintenance, and product life cycle environmental impact. In industrial application, chilled water or other liquid from the chiller is pumped through process or laboratory equipment. Industrial chillers are used for controlled cooling of products, mechanisms and factory machinery in a wide range of industries.  Boiler A boiler or steam generator is a device used to create steam by steam by applying heat energy to energy to water . A boiler or steam generator is used wherever a source of steam is required. The form and size depends on the application: mobile steam engines such as steam locomotives, locomotives, portable engines and engines and steam powered road vehicles typically vehicles typically use a smaller boiler that forms an integral part of the vehicle; stationary steam engines, engines, industrial installations and power stations will usually have a larger separate steam generating facility connected to the point-of-use by piping.

AIR HANDLING UNIT (AHU) An Air Handling Unit (most of the times abbreviated to AHU), or Air Handler, is a central air conditioner station that handles the air that, usually, will be supplied into the buildings by the ventilation ductwork (connected to the AHU).Handling the air means that the air will be delivered into the building spaces with thermo-hygrometric and IAQ (Indoor Air Quality) treatment. The accuracy of the treatment will depend from the specificity of each project,). This means, the Air Handling Unit treat the air by filtering, cooling and/or heating, humidifying and/or dehumidifying. EFFLUENT TREATMENT PLANT (ETP) Industries use water that obtained from the water treatment s ystem for a variety of purposes, such as for manufacturing goods, heating, cooling, carrier of raw material, carrier of waste matter, as a


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Training Report | Cadila Pharmaceutical Limited solvent etc. The resulting water is then classified as a wastewater.The indiscriminate discharge of these wastewater streams into the environment can - Render soils "sick ". - Pollute the receiving bodies of water. - Cause air pollution by generating obnoxious gases To prevent any health hazards caused by discharging wastewater into the environment and protect domestic sewage, the wastewater must be treated before discharge. Screening

The first unit operation encountered in wastewater-treatment plants is screening. A screen is a device with openings, generally of uniform size that is used to retain the coarse solids found in wastewater. According to the size of openings, screens are designated as coarse or fine. Coarse screens have openings of ¼ inch or more, and fine screens have openings of less than ¼ inch.

Oil Separation

It is a process in which Floatables, namely non-emulsified oil and organics separates from wastewater. The design of the separator is based on the specific gravity difference between the oil and the wastewater and between the suspended solids and wastewater. In general, this separator can handle very large flow. However, its disadvantage is the long retention time required for efficient oil separation. Flow Equalization

Flow equalization is used to overcome the operational problems caused by flow variations, to improve the performance of the downstream processes, and is also used as an emergency tank to equalize wastewater effluent in case of any process failure in the treatment process.The design must provide for sufficient mixing to prevent solids deposition and concentration variations and also to provide aeration to prevent odor problems.

Sedimentation

Sedimentation is the separation from water, by gravitational settling, of suspended particles that are heavier than water.Sedimentation is used for separation of grit and particulate matter in the primary settling basin, separation of biological-floc in the activated-sludge settling basin, and separation of chemical-floc when the chemical coagulation process is used. It is also used for solids concentration in sludge thickeners. Sam Higginbottom Institute of Agriculture, Technology & Sciences (SHIATS) Allahabad.

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Training Report | Cadila Pharmaceutical Limited Neutralization

Industrial wastes often contain acidic or alkaline components which require neutralization before discharge or treatment. For wastes that are discharged to receiving waters, a pH between 6 and 9 is frequently specified by regulatory agencies. For wastes entering biological treatment processes, the pH should be maintained between 6.5 and 9 for optimum growth of the microorganisms. Acidic wastes are commonly neutralized with waste alkaline streams, lime, dolomite, ammonia, caustic soda, or soda ash.Lime is the most widely used alkaline material for neutralization acid wastes because of its low cost. Lime may be slow to react and may form insoluble precipitates.Alkaline wastes usually require treatment with a waste acidic stream, sulfuric acid or hydrochloric acid. Activated Sludge

The conventional activated sludge system contains a tank for wastewater aeration followed by a settler and solids recycle line.The wastewater flows through under constant aeration in the presence of activated sludge and exits at the end of the tank after 4-8 hours of residence time. The oxygen concentration in the reactor should be 0.5-2 mg/l throughout, where values over 2 mg/l are considered lost energy. Extended Aeration is the modified form of a conventional activated sludge process in which the production of excess sludge is minimized by oxidation and an increase in residence time, i.e. through the larger size of the aeration tank.The retention time is extended to 1-2 days, which results in a very low net yield of sludge due to its consumption of endogenous endogen ous respiration.


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Training Report | Cadila Pharmaceutical Limited RAW MATERIAL AND FINISHED GOODS SECTION RAW MATERIALS

A raw material , also known as a feedstock or or most correctly unprocessed material , is a basic material that is used to produce goods, finished products, energy, or intermediate materials which are feedstock for future finished products. As feedstock, the term connotes these materials are bottleneck assets and are highly important with regards to producing other products. Pharmaceutical raw materials comprise substrates or elements that are used for manufacturing different types of drugs e.g. endocrine disorder drugs, musculoskeletal system drugs, antiinfective drugs viz. cephalexin, cephalexin, penicillin, ampicillin, cephradine, cephradine, etc. Pharmaceutical excipients and ingredients or raw materials used to manufacture drugs are extracted from different types of sources. These sources could be natural or synthetic. Recently, many of the raw materials previously derived from natural sources are being produced synthetically in part or even biotechnologically. This is so because manufacturing them artificially is economical, safer, and much quicker. Pharmaceutical raw materials are manufactured using different types of acids, alcohols, esters, phenones, pyridines, etc. Pharmaceutical raw materials are essential to producing pharmaceutical drugs and include active pharmaceutical ingredients (API), also known as bulk active, are pharmaceutically active, and have the desired pharmacological effects on the body e.g. alvimopan, sparfloxacin, sparfloxacin, sapropterindihydrochloride, lanreotideacetate,nicotinic lanreotideacetate,nicotinic acid, acid, etc. In contrast pharmaceutical excipients are the pharmaceutically inert substances which help in delivering the active ingredient, e.g. antiadherents, binders, coatings, disintegrants, fillers, etc. STEPS INVOLVE IN RAW MATERIAL WAREHOUSE 

receiving



sampling



storing



dispensing

RECEIVING  raw material is supplied by vendors by placing order  after receiving the raw material check the “observation on pack”  segregate the raw material according to batch number  pre entry cleaning of raw material by vacuum cleaner  weighing of the raw material


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Training Report | Cadila Pharmaceutical Limited SAMPLING  before sampling get line clearance by QA person

sample of raw material material under LAF by different tests and and fill it in  QC person test the sample “observation on sampling area &pack ” and “certificate of analysis ”  warehouse operators will paste the labels of “approvedlabel ” and “sampledlabel ”  next sent raw material for storing

STORING  the raw material is stored at 3 different temperature zones 

Ambient: not more than 35 °c



Controlled temperature room: 15 to 25 °c



Cold room: 2 to 8 °c

Temperaturepoint: It is the point where the temperature is checked by placing digital thermometer on daily basis DISPENSING  Raw material is picked for dispensing according to “ materialpicklist for process order”

and dispensed according to BMR prepared by QA personnel  Selection of raw material is done according to “firstexpiryfirstdispense ”  Raw material is dispensed from dispensing booth under LAF to the production area

FINISHED GOODS

goods that have completed the manufacturing manufacturing process but have not Finished goods are goods yet been sold or distributed to the end user. A good purchased as a "raw material" goes into the manufacture of a product. A good only partially completed during the manufacturing process is called "work in process". When the good is completed as to manufacturing but not yet sold or distributed to the end-user, it is called a "finished good". This is the last stage for the processing of goods. The goods are ready to be consumed or distributed. There is no processing required in term of the goods after this stage by the seller.


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Training Report | Cadila Pharmaceutical Limited PROCEDURE 

Receive the finished good transfer ticket from production duly authorized by production supervisor and checked by QA



Following are to be made in finished good transfer ticket after received from production  Name of product  Batch No.  Manufacturing date  Expiry date  Quantity (No of box x per pack)  Date of transfer tickets



Verify the received goods against transfer with above d etails



Ensure the all details are complete as per out requirement



In case of any observation, intimate to production department and get it corrected



Enter the physically verified quantity in SAP system.


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Training Report | Cadila Pharmaceutical Limited CONCLUSION Industrial training is very much essential for Pharmacy Students. It is also a great opportunity to acquire practical knowledge. During my training period, in the industry I acquired lots of experiences in Pharmaceutical Production and Production management. This will help me toclarify my theoretical knowledge. I hope and pray that it will help me much in my future profession. During our training period, we had seen various instruments and apparatus in the industry. The highly sophisticated instruments that work precisely must be operated with intense care for optimum use. We could acquire a lot of information regarding the latest instruments and their working procedures. It was taught to us that, the CGMP guidelines a re to be strictly followed in the industries indu stries in each and every section. And the same guideline was seen followed in Cadila Pharmaceutical Limited (J&k). It helped us to acquire knowledge on punctuality, regularity and working environments in industries. Training in cadila reshape my mind in different sectors based on education, communication and interactions, zero determination of error, commercialization and many more.


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Training Report | Cadila Pharmaceutical Limited BIBLIOGRAPHY  Cadilapharma.com

 Wikipedia

 www.slideshare.net

 GPAT Cracker

 Standard Operating Procedure Records (SOPs)

 Batch Manufacturing Records (BMRs)


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Cadila Industrial Training Report

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