industry report

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A REPORT ON IN-PLANT TRAINING AT ELDER UNIVERSAL PHARMACEUTICALS (NEPAL) PVT.LTD. For the partial fulfillment of the requirement for the Degree of Bachelor of Pharmacy Submitted By Rudra Pangeni School of Health and Allied Sciences Pokhara University, Kaski, NEPAL September, 2011 Submitted To Department of Pharmacy School of Health and Allied Sciences Pokhara University

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A REPORT

ON IN-PLANT TRAINING AT ELDER UNIVERSAL PHARMACEUTICALS

(NEPAL) PVT.LTD.

For the partial fulfillment of the requirement for the Degree of Bachelor of Pharmacy

Submitted By

Rudra Pangeni

School of Health and Allied Sciences Pokhara University, Kaski, NEPAL

September, 2011

Submitted To

Department of Pharmacy School of Health and Allied Sciences

Pokhara University

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This is to certify that Mr. Rudra Pangeni has successfully completed the three weeks in-plant training (Industrial Internship) at Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd. from September 12, 2011 to September… , 2011 for the partial fulfillment of the requirement for the Degree of Bachelor of Pharmaceutical Science.

…………………….. …… Mohammad Safi Ulha

General Manager

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ACKNOWLEDGEMENT

It is my privilege and opportunity to complete my in-plant training (Industrial Internship) at Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd. I would like to thank Elder Universal for allowing me to complete my internship program which is the part of my B.Pharm. Syllabus. I would like express my sincere thanks to Associate Prof. Gulam Mohammad Khan, Program Coordinator, Department of Pharmacy, School of Health and Allied Sciences, Pokhara University for arranging to carry out the industrial internship program along with the continuous support throughout the training period. I am very grateful to Mr. Noor Pratap J.B. Rana, Chairman, Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd. for providing the chance to do the training. I am also very grateful to Mr. Mohammed Safi Ulha, General Manager, Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd. for his continuous and valuable support, guidance, encouragement and supervision throughout the training period. I am deeply obliged to Phr. Asgar Ali Mikarani, Quality Assurance Manager for his continuous support, supervision, comments and encouragement. I would also like to express my gratitude to Mr. Rajesh Jha, Production Manager for providing me with the practical knowledge on formulation of various dosage forms, instruments and equipments used in production department along with various IPQC procedures. I would like to express my sincere thanks to Mr. Pradeep Jayshswal, Quality Control Manager, for providing me continuous information about the equipments, instruments, analytical procedures used for the pharmaceutical materials along with the chemical analysis procedure.

My special thanks go to Phr. Ram Prakash Mandel, Phr. Yuga Raj Sapkota for providing practical knowledge in the production department. Likewise, I would like to express my thanks to Mr.Ghanashyam Majhi, Department of Microbiology and Mr. Shrawan Kumar Kohar for providing practical knowledge in Quality control department. I am also grateful to Mr. Bhairav Silwal, Store Incharge and …… Finally, supports from all the operators, staffs and workers in three weeks in-plant training will be memorable. . Rudra Pangeni

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ABSTRACT It is a matter of great pleasure for me to be a trainee at Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd., one of the well known, highly equipped, and sophisticated and WHO-GMP certified pharmaceutical company of Nepal. During my training at Elder Universal, I was posted to different departments of the company such as Production, Quality Control, RO, Maintenance and Store. I have taken this opportunity as to gain practical knowledge on these departments. I got aware of importance of documentation and the various documents used in a pharmaceutical industry. I also understood the role of pharmacists in a pharmaceutical industry. Thus, this training was very helpful for me.

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INTERNSHIP SCHEDULE

S.No. Department Date

1. Production Sep 12-Sep 18 2. Quality Control Sep 19-Sep 25 3. RO & Maintenance Sep 26 4. Store Sep 27 5. Report Preparation Sep 28 onwards

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Objectives To get, feel and overview of working environment in a pharmaceutical industry. To obtain the practical knowledge of formulations of different drugs. To use the knowledge taught and experiences gained in the lecture rooms in the

real industrial training situations. To get expose to different formulation and engineering which are not covered in

lectures. To get the exposure about the ethics and responsibilities of a pharmacists. To learn practically the working principles of different instruments. To obtain the complete knowledge about production, Quality control and Quality

Assurance along with their complete documentation. To learn about the inventory control and storage of raw materials along with

finished medicines. To get familiar with the plant layout, analytical instruments, microbial testing,

real and accelerated time study, water treatment and so on.

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List of Abbreviations AC Air Conditioning AHU Air Handling Unit BMR Batch Manufacturing Record BPR Batch Packaging Record BP British Pharmacopoeia FBD Fluidized Bed Drier GMP Good Manufacturing Practice HEPA High Efficiency Particulate Air HVAC Heating Ventilating Air Conditioning IP Indian Pharmacopoeia IPA Isopropyl Alcohol IPQC In-Process Quality Control MFR Master Formulation Record PVC Polyvinyl Chloride QA Quality Assurance QC Quality control RH Relative Humidity RMG Rapid Mixer Granulator SOP Standard Operating Procedure

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Table of Contents

1. Introduction 1-

2. Production

3. Quality Management

3.1

3.2

4. Reverse Osmosis

5. Maintenance

6. Store

7. Conclusion and Recommendation

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INTRODUCTION

Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd. is a WHO-GMP certified company which was established in 2006. Since then it has been working continuously for providing quality drug as per the need of the nation. Quality product is attained as a result of a proper and well managed system, good manufacturing practices, modern sophisticated and high capacity production machineries, well equipped quality control laboratory, highly devoted and competent personnel’s along with the sensible and prompt acting management system for standard and quality production. Elder Universal has also poured its focus on the research in process technology and dosage form design, environmental policy as air, water and solid waste management as per the national and WHO-GMP standards. It has been looking for the robust formulation which enables to shorten the development time and to increase the product quality. It has a close cooperation with other pharmaceutical industries.

Elder Universal Pharmaceuticals is a large scale industry that is mainly focused on the production of quality medicines. There are two production departments namely β-Lactam and non β-Lactam departments. Both the department contains sufficient machineries for conducting separate production of quality medicines. As quality is never attained as an accident, it has been using a intelligent efforts for the medicines. The industry is involved in the production of following dosage forms:

Tablets Capsules Dry Syrups Liquids Ointments

However, ointment products are under the trial. Location Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd. is located in Chilhiya-2, Bhairahawa, Rupandehi, Lumbini, Nepal which is 4 km north from Bhairahawa market. It is built outside the industrial state in a silent and open area. Hence there is less risk of environmental hazards due to the establishment of the pharmaceutical industry.

Premises

The production unit is according to the requirement of DDA with complete separation of grey and black area. The β-Lactam and non β-Lactam units are in separate blocks as per the WHO-GMP guidelines.

Area of β-Lactam building- 6833.88feet2 Area of non β-Lactam building-14903.0 feet2

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The building is of brick wall plastered with smooth cement and painted with epoxy paints. Floors are painted with labeling epoxy paint without any cracks and gaps, so they can be easily cleaned with detergents as per the SOP. The joints between walls and floors are curved so to prevent the accumulation of dust. The doors are made of aluminum with glass in all areas. The opening of the doors are maintained according to the pressure i.e. Positive or Negative.

List of Products formulated in Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd.

SN Product Name Dosage form 1. Cefi-100 Tablet 2. Cefi-200 Tablet 3. Cefi-50 DT Tablet 4. Cepodox-50 DT Tablet 5. Cepodox-200 Tablet 6. Unidrox-125 DT Tablet 7. Cepodox-100 Tablet 8. Unidrox-250 DT Tablet 9. Amifru-S Tablet

10. Cefi-100 DT Tablet 11. Amifru 40 Tablet 12. Cefi-400 Tablet 13. Cefi-200 DT Tablet 14. Flavoxate Tablet 15. Widcef-250 Tablet 16. Widcef-500 Tablet 17. Aceflam-500 Tablet 18. Elderaze-250 Tablet 19. Elderaze-500 Tablet 20. Cepodox-100 DT Tablet 21. Megaclox-500 Capsule 22. Unidrox-500 Capsule 23. Unifclor-250 Capsule 24. Unifclor-500 Capsule 25. Unimox-500 Capsule 26. Upiclox-500 Capsule 27. Unilexin-500 Capsule 28. Uilexin-250 Capsule 29. Cefi- 30ml Dry syrup 30. Unidrox- 30ml Dry syrup 31. Unifclor-30ml Dry syrup 32. Unimox-60ml Dry syrup 33. Megaclox-60ml Dry syrup 34. Unilexin-60ml Dry syrup

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35. Mint guard mixed Suspension 36. Mint guard mint Suspension 37 Elitvate -200 ml Syrup 38. Univit-100 ml Syrup 39. Univit-200 ml Syrup 40. FIFA-100 ml Syrup 41 FIFA- 200ml Syrup

Organizational structure of Elder Universal Pharmaceuticals (Nepal) Pvt. Ltd.

Chairman

General Manager

Quality Control Manager

Production Manager

QC Officers

Microbiologist

Sr. Production Officer

Production Officer

QA Manager

Eng. In-charge Human Resource Head

Account Officer

Store In-charge

QA/IPQC Officer

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QUALITY MANAGEMENT Elder-Universal believes “The endeavor to provide quality products can only come through continuous technological development and improvement in products, process and service, constant optimization in technique and a trained motivated workforce. This in turn requires management and employees to work together as a team to support the quality initiative and continuous reviewing performance to ensure the achievements of the objectives.”

QUALITY CONTROL QC is the department which ensures that the initial, intermediate, final product as well as all the raw materials are pure, safe and effective and are released only after thorough analysis as per stringent specifications, methods and procedures developed according to international guidelines. Along with the laboratory operations, QC is also involved with all decisions concerning the product quality. QC laboratory has almost all necessary instruments for analysis of API, finished products, packaging and related materials used. QC department mainly deals with analysis of

Raw materials and Packaging Materials Intermediate bulk Finished products Stability studies

Raw material analysis and Packaging Materials Analysis Procured Label

Raw Material Packaging Materials

Receipt and Quarantine

Verification

Sampling by QA/ QC

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Fig: Raw material and Packaging material Inspection Intermediate product analysis Fig: Intermediate Products Investigation Finished product analysis

Under Test

QC Testing

Approved Rejected

For Manufacturing Return to Supplier/ Destruction

Received In-process requisition along with sample

Testing as per the specification

Result conveyed to production

Batch completion of Finished Products

Sampling by QA

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Fig: Finished Products Investigation Stability studies Stability studies are a critical part of the drug development process and are essential for any drug product marketing approval. They are carried out at all phases of the drug development cycle for different purposes with the ultimate goal of having a stable product on the market. Any new products manufactured within the pharmaceuticals is subjected to accelerated stability studies in a humidity chamber which subjects the products to extreme of temperature(40±2˚C) and humidity (75±5%) in order to test the stability period. For any marketed batch, samples are taken in a room with control samples and kept up to expiry date periods to check real time stability studies. All these testing processes are carried out in the separate areas. The main areas of QC are divided into followings:

Instrumental Analysis Room Chemical Laboratory with raw material testing Microbiology Laboratory Real Time and Accelerated testing Room

Instrument Room I grabbed the opportunity to use different instruments in various quality control activities in QC laboratory. Mostly I tried to learn the principle and application of the instruments practically. The instruments used for QC activity are as follows:

Melting point apparatus- Thermonic MBP-708 Digital Hardness Tester- Thermonic C-DHT100 Tablet Friability Test Apparatus- Thermonic C-FT20 Bulk Density Apparatus- Thermonic C-BO-100 Micro pH meter- Systronics 361 Dissolution Tester (8 vessel)- Electrolab TDT-08L Tablet Disintegration Tester- Thermonic C-TD-20

Under Test

QC Testing

Preparation of Report and Checking

Approved Rejected

For Manufacturing Reprocess/ Destruction

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Karl Fischer Titrator UV spectrophotometer- Thermo Electron Nicolet Evo;ution-100 Polarimeter Electronic Balance UV Chamber Dessicator

Chemical Laboratory Chemical laboratory of QC in Elder Universal Pharmaceuticals was well managed. All the required reagents are labeled alphabetically in the racks. Chemicals are well separated. It also contains fume removing hood. The instruments used in chemical laboratory are as follows:

Water bath- Sonar Hot air oven- JRIC-7A Vacuum oven with vacuum pump-JRIC 8A Muffle furnace- JRIC- 12A Magnetic stirrer-Sonar Distillation chamber

Every equipment has their own SOPs (Standard Operating Procedures) attached near them. There is proper documentation after any of the equipments is used. The process is according to the standard procedures which are validated and are well documented. For the analysis recommended pharmacopoeias are referred:

United States Pharmacopoeia; 2004 British Pharmacopoeia; 2005 Indian Pharmacopoeia 1996 and 1997

Microbiology Laboratory Microbiology department has the major responsibility of routine testing of drugs as well as environments, complete water analysis; limit test, identification of pathogens by culture and microbial tests of raw materials. Various equipments used in the microbiology lab are:

Autoclave steam sterilizer Bacteriological trays with two trays Hot air oven Horizontal laminar airflow

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QUALITY ASSURANCE (QA) Quality Assurance department in any pharmaceutical company is responsible to ensure the quality of the product manufactured under its supervision as it is important integral of Quality Management System. The process of the product manufacturing, analysis, sampling, cleaning and sanitation are validated under the supervision of quality assurance department. This department is responsible for Maintaining WHO-GMP standards Monitor the performance of quality system and analyze the effectiveness Assure the validation of manufacturing procedure Assure regulatory and company standard Approve master processing procedure, master packing procedure and master analytical

procedure Perform self-inspection and GMP training Handle product complaint and product recall Check filling and packaging as well as critical manufacturing operation Perform the periodic inspection raw materials, bulk product and finished product storage

areas Review and update master formula record and related documents Supervise the disposal of returned goods and salvaging operations Supervise the change control system and approve change

Documents Documentation: Do what is written, Write what you have done Good documentation constitutes an essential part of the quality assurance system. The preparation, distribution and revision of all necessary documents are controlled by QA department in coordination with all departments. The following documents are prepared, maintained and used as per their requirements: Site master file Raw material specification Micro SOP Finished product specification QC SOP Master SOP warehouse Master validation Master Batch Manufacturing Records (BMR) Quality manual PM specification

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PRODUCTION The department is concerned with the production of various pharmaceuticals products. The section under the production department is cited below:

Tablet section Capsule section Dry syrup section Liquid section

Tablet Section In the tablet section, we were able to go through the manufacturing procedures of following products:

Cefi-200 (Cefixime 200mg) Cepodox-200 (Cefpodoxime proxetil tablet)

Manufacturing procedure The general steps involved in the manufacturing process of tablet dosages forms are given below: Shifting The active pharmaceutical ingredients along with excipients must be passed through appropriate sieve in order to break any lumps and obtain fine. Mixing All the excipients along with active ingredients are appropriately mixed in RMG for suitable period of time. Wet Granulation In some cases, to assure the content uniformity the mixed powders are wet granulated. Example: Amifru 40. Drying After granulation, granules are dried in FBD at approximately 45˚c for 30-45 minutes. Sieving After final drying, the granules are passed through the appropriate size to obtain granules of desired size. Lubrication

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The final dried sieved granules are now mixed with appropriate quantity of suitable lubricant in octagonal blender for specified time. Now the bulk is ready for compression. QC sampling Once the lubrication is over, the intermediate bulk is sent to QC for analysis. Only after obtaining the analysis report from QC department, the product is forwarded for further compression. Compression After obtaining the bulk product analysis report from QC, the granules are taken for compression. Coating Coating is required to prevent moisture permeation from product and also to mask the unpleasant taste of product. Equipments used: The following equipments are used in the tablet section:

Vibro shifter RMG FBD Multi-mill Octagonal blender Paste maker Tray Dryer 20 and 29 Station compression machine (Single Rotatory) 28 Station compression machine (Double Rotatory) Coating pan with hot air oven Tablet inspection machine Strip packaging machine Blister packaging machine

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Capsule Section Manufacturing procedure: The basic steps involved in manufacturing of the capsules are:

Equipments used: The following equipments are used in capsule section:

Vibro shifter Octagonal blender Semi-automatic capsule filling machine Capsule sealing machine Capsule sorting machine Capsule polishing machine Strip packaging machine

Raw materials dispensed: Received by production

Sieving using the sieve of suitable mesh size

Mixing all the ingredients in octagonal blender

Empty gelatin capsule loaded

Filling in semi-automatic capsule filling machine

Sorting and polishing

Packaging

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Dry Syrup Section The product manufactured in this section during our training was Cefi Dry syrup. Manufacturing procedure The basic process involved in the manufacturing of dry syrup is: Drying The sugar was dried in FBD. Milling Milling of dried sugar was done in multi mill. Sieving Sieving of all excipients, flavor, color and active ingredients was done in shifter to get the desired size. Mixing The mixing of the ingredients is done in octagonal blender. Filling The product is now ready for filling and transferred to dry syrup filling area where the powder is filled by semi automatic dry syrup filling machine. The filled bottle is then subjected to visual inspection test and then labeled and packed. Equipments used: The following equipments are used in the dry syrup section:

Bottle washing machine FBD Octagonal blender Semi automatic dry syrup filing machine Cap sealing machine Humidity controller

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Liquid Section For syrups and suspensions, water is DM water, It consists of following sections:

Primary syrup preparation room

Final syrup Preparation room

Filling/sealing room

Packaging room

Equipments used in liquid section are:

Primary syrup Preparation Tank.

Mixing tank(Baffled type)

Colloid mill

Transferring pump

Filter pads

Automatic filling and sealing machine

Automatic labeling machine

Rotary bottle washing machine

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IN-PROCESS QUALITY CONTROL (IPQC)

To monitor the overall activities of the manufacturing area, an IPQC section is also set up in manufacturing area. The main objective of IPQC is to ensure that is manufacturing process is going on properly and no deviation arises from the specification. The IPQC looks after all the products in both penicillin and non penicillin section of the factory. The following equipments are used in IPQC section

Leak test apparatus Frability test apparatus Digital balance Tablet DT machine Hardness tester

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OTHER SECTIONS 1. Store Sections The store section consist of 3 sections

Raw material store Packaging material store Finished product store

Raw material store Raw material store is situated in the ground floor. Raw material in this section is tagged containing: name of raw material, lot number, manufacturing date, expiry date, gross weight, net weight, manufacturing license and manufacturer’s name. Now the sampling of the raw material is done. The sample under test is given a tag containing: name of material, batch number, and manufacturing date, expiry date, sampled by, manufacturer and sampling date. After sampling, if it is approved by QC department, it is dispensed to the production along with analytical report no. The tag of the dispensed material contains: batch number, analytical report no, gross weight, net weight and tare weight and the sign of store in-charge. Active materials are stored in a thermolabile raw material room whereas other materials are stored at the prescribed temperature as required. Packaging material store For the storage of packaging material control environment is not required so they are stored at a room temperature. Finished Product Store The finished product is packed well and stored. The finished products are then stored in a finished goods quarantine. The tag contains the following information about the product; product trade name, batch number, manufacturing date, expiry date, packaged quantity, pharmacist sign and shipper no. FIFO and FEFO system are followed for dispatching finished goods. Documentation in store section

Raw material inventory card Packaging material inventory card Secondary packaging inventory card Raw material requisition file Raw material analysis report Raw material invoice file Packaging material test report Temperature and humidity record

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2. Packaging Section Primary packaging section This area is for the primary packaging of tablets and capsules. The room is maintained at the optimum temperature and humidity depending upon the product type. This section is again divided into: strip packaging and blister packaging. Strip packaging: For the products that are highly sensitive to light and moisture strip packaging is done. The primary packaging material is opaque plastic coated aluminum foil which provides barrier to light and moisture. This packaging is expensive compared to blister packaging. The packaging material is previously printed with the information about the product and batch number, manufacturing date, expiry date are printed simultaneously in the machine itself during the packaging. Heat sealing is done at155˚c aided by the layer of vinyl methylcellulose in either foil. The pocket formed varies depending upon the size of tablets and capsule. After sealing, they are cut into desired strip and are directed towards the secondary packaging room. Blister packaging: It is done for the products that are not much sensitive towards light and moisture. The film heater heats the poly vinyl chloride and poly vinyl dichloride and the pockets are formed by creating vacuum and heating at 150˚c. These pockets are released after cooling. When the tablets and capsule is filled in each pocket sealing is done by heating at 192˚c. After sealing they are cut into desired blister size and directed towards secondary packaging. Secondary Packaging section After the primary packaging is done, the product moves into secondary packaging room where the products are packed manually. As this section falls in black area the mode of separate entry is made with the change rooms. The packaged material is then moved into the finished goods quarantine. Documentation in packaging section;

Labels Specification and testing procedure Master formula Packaging instruction Batch manufacturing record Batch packaging record SOP and related records

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3. Engineering and Maintenance Department The engineering department is self sustaining and promising in terms of the service it is providing to the company. The department is concerned with the maintenance and installing of all the machines and utilities present in the plant. This department is involved in handling of heating ventilation an air condition (HVAC) system, water treatment and breakdown and prevention maintenance. Air Handling Unit (AHU) An integrated air-handling unit composed of different sub-units handles the air supplied to the different sections. The atmospheric air is collected and passed through different filters to the compressor. The types of filters are:

Pre-filter with the pore size of 10µ and is washable Bag filter with the pore size of 0.5µ and is not washable Terminal filter (with HEPA filter) with the pore size of 0.3µ Return filter

Then the compressed air is allowed to cool and the chilled air is distributed to the different departments. Air supplying system varies in the different departments.

Chilling method in non β lactam section Direct compression system in penicillin block Recirculation and fresh air in corridor.

Water Treatment Pretreatment of water For the pretreatment, water is sent to sand filter, carbon filter, resin filter and finally to micro filter. Sand filter and carbon filter removes the turbidity and odor resply of the water. Water softener The water from the carbon filter is then passed into resin filter to remove the hardness. Reverse osmosis The water is then passed through the semi-permeable membrane in opposite direction of osmosis using pressure. RO water is then passed through catridge filter of 1µ and water is then passed through pump to UV light, ozone generator and to outlet. Boiler Elder-Universal has the boiler plant for the generation of the steam.

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CONCLUSION AND RECOMMENDATION After the completion of In-plant training in Elder-Universal Pharmaceuticals, we found that the company is dedicated to produce quality medicine and at the same time preserving the environment. We learned the various aspects of Pharmaceutical Management and production during the period. We found all the staffs very friendly and cooperative. The physical environment of the company is definitely one of the exemplary in the nation. We found that company need to develop wide range of therapeutic category to meet the needs of general public. We hope that the bilateral relation between Pokhara University and Elder-Universal Pharmaceuticals would flourish much in the years to come. At last but not the least we would like to extend our best wishes to Elder-