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omagor nicholas

This document is an industrial training report submitted by Omagor Nicholas, a second year chemical engineering student at Kyambogo University. The report details his 8-week industrial training at Cipla Quality Chemical Industries Limited (CiplaQCIL), a pharmaceutical manufacturing plant in Kampala. The report includes sections on quality assurance, stores management, quality control, production processes, and engineering systems at the plant. It also discusses the objectives and methodology of the training, as well as lessons learned and recommendations.

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KYAMBOGO UNIVERSITY TITLE: INDUSTRIAL TRIANING REPORT NAME OF STUDENT: OMAGOR NICHOLAS REG. NO: 13/U/7251/CHE/PE YEAR OF STUDY: YEAR II ACADEMIC YEAR: 2014/2015 PROGRAM OF STUDY: BACHELOR OF SCIENCE IN CHEMICAL ENGINEERING NAME OF INDUSTRY: CIPLA QUALITY CHEMICALS INDUSTRIES LTD
i DECLARATION I OMAGOR NICHOLAS a student of KYAMBOGO UNIVERSITY declare that I have written this report myself as an academic requirement. All the material contained in this report is an original record of the work and activities I was involved in during my industrial training at CIPLA QUALITY CHEMICAL INDUSTRIES LIMITED (CiplaQCIL). …………………………………
ii APPROVALS This is to certify that OMAGOR NICHOLAS had his industrial training for eight weeks here at CiplaQCIL and that this report is a true record of the work he did under our supervision. Signature……………………………….. Date…………………………………… Mr. JOHN KAMILI INDUSTRIAL SUPERVISOR Signature………………………………… Date……………………………………. Mr. MANANO JOHN ACADEMIC SUPERVISOR
iii DEDICATION This document is dedicated to my dear parents Mr. and Mrs. Enginyu, lecturers of Kyambogo University, the staff of CiplaQCIL and to my fellow class mates. It is most especially dedicated to those who directly or indirectly assisted during my training at CiplaQCIL.
iv ACKNOWLEDGEMENTS It is always a pleasure to remind the fine people at CIPLAQCIL for the sincere guidance I received to uphold my practical as well as theoretical skills in engineering. Firstly, I would like to thank CIPLAQCIL for convincing me on the saying that “Whatever is imagined, can be achieved”, treating me as an employee of their own and guiding me to the real flavour of engineering discipline. Secondly, I would like to thank the staff at CIPLAQCIL for the positive attitude they should for my work, always allowing me to question them and giving prompt replies for my uncertainties in all the fields including educational, social and managerial to labor work. Thirdly I would like to thank Ms. Achen Irene of Department of quality assurance and Mr. Kamili John regulatory affairs executive for extending their friendship towards me and making a pleasure-training environment at the factory. A paper is not enough for me to express the support and guidance I received from them almost for all the work I did there. Mr. Manano John our academic supervisor for checking on us at the factory and giving us support on how to go about with the training. Opening our minds on some areas we didn’t raise queries in the training. I thank all the trainees who underwent training with me the mutual support I received from them. Department of chemistry Kyambogo is much thanked for allowing me to have my training in CIPLAQCIL. I also would like to thank my family for the support they gave to me during this whole internship period making sure I turn up on time and all that I can’t mention. Finally I apologize all other unnamed who helped me in various ways to have a good training Knowledge is power and unity is strength.
v ABBREVIATIONS; ACF-ACTIVATED CARBON FILTER AHU-AIR HANDLING UNIT API- ACTIVE PHARMACEUTICAL INGREDIENT ARV-ANTI RETROVIRAL BMR-BATCH MANUFACTURING RECORD BPR-BATCH PACKAGING RECORD CAPA- CORRECTIVE AND PREVENTIVE ACTION cGLP- current GOOD LABORATORY PRACTICES cGMP – current GOOD MANUFACTURING PRACTICES CiplaQCIL –CIPLA QUALITY CHEMICALS INDUSTRIES LIMITED DT-DISINTERGRATION TIME EDTA- ETHYLENE DIAMINO TETRA ACETIC ACID EFV- EFAVIRENZ ETP- EFFLUENT TREATMENT PLANT FAT-FACTORY ACCEPTANCE TEST FBE-FLUIDIZED BED EQUIPMENT FIFO/FEFO-FIRST IN FIRST OUT /FIRST EXPIRY FIRST OUT GC-GAS CHROMATOGRAPHY GMP-GOOD MANUFACTURING PRACTICES GRN- GOODS RECEIVED NOTE
vi HDPE- HIGH DENSITY POLYETHENE HPLC-HIGH PERFOMANCE LIQUID CHROMATOGRAPHY HVAC-HEATING, VENTILATION AND AIR CONDITIONING SYSTEM IPA-ISOPROPYL ALCOHOL IPQC-IN PROCESS QUALITY CHECKS IRS – INFRA RED SPECTROSCOPY LAF-LAMINAR AIR FLOW MGF-MULTIGRADE FILTER MIPC-MACHINERY IN PROCESS CONTAINER NDA-NATIONAL DRUG AUTHORITY NMT-NOT MORE THAN NWSC-NATIONAL WATER AND SEWAGE COOPERATION PVC-POLYVINYL CHLORIDE QA-QUALITY ASSURANCE QCIL-QUALITY CHEMICALSINDUSTRIES LIMITED QC-QUALITY CONTROL R&D- RESEARCH AND DEVELOPMENT RH-RELATIVE HUMIDITY RMG-RAPID MIXER AND GRANULATOR RO-REVERSE OSMOSIS SAT-SITE ACCEPTANCE TEST
vii SCA-SUBAROUD CHLORAMPHENICOL AGAR SCDA-SOYA BEAN CASEIN DIGEST AGAR SDI-SLIT DENSITY INDEX SMB-SODIUM METABISULPHATE SMG-SAIZONER MIXER, GRANULATOR SOPs- STANDARD OPERATING PROCEDURES SPV-SOLUTION PREPARATION VESSEL SS-STAINLESS STEEL TRIPS -TRADE RELATED INTELLECTUAL PROPERTY RIGHTS. UV-ULTRA VIOLET VMP-VALIDATION MASTER PLAN
viii ABSTRACT Industry training started on the 1st June for 8 weeks. Industrial training for undergraduates in Uganda universities is widely practiced. It provide hands-on experience and up-to-date information to the graduates who are about to enter the competitive job market. The report identifies specific approaches used for collecting the data on daily basis. It points out areas of experience gained from observations, interactions, hands on practice and analysis of data. The document highlights main findings of the training in the domain of management, unit operations, marketing, packing and storage that at all levels insured quality. However the report mentions some key challenges that could be useful in future review of field tools for chemical engineering students and recommends actions for future improvements. In conclusion, the report points out good practices in the industry, a linkage between theoretical exposure from the university and practical experience at the industry.
1 Contents DECLARATION................................................................................................................................ i APPROVALS................................................................................................................................... ii DEDICATION................................................................................................................................. iii ACKNOWLEDGEMENTS................................................................................................................iv ABBREVIATIONS............................................................................................................................v ABSTRACT...................................................................................................................................viii 1 INTRODUCTION AND BACKGROUND...................................................................................1 1.1 INTRODUCTION...............................................................................................................1 1.2 BACKGROUND.................................................................................................................1 1.3 OBJECTIVES OF TRAINING.............................................................................................2 1.4 TRAINING METHODOLOGY............................................................................................2 2 QUALITY ASSURANCE...........................................................................................................3 2.1 ROLES OF QA ...................................................................................................................3 2.2 GOOD MANUFACTURING PRACTICES. (GMP)..............................................................4 2.3 PHARMACEUTICAL QUALITY SYSTEM........................................................................4 2.4 cGMP .................................................................................................................................5 2.5 SELF INSPECTION:...........................................................................................................7 2.6 COMPLAINTS AND RECALLS:........................................................................................8 2.7 VALIDATION....................................................................................................................8 2.8 QUALIFICATION;...........................................................................................................10 2.9 DOCUMENTATION;........................................................................................................12 3 STORES...................................................................................................................................13 3.1 RECEIVING BAY AREA..................................................................................................14 3.2 RAW MATERIAL QUARANTINE AREA.........................................................................14 3.3 SAMPLING AREA. ..........................................................................................................14 3.4 APPROVED RAW MATERIAL AREA. ............................................................................15 3.5 DISPENCING...................................................................................................................15 3.6 PACKAGING MATERIAL STORES.................................................................................15
3.7 FINISHED GOODS STORE..............................................................................................16 4 QUALITY CONTROL..............................................................................................................17 4.1 WET CHEMISTRY...........................................................................................................22 4.2 WEIGHING SECTION......................................................................................................22 4.3 TITRATION and STANDARD AREA ...............................................................................23 4.4 WASHING AREA.............................................................................................................23 4.5 MICROBIOLOGY SECTION............................................................................................23 5 PRODUCTION.........................................................................................................................27 5.1 PRODUCTS OF CIPLAQCIL............................................................................................27 5.2 GRANULATION..............................................................................................................28 5.3 BLENDING......................................................................................................................32 5.4 COMPRESSION...............................................................................................................35 5.5 COATING ........................................................................................................................41 6 ENGINEERING........................................................................................................................45 6.1 BOILERS..........................................................................................................................46 6.2 CHILLER.........................................................................................................................47 6.3 HVAC system...................................................................................................................47 6.4 ETP ..................................................................................................................................48 6.5 WATER TREATMENT.....................................................................................................48 7 LESSONS LEARNT.................................................................................................................52 8 CHALLENGES ........................................................................................................................52 9 CONCLUSIONS.......................................................................................................................52 10 RECOMMENDATIONS.......................................................................................................53 11 REFERENCES......................................................................................................................53
1 1 INTRODUCTION AND BACKGROUND 1.1 INTRODUCTION Kyambogo University like any other university would like to maintain standards and integrity in the employment market so as their students are attractive to the future employeers.it is on this perspective the university emphasizes on both theoretical and practical training for their students .As for the program of bachelor of science in chemical engineering, usually at the end of semester two of your second or third year, one is granted the opportunity to take part in industrial training as part of the academic requirement. This is done under the supervision of the university and the factory technical personnel. 1.2 BACKGROUND According to the national development plan (2014/2015) the policy of the country prioritises on promotion of science and technology hence the need to support the training of science students especially engineers in order to reduce the human resource gap in economic development. In response to this government thru ministry of Education has made provisions for science students to go to university through student’s loan scheme and government sponsorship. The country relies more on imported human resource for its highly trained labour market .Kyambogo university is one of the beneficiaries among the public university. It is traditionally renowned for its competent engineers because of its emphasis on practical skills, partnership with local industries and institutions. In chemical engineering, there are number of chemical based industries which are in partnership with the university. They have state of the art modern facilities suitable for industrial training. Most of the industries are in support of the industrial training of students to increase potential source of labour. Potential industries in need of the chemical engineers include pharmaceuticals, food processing plants, oil refineries, breweries and mineral processing plants just to mention but a few. The university has therefore encouraged students to apply to any of the industries for placement, because they provide more knowledge, skills and practices for effective modelling of students for future employers. It is in view of this, I was fortunately selected by Cipla Quality Chemical Industries Limited (CiplaQCIL) against competing demands from other universities.
BRIEF INFORMATION ABOUT THE COMPANY: Cipla Quality Chemical Industries Limited (CiplaQCIL) is a state of the art pharmaceutical manufacturing plant located in Kampala, specializing in manufacturing Anti-retroviral drugs (ARVs) and Artemisinin-based Combination Therapies (ACTs) to combat HIV/AIDS and Malaria respectively. The company was founded in June 2005 as a joint venture between Quality Chemicals Limited (QCL), a Ugandan company dealing in the importation and distribution of pharmaceutical drugs, and Cipla Ltd, a leading Indian pharmaceutical company. The joint venture then attracted Capitalworks Investments of South Africa at 14.4% and TLG Capital Investment of United Kingdom at 12.5% leaving Cipla and QCIL at 36.55% each with a vision to become a center of pharmaceutical manufacturing excellence in the region. QCIL sold more shares to Cipla Ltd. in 2013 to facilitate more pharmaceutical production and technology transfer. Cipla now owns 51.05% of the shareholding with QCIL holding onto 22.05%. CiplaQCIL is designed to meet the world’s most stringent pharmaceutical regulatory standards and is pre-qualified by the World Health Organization (WHO) as an additional contract manufacturing site for Cipla Ltd antiretroviral and anti-malaria 1.3 OBJECTIVES OF TRAINING The objectives are based on identified training needs from students and employers. They specifically include:  To gain practical work experience and to be able to see theory in practice.  To learn accepted safety practices in the industry.  To develop personality and communication skills for future roles as leaders in the scientific and technological world.  To improve the student’s manual skills associated with scientific and technological operations in the manufacturing industry. 1.4 TRAINING METHODOLOGY The industrial training considers a range of methods for collecting data and analyzing it which informed the field report writing. Specific methods included
 Data collection forms from the university and industry.  The industry provided a checklist on what was to be learnt in each department  Orientation was done in two days from both the outside and inside of the facility. It was done on rotational basis from one department to another.to allow everybody to know what happens in every unit.  Reading documentation like SOPs which were available in all the rooms in the facility for safety and quality assurance purposes.  In order to gain deeper understanding of the industrial training, discussions with supervisors were done. Academic and industrial supervisors were also tracking the performance to ascertain we are in the right direction.  Some activities such as sifting, packing, in process checks, validation were done practically so as to gain confidence. 2 QUALITY ASSURANCE With regard to pharmaceuticals, quality assurance can be divided into major areas: development, quality control, production, distribution, and inspections. With regard to pharmaceuticals, quality assurance can be divided into major areas: development, quality control, production, distribution, and inspections. 2.1 ROLES OF QA  Responsible for all quality management systems of the facility  Approving or rejecting all components, drug product containers, closures, in-process materials, packaging material, labelling and drug products.  Review production records.  Ensure that if errors have occurred, that they have been fully investigated.  Approving or rejecting drug products manufactured, processed, packed or held under contract by another company.  Approving or rejecting procedures or specifications  QA ensures all activities involved in all the above departments are done the right way as stipulated in the SOPS and cGMP is followed.
The QA department is made up of the following areas;  QA office  Document room ,were records are kept  Training Centre were training takes place from. It operates on the following principles;  Quality safety and effectiveness must be designed and built into a product  Quality isn’t tested it’s made.  Responsibility for quality is a collective one is all individuals involved.  Quality aims at continuous improvement of systems  Each step of manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications hence process validation. 2.2 GOOD MANUFACTURING PRACTICES. (GMP) GMP protects patients. GMP ensures that they receive medicinal products of uncompromised high quality. Compliance with these quality standards is imperative during the manufacture, processing, packaging and storage of medicinal products. Manufacturing authorization will be denied to any company that fails to comply with GMP regulations. This is governed all over the world by acts of law, regulations and guidelines issued by government bodies, ministries and international organizations. Their goal is to put safe and effective medicinal products on the market with no harm to the patients. 2.3 PHARMACEUTICAL QUALITY SYSTEM The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. To achieve this quality objective reliably there must be a comprehensively designed and correctly implemented pharmaceutical quality system (PQS) incorporating GMP and QRM Quality management is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. Quality management, therefore, incorporates
GMP and other factors, including those outside the scope of this guide, such as product design and development. 2.4 cGMP GMP applies to the life-cycle stages from the manufacture of investigational medicinal products, technology transfer, and commercial manufacturing, through to product discontinuation. Components of cGMP PREMISES.  The rooms are designed and constructed to minimize risks of errors and cross contamination while promoting easy cleaning and maintenance.  Proper arrangement of a room and design will promote quality of final product since it will be minimizing cross contamination. This can be seen on the epoxy floors used in the facility which promote easy cleaning.  The design of the production area allows for unidirectional flow.  Double skinned windows in production area and all utility fixtures are fitted in to the wall and ceiling. There is also a walk able ceiling used to do maintenance work like on lighting.  The floor in production area is made of epoxy and the walls are painted with white poly urethane coat that has antifungal properties.  There are no corners in the rooms or curved wall joints for easy cleaning. PERSONNEL. The element of personnel comprises majorly of hygiene, medical checkups, gowning procedures and training of the workers in the facility .Since the workers are likely to get into contact with the materials and products in the manufacture of drugs .The following procedures were followed in the facility.  The facility has got an adequate number of qualified people with practical experiences that are given initial training in GMP and continuous training.
 There is restricted access to the production area.  Heads of production and quality control are independent of each other.  All personnel prior to and during employment undergo health examination. Before moving from one area to another all personnel thoroughly disinfect their hands. Adequate changing facilities with washrooms are available and a standard operating procedure is followed. EQUIPMENT This aspect comprises of the machines and equipment that are used in the drug manufacture. Characteristic properties that the material they are made of include:  Generally the equipment are made of materials that are generally non corrosive, non- absorptive and nonabrasive in nature e.g. SS 316.  All the equipment are located, designed, constructed, adapted and maintained to suit the operations to be carried out.  The design of the equipment allows for easy cleaning.  Moving parts of the machines are enclosed.  Equipment used for production is made of SS 316 for contact parts that has a mirror finish and SS 304 for non-contact parts. MATERIALS The materials used in production are purchased from approved and certified suppliers. Before use QC has to carry out tests to confirm their identity and quality standards. The materials are stored in the required conditions as specified by the manufacturer. Material personnel contact is minimized by laminar air flow unit during sampling and dispensing .The use of lifts also limits personnel contact to the materials. The storage of the materials involves labels and status boards for identity. All raw materials are procured from approved vendors and are quarantined immediately after receipt until released by QC. There are adequate facilities for storage of the raw materials and are segregated .A provision is available for cold storage.
2.5 SELF INSPECTION: Self-inspection is basically a method of objective overall review of operation on aspects that may have on quality effect on quality assurance. In general, self-inspection aims at identifying deficiencies in cGMP whether of critical, major or minor nature. Self-inspection is conducted by designated competent persons from the company. Self-inspection program is conducted in order to monitor the implementation and compliance with current GMP principles and to ensure that the necessary corrective measures are taken. Coverage of Self inspection: The Self inspection team should carefully study every point in the GMP guidelines and drive questionnaires fitted to the company needs. The following items should undergo self-inspection so as to ensure GMPs in the premises as per WHO requirement.  Personnel  Premises and Equipment  Maintenance  Storage of starting and finished products  Production and in-process controls  Quality control  Documentation  Sanitation and Hygiene  Validation and revalidation program  Distribution  Product complaint and recall  Calibration of instruments  Labels control  Results of previous self-inspection and corrective action taken Corrective Action:  Should be appropriate to correct deficiency  Must prevent re-occurrence  Must be completed in a timely manner
 It should be documented and records maintained  Must be monitored 2.6 COMPLAINTS AND RECALLS: A complaint is an expression of dissatisfaction conveyed to an organization about a product, written, electronic or oral communication that alleges deficiencies related to the identity, quantity, durability, safety, effectiveness or performance of a drug after it is released for distribution. CHANGE CONTROL Any change has to go through a clear approval by the QA manager. Change may be; Major (majorly affect other processes), Moderate (may or may not affect any process. Minor (impact no change on process). The change may be process related or product related. Change control goes through stages which include Initiation, approval, and implementation. 2.7 VALIDATION Involves establishing evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. Validation generally implies that a process, product or machine does what it’s supposed to do .Validations are done after finalizing a formula for a product, processes, before or after new drug application approval for example for a new drug product three batches are validated before applying for marketing authorization. The major aim of carrying out this process is to assure that products have identity, strength, quality, and purity they are represented to possess (purport). TYPES OF VALIDATION:  Process validation: ensures that a given process is capable of producing products that are of the required standard  Prospective validation: which is done prior to distribution of the products  Concurrent validation: generation of validation data with normal production
 Retrospective validation: validation which is done to products already in distribution  Cleaning validation; done to verify the effectiveness of cleaning procedure for removal of the product residues, degradation products, preservatives, excipients and or cleaning agents so that analytical monitoring may be reduced to a minimum in the routine phase. DOCUMENTATION IN VALIDATION: Validation MasterPlan: It’s a document that summarizes the firms overall philosophy, intentions and approach to be used for establishing performance adequacy. It is a clear concise reflection of the key elements of the Validation program contains at least;-  A validation policy  Organizational structure of validation activities  Summary of facilities, systems, equipment and processes validated and to be validated  Documentation format (e.g. protocol and report format)  Planning and scheduling  Change control  References to existing documents. The uses of the VMP include:  To know what validation program involves with respect to time, people and money and to understand the necessity of the program  Helps Validation team to know their tasks and responsibilities  Helps GMP inspectors to understand a firm's approach to validation and the set up and organization of all validation activities.  Capacity planning. Validation protocol: a written plan stating how validation process will be conducted including the test parameters, product characteristics, production equipment and the acceptance criteria.
Validation report: a written report on the validation activities, validation data and conclusions drawn. 2.8 QUALIFICATION; It’s like validation but applies to systems, equipment and facility area. Is an action of providing documentation that premises, systems and equipment’s are properly installed, and/or work correctly and lead to the expected results. Qualification is part of Validation process only that it is always used for the equipment’s, utilities and system. It is also the initial step of validation process. Validation is used for the processes. Qualification has been divided into the following parts; Designqualification (QC) Installation qualification (IQ) Performance qualification (PQ) Operation qualification (OQ) Qualification has got stages that include the following; In case of new machines a process is passed through a process that involves a machine certifying that a machine that is suitable for its function. IQDQ PQOQ GMPcertification DQURS SATFAT OQIQ PQ
User Requirement Specification: The Company makes URS that includes description of equipment, GMP aspects, parts, capacity, speed, location suitability, details of utilities. DesignQualification: Evidence that the equipment and process have been designed in accordance with requirements of GMP. After manufacturer has received the user requirement specifications, he sends a document with the design of the machine he can manufacture depending on design sent. Factory Acceptance Test: When the user has seen that the design can work for required purpose, he sends a factory acceptance note to manufacturer, giving him a go ahead to manufacture machine .Before machine taken to premises it’s then tested from the factory under strict supervision by the company purchasing. The FAT is issued if it’s perfect and machine is shipped. SAT: Site Acceptance Test prepared by the company to ensure that the FAT, utilities required for the equipment if any and prove that equipment meets requirement. This is done to ensure that the machine is functioning properly at site of the user. Installation qualification; provides documented evidence that premises, supporting utilities and equipment have been built and installed in compliance with their specification. Operation qualification: provides documented evidence that the operation of a machine complies with the required specification. After installation the machine, it is first run on dry runs, to check for its operation as specified by the manufacturer. It’s qualified for operation. Performance qualification: Process/ equipment will consistently produce a product meeting its predetermined specification and its quality attributes. A hand over certificate conducted during the 1st three batches using placebo batch and product in the following combinations:  All three batches of placebo  One batch of placebo and two batches of the same product  One batch of placebo and two batches of different products (commercial)  Three batches of different products  The documents that are used in validations include
STANDARD OPERATING PROCEDURE Logical sequence of events in instructional form of how, when, where and by whom an activity is to be carried out .In the facility SOPs where found in all the cubicles hanged on the walls. SOP consist of the following;  Examples of SOPs  SOP of SOPs  SOP of complaint handling and record  SOP of deviation handling  SOP of annual product quality review  SOP of recall procedure.  Etc. 2.9 DOCUMENTATION; It’s an important aspect of cGMP. Importance of documentation is given below;  Ensure that there are specifications for all materials and methods of manufacture and control.  Ensure all personnel know what to do and when to do it.  Ensure that authorized persons have all information necessary for release.  Provide audit trail.  To provide history of manufacture of a product. TYPES OF DOCUMENTATION.  Labels, specifications and master formulae.  Batch processing and BPR.  SOPs.
3 STORES How goods move in facility Production starts at stores and ends at stores. Before raw materials are bought .they source the manufacturers who are to supply the factory with the materials. The approved manufacturers are then placed on a list. The list is then sent to procurement to decide who to purchase from. Before the use of materials they are stored in well configured areas for inspection and approval .The storage of these materials is a responsibility of the stores department. The function of this department is the reception of procured materials and finished materials. The materials are stored in a way to ensure that there is no cross contamination .Before production or packing the various departments send BMR or BPR respectively. These contain a description of how much is needed for the activity to take place. If a certain material is out or almost out of stock. A requisition is made and sent to procurement which spearheads the purchase of the material. STORES ALSO HAS CERTAIN PRACTICES TO ENSURE cGMP: They include the following  Storing items on mobile racks. RECIEVING BAY QUARANTINE GOODS STORE SAMPLING AREA BY QC APPROVED GOODS STORE DISPENSING STORE PRODUCTION FINISHED GOODS STORE DOCUMENT REVIEW BATCH RELEASE CERTIFICATE DISPATCH
 Preventing the items from getting into contact with the ground using the racks  Cleaning the floor regularly  Having separate sampling and dispensing rooms for both active and inactive ingredients  Documentation of the activities done.  Monitoring the conditions of the rooms since certain items require specific conditions.  Following the correct gowning procedures for activities like sampling and dispensing  Displaying SOPs around the different store areas  Using trolleys to carry materials instead of man  Control access is limited to most areas using a thumbprint, padlocks  Using double seal locks  Dispensing and sampling rooms have laminar air flows to prevent cross contamination Stores is divided into 6 areas which include; 3.1 RECEIVING BAY AREA Materials that have been purchased enter the facility through the receiving bay .The receiving bay is divided into two areas .The packaging material and raw material receiving bay .each receiving bay has a change room of its own. The doors at entrance to receiving bays have air curtains to prevent mixing of inside and outside air. 3.2 RAW MATERIAL QUARANTINE AREA. Before materials are used, they are quarantined for sampling tests .in order to determine their quality. Tests include assay, if they pass the physical and chemical tests at QC. This area has a sampling area for both active and inactive raw materials. The materials under tests are labeled with an UNDER TEST label (yellow) and those awaiting reanalysis have REANALYSIS label (red). The room is kept at a temperature of (2-25) º C and RH of 45%-60%. The pressure is also monitored using manometer, while temperature and humidity monitored by a hygrothermometer. The active materials and inactive materials include 3.3 SAMPLING AREA. This area is used by QC department for the sampling process done for materials under test. Whereas QC uses this area stores maintains it. The sampling areas include the inactive and active
sampling area. Each sampling area has its own change room .the materials are received into the sampling areas through raw material pass box .The sampling unit is a class 5 ISO classified .It is made of a laminar air flow unit .Sampling is done in the laminar air flow unit prevention of cross contamination between the sampler and the material is achieved due to the unidirectional air flow. 3.4 APPROVED RAW MATERIAL AREA. When the material has passed the test carried out during sampling, it is given a PASSED LABEL (green). These materials are then taken to the raw material approved area .They are then kept in this area before dispensing. The materials are kept on a mobile rack system and the temperature and humidity measured by hygrothermometer and pressure measured by nanometer. Some Materials which require cool conditions are kept in cool walk in chamber .When excess material was in the approved room due to the less space in the quarantine room, the yellow rope is removed and replaced by a green rope. The materials are kept separated segregated batch wise as pallets / item wise as pallets / shelf. 3.5 DISPENCING Dispensing is done under ISO class 5 Reverse Laminar Air flow booth. Active and inactive are dispensed separately. This is done after a requisition has been made by the department in need 3.6 PACKAGING MATERIAL STORES This store is divided into two; primary packaging material store and tertiary, secondary store .The tertiary and secondary material are stored in the same cubicle which has no ISO classification. The packing materials in this area are kept off the floor on pallets and in a mobile rack system PRIMARY PACKING MATERIAL. Primary packing material are material directly attached to drug .This cubicle contains a laminar air flow unit and a mobile rack system. The materials are kept off the flow on mobile racks. There are a variety of primary packing materials which include;  PVC ACLAR  FOIL
 HDPE bottles  Caps Procedure of receipt. Has sections; - primary, secondary, and tertiary packing material store. After receipt of these materials each is kept in its respective store where it’s first quarantined until it passes QC tests then they are passed. Primary packing material must be sampled and dispensed under a lamina air flow cabinet. SECONDARY PACKING MATERIAL  Cartons  Enclosures  literature  Cotton  Silica gel  Labels TERTIARY PACKING MATERIALS  Shippers  BOPP Tapes  Fitments  Labels 3.7 FINISHED GOODS STORE. The finished pharmaceutical products are stored here before dispatch. Before dispatch the store must first issue a batch release certificate. This area is involved in the storage of the finished goods temporarily until the QC and QA tests are complete. If passed, the goods are then ready for distribution. The finished goods are kept on a mobile rack system off the ground batch wise. They are also kept on SS pallets together as a batch .The temperature and humidity are monitored using a hygrothermometer and pressure using a manometer .temperature (19-25) º C and RH (45-60) %. The goods can be attached with UNDER TEST and PASSED status boards.
4 QUALITY CONTROL Quality control is divided into two main departments’ chemistry and microbiology. Chemistry department mainly deals with the active ingredients and some other tests like packaging materials. Microbiology deals with the inactive and microbiological organisms this department ensures that manufactured products, materials or performed services adhere to a defined set of quality criteria or meets the requirements of client and also detect defects. The department carries out chemical and physical analyses of different samples like  Water.  Air  Primary packaging materials  Raw materials.  Finished products The instruments found in QC include; Analytical Balance an analytical balance is used to measure mass to a high degree of precision and accuracy. To some the analytical balance may simply be known as a set of scales, but an analytical balance is able to measure down to the ten thousandth of a gram. An analytical balance, also known as a precision balance, it most often found in a laboratory setting and is used only with the most meticulous of measurements. They require a draft-free location on a solid bench that is free of vibrations. Some modern balances have built-in calibration masses to maintain accuracy. pH Meter a pH meter is an electronic instrument used for measuring the pH (acidity or alkalinity) of a liquid (though special probes are sometimes used to measure the pH of semi-solid substances). A probe is placed in a liquid, and it generates an electrical voltage that is converted to a logarithmic pH reading. The pH scale range is 1 to 14. Polarimeter a polarimeter is a scientific instrument used to measure the angle of rotation caused by passing polarized light through an optically active substance. Anisotropic crystalline solids, and samples containing an excess of one enantiomer of a chiral molecule, can rotate the orientation of plane-
polarized light. Such substances are said to have optical activity. Measurement of this change in polarization orientation is called polarimetry, and the measuring instrument is called a polarimeter. These measurements are useful for studying the structure of anisotropic materials, and for checking the purity of chiral mixtures. • Isolating and identifying unknowns crystallized from various solvents or separated by high performance liquid chromatography (HPLC). • Evaluating and characterizing optically active compounds by measuring their specific rotation and comparing this value with the theoretical values found in literature. • Investigating kinetic reactions by measuring optical rotation as a function of time. • Monitoring changes in concentration of an optically active component in a reaction mixture, as in enzymatic cleavage. • Distinguishing between optical isomers. IR Moisture Balance: A high performance compact, dependable Infra-red Moisture Balance for measurement of moisture content of material not affected by radiation while losing water under of moisture exposure to Infra-red radiation. IR moisture balance is an accurate method for moisture content and dry weight analysis of a wide range of products and materials. KF Titrator Karl Fischer titration is a classic titration method in analytical chemistry that uses coulometric or volumetric titration to determine trace amounts of water in a. KF titration - is highly specific and precise - covers a wide concentration range: from ppm up to 100%. - has short determination times. IR Spectrophoto Meter It is used to measure the maximum absorption of infrared spectrum compound and the determination of IR radiation. Ultraviolet-Visible spectrophotometer Ultraviolet–visible spectroscopy or ultraviolet-visible spectrophotometry (UV-Vis) refers to
absorption spectroscopy or reflectance spectroscopy in the ultraviolet-visible spectral region. This means it uses light in the visible and adjacent (near-UV and near-infrared (NIR)) ranges. UV/Vis spectroscopy is routinely used for the quantitative determination of different analytes, such as transition metal ions, highly conjugated organic compounds, and biological macromolecules. Determination is usually carried out in solutions. • Solutions of transition metal ions can be colored (i.e., absorb visible light) because d electrons within the metal atoms can be excited from one electronic state to another. The colour of metal ion solutions is strongly affected by the presence of other species, such as certain anions or ligands. For instance, the colour of a dilute solution of copper sulfate is a very light blue; adding ammonia intensifies the colour and changes the wavelength of maximum absorption (λmax). • While charge transfer complexes also give rise to colours, the colours are often too intense to be used for quantitative measurement. Particle counter a particle counter is an instrument that detects and counts particles. By its very nature a particle counter is a single particle counter, meaning it detects and counts particles one at a time. The nature of particle counting is based upon either light scattering or light obscuration. A high energy light source is used to illuminate the particle as it passes through the detection chamber. The particle passes through the light source (typically a laser) and if light scattering is used, then the redirected light is detected by a photo detector. Or if light blocking (obscuration) is used the loss of light is detected. The amplitude of the light scattered or light blocked is measured and the particle is counted and tabulated into standardized counting bins. The image to the right shows a light scattering particle counter diagram. Dissolution test apparatus In the pharmaceutical industry, drug dissolution testing is routinely used to provide critical in vitro drug release information for both quality control purposes, i.e., to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and drug development, i.e., to predict in vivo drug release profiles. The designs of the dissolution apparatuses and the ways of operating dissolution apparatuses have huge impacts on the hydrodynamics, thus the performances. Disintegration test apparatus it is used to measure the tablet disintegration time and subsequent drug dissolution.
Friability Test Apparatus Tablet friability test apparatus are used for determination of durability of tablets at the time of production. The apparatus is designed to provide the precise value of rate of abrasion and impact hardness of the tablets. Friability is important since it affects in particle size distribution of granules affecting compressibility into tablet, tablet weight variation, granule flowability. Friability is determined carrying out Tumbler Test or using Friability Tester (RocheFriabilator) and % loss is determined. Hardness test facilities It is to measure the hardness the tablet and it is essential to determine the disintegration and dissolution of drug and efficient of drug. High-performance liquid chromatography (HPLC) High-performance liquid chromatography HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in quality control chemistry to identify, quantify and purify the individual components of the mixture. HPLC typically utilizes different types of stationary phases contained in columns, a pump that moves the mobile phase and sample components through the column, and a detector to provide a characteristic retention time for the analyte and an area count reflecting the amount of analyte passing through the detector. HPLC is really the automation of traditional liquid chromatography under conditions which provide for enhanced separations during shorter periods of time, utilizing
very small particles, small column diameters, and very high fluid pressures HPLC is accomplished by injection of a small amount of liquid sample into a moving stream of liquid (called the mobile phase) that passes through a column packed with particles of stationary phase. Separation of a mixture into its components depends on different degrees of retention of each component in the column. The extent to which a component is retained in the column is determined by its partitioning between the liquid mobile phase and the stationary phase. In HPLC this partitioning is affected by the relative solute/stationary phase and solute/mobile phase interactions These instruments are calibrated regularly monthly and annually using standard weights The factors which influence the HPLC performance  Internal diameter of column  the smaller in diameter, the higher in sensitivity  Pump pressure  the higher in pressure, the higher in separation  Sample size
 The polarity sample, solvent and column  Temperature  the higher in temperature, the higher in separation  To control the drug stability  Quantity of drug determination from pharmaceutical dosage forms  Quantity of drug determination from biological fluids, ex: blood glucose level DEPARTMENTS OF QC 4.1 WET CHEMISTRY The equipment used includes: Dissolution tester; Materials Lumartem, Duovir-N 4.2 WEIGHING SECTION The following instruments were seen in this section.  Analytical balance; for weighing material  Karl Fischer auto Titrator example Nevirapine, Lumartem tablets. .HOT ZONE AREA. Chemicals used here include;  Fuming chemicals for example HCl, H2SO4, HNO3, glacial acetic.  Triethtlemine GR-adjust pH of HPLC water. Equipment used include;  Vacuum oven-drying of substances in absence of air  Muffles furnace-determine sulfated ash-corn starch.  Precision hot air oven-analysis of ox-disable substances in H2O.  Ultrasonic cleaner-dissolving substances.
 Fuming hood –for safety from dangerous acids through absorption of fumes by use of active carbon holding acids.  Heating mentle-boiling point 4.3 TITRATION and STANDARD AREA This area consists the following instruments;  pH meter-determine pH purified water  Bio-containment work station –prepare a compensate sample.  Magnetic stirrer-dissolving substances  Conductivity meter-determines water conductivity 4.4 WASHING AREA  Glassware drying oven –drying  Water purification system –purifies water for HPLC.  Water bath-heating, evaporation and warming. 4.5 MICROBIOLOGY SECTION Microbiology is under responsible for determining the microbial contamination in an environment, raw materials and finished products. It’s divided into five areas: Preparatory area. This is where activities are done in preparation for analysis. For example, sterilization of equipment, media preparation among others. Sterilization: this is done to kill all micro-organisms on the equipment to be used in the lab for analysis. There are two types of sterilization that are mainly used at Cipla QC. Steam sterilization;
It is carried out using an autoclave. It’s carried out at 1210C for approximately 20 minutes. Materials sterilized using this method are sensitive to high temperatures for example Glass apparatus and equipment, dressings and fabrics and Plastic and rubber closures Dry heat sterilization; It uses a laboratory oven at 1600C for 2 hours. This method uses high temperatures and a high penetrating power. Materials sterilized by this method are not sensitive to high temperatures and include Glassware (sterilized up to 250° for 2 hours to effect depyrogenation) Media preparation; The process of preparation includes weighing the required amount and then adding a specified volume of water. Equipment present in the preparatory room includes;  Autoclave: For sterilization of media and other equipment used in the microbiology lab. It’s also used for destruction of media before it’s released to the environment.  Weighing balance: for weighing media during media preparation.  pH meter: for measuring the pH of the media.  Oven: For sterilization of instruments sensitive to moist heat.  Incubator  Refrigerator  Hot air oven: for drying. The types of analysis that occur in the microbiology laboratory include; Water analysis: To identify or quantify any microorganisms present for example pseudomonas aeroginosa, E.Coli, Salmonella, etc. Micro testing room: The area has laminar air flow. Hers a pass box foe passage of materials to and from the micro testing room. Incubation area:
Various incubators are present and they incubate different microorganisms. The incubators are at different temperatures to favor growth of specific microbes for example:  40oC to 45oC for E.Coli.  35 to 37oC for pathogens.  25oC for fungi. Culture handling room: there is a bio containment work station where procedures are carried out from. It has vertical laminar airflow to protect personnel. It has a pass box where materials are passed to avoid cross contamination. Activities done in this area include; water analysis which is done under laminar air flow and dispensing of culture media. TYPES OF MEDIA AND THEIR USES. There are two types of media present in the microbiology section at Cipla QC; that is liquid media (broth) and solid media (agar). Examples of media present in the lab include; Media Use deoxycholate citrate Agar Selective for salmonella & shigella species EMB Agar (Levine) Isolation enumeration & differentiation of Columbian Agar Detect clostridium sporogenes from pharmaceuticals Bismuth sulphate Agar medium Selective isolation of salmonella from faces ,urine Brilliant green agar base Selective isolation of salmonella other than s. typhi Nutrient broth medium Sterility testing for aerobes Pseudomonas agar (for fluorescing ) Fluorescein production by pseudomonas SCM (Broth medium) General purpose medium for microbes Reinforced clostridia agar Sterility testing for moulds & lower bacteria clostridia & other aerobes. Sabourand dextrose Agar Cultivation of yeast moulds & acidified microorganism
Triple sugar iron agar Identification of gram negative enteric bacilli on the basis of dextrose, lactose & sucrose, fermentation &H2S production Yeast maltose broth Acidify for selective medium Vogel Johnson agar base yeast, mould, & aciduric MOs staph aureus Yeast maltose agar Isolation & cultivation of yeasts, moulds & other aciduric micro organism
5 PRODUCTION After the dispensing of materials from the raw material approved room in response to the work order, they are taken to the production department. Production department is made of granulation, compression, coating and packing sections. The flow of materials in production is uni-flow from granulation, compression, and coating and finally to packing section .The production department is completely involved in the drugs manufacturing process .During the process manufacture IPQC checks are carried out to ensure quality in process of production and prevent batch failure. When raw materials are required in the production of drugs, the production department makes an order to the stores department which them dispenses off the material. In case of excess raw materials. The materials are returned. In case of less raw materials an extra material memo is made .the following products are produced 5.1 PRODUCTS OF CIPLAQCIL ARVS DRUG ACTIVE INGREDIENTS Effavir 600 Efavirenz 600mg Duovir Zidovudine USP 300mg, Lamivudine USP 150mg Duovir-N Zidovudine USP 300mg, Lamivudine USP 150mg, Nevirapine USP 200mg Nevimune Nevirapine USP 200mg Duomune Tenofovir DisoproxilFumarate 300mg Lamivudine USP 300mg Trioday Lamivudine 300mg Tenofovir DisoproxilFumarate 300mg Efavirenz 600mg Texavir Tenofovir 300mg
ACTs DRUG ACTIVE INGREDIENTS Lumartem Lumefantrine 120mg ArtmetherPhint 20mg 5.2 GRANULATION Granulation is the process of forming granules from powder particles. The small powder particles are made to adhere to make bigger granules .The powder particles are made to adhere for many reasons which include Tablets are the most common drug dosage form today, and thus granulation, which allows primary powder particles to adhere and form granules, is one of the most important unit operations in drug manufacturing. Understanding granulation grows more complex each year. Particle-bonding Mechanisms a) Adhesion and cohesion forces in immobile films. If sufficient liquid is present in a powder to form a thin, immobile layer, there will be an increase in contact area between particles. The bond strength between particles will increase, as the Van der Waals forces of attraction are proportional to the particle diameter and inversely proportional to the square of the distance of separation. b) Interfacial forces in mobile liquid films. During wet granulation, liquid is added to the powder mix and distributed as films around and between the particles. There are three states of water distribution between particles. At low moisture levels, the pendular state, particles are held together by surface tension forces of the liquid/air interface and the hydrostatic suction pressure in the liquid bridge. When all the air has been displaced from between the particles, the capillary state is reached, and the particles are held by capillary suction at the liquid/air interface. The funicular state represents an intermediate stage between the pendular and capillary states. Moist granule tensile strength increases about three times between the pendular and the capillary state. These wet bridges are,
however, a prerequisite for the formation of solid bridges formed by adhesives present in the liquid, or by materials that dissolve in the granulating liquid. Solid bridges can be formed in two ways: Hardening binders. When an adhesive is included in the granulating solvent it forms liquid bridges, and the adhesive will harden or crystallize on drying to form solid bridges to bind the particles. Crystallization of dissolved substances. The solvent used to mass the powder during wet granulation may partially dissolve one of the powdered ingredients. When the granules are dried, crystallization of this material will take place and the dissolved substance then acts as a hardening binder. c) Attractive forces between solid particles. In the absence of liquids and solid bridges formed by binding agents, there are two types of attractive force that can operate between particles in pharmaceutical systems, electrostatic forces and Van der Waals forces. Van der Waals forces are about four orders of magnitude greater than electrostatic and add to the strength of granules produced by dry granulation. Mechanisms of Granule Formation a) Nucleation. Granulation starts with particle-particle contact and adhesion due to liquid bridges. A number of particles will join to form the pendular state. Further agitation densifies the pendular bodies to form the capillary state, and these bodies act as nuclei for further granule growth. b) Transition. Nuclei can grow in two possible ways: either single particles can be added to the nuclei by pendular bridges, or two or more nuclei may combine. The combined nuclei will be reshaped by the agitation of the bed. This stage is characterized by the presence of a large number of small granules with a fairly wide size distribution.
c) Ball Growth. If agitation is continued, granule coalescence will continue and produce an unusable, over-massed system, although this is dependent upon the amount of liquid added and the properties of the material being granulated. There are four possible mechanisms of ball growth, which are illustrated in the illustration  Coalescence. Two or more granules join to form a larger granule.  Breakage. Granules break into fragments which adhere to other granules, forming a layer of material over the surviving granule.  Layering. When a second batch of powder mix is added to a bed of granules, the powder will adhere to the granules, forming a layer over the surface and increasing the granule size.  Abrasion Transfer. Agitation of the granule bed leads to the attrition of material from granules. This abraded material adheres to other granules. Granulation Methods Dry Granulation. This requires two pieces of equipment, a machine for compressing the dry powders into compacts or flakes, and a mill for breaking up these intermediate products into granules. The dry method may be used for drugs that do not compress well after wet granulation, or those which are sensitive to moisture/water. Wet Granulation. In this method, the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required. Because direct compressing is not the best technology for many active substances, wet granulation is still a preferred method. Even if the active substance is sensitive to hydrolysis, modern equipment (e.g., a fluidized bed) eliminates all problems in wet granulation. Factors Affecting Granulation Methods  Liquid Requirement. High-shear mixers may exhibit a narrow margin between the liquid required to obtain granule growth and the amount that results in an over-wetted mass. Because of the intensive wet massing and densification of the granules, less liquid is
normally required with high- than with low-shear mixers .In addition, impeller rotation speed influences the liquid requirements, as does evaporation of the solvent, usually water, in the binder solution. Especially with high-shear mixers, intense agitation results in a temperature rise and loss of solvent by evaporation. Effects of Raw Material Properties. The following properties influence granule formation and growth:  Contact angle of the binder liquid to the solids  Solubility of the particles in the binder liquid  Mean particle size and size distribution of the solids  Particle shape and surface morphology  Packing properties of the solids  Raw materials must have good wetting properties if there is to be uniform liquid distribution and, hence, controlled granule growth. The smaller the particle size of the raw material, the more binder liquid required. Binder Properties Binder Concentration. The binder forms an internal matrix; consequently, the granule strength and tablet strength increase as binder concentration increases. Mechanical Properties of Binder. The mechanical properties of the binder determine binder strength and deformation behavior of the binder matrix. Properties of Drug and Other Excipients in the Formulation Wet granulation depends upon wetting of powder by the binder solution, surface tension of lenticular bridge films formed and solution viscosity. Binder Distribution. The distribution influences the binder’s ability to produce strong and non-friable granules. The processing method used to distribute the binder influences binder efficiency.  To improve the particle size distribution so as to improve the compressibility.  Prevent segregation of the constituents of the mix  Improve flow properties of the mix
 Reduce hazard of toxic materials associated with handling.  Reduce possibility of caking with hygroscopic material  Improve drug release properties.  It makes occupation of less volume per weight, hence easy handling. CONDITIONS The granulation area is a critical area, with the temperatures and relative humidity monitored and kept within the required limits .Temperature (19-22 ºc) and relative humidity (45- 60%).Deviations from the required limits can lead to reduced quality of the end product. It is mainly applied to heat labile and moisture sensitive materials like Duovir (Lamivudine and Zidovudine). The granulation section has three granulation cubicles, granulation I, II, III. Each cubicle is divided into a binder solution preparation room, washing area and an area were sifting, sizing and granulation occur. 5.3 BLENDING This is done using an octagonal blender after line clearance has been done. Manufacturing process containers are first re-weighed and then attached to the blender mouth. The blender is then rotated 180◦ to load the granules into the octagonal blender a process known as charging, after the blender is rotated back to its normal position and the MIPC is disconnected. This is repeated until all the granules have been loaded to the maximum capacity of the blender. Lubricants such as magnesium stearate are also added. The blender is then set to rotate through 360◦ at a specified rpm. After blending, the granules are offloaded into MIPCs which are first tared and the re-weighed with the blend and stored in the bulk store according to batch in lines, where they are later picked for compression into tablets MACHINES USED IN GRANULATION Rapid Mixer Granulator Works on the principle of high shear to achieve only mixing and granulation of the powders. This mixer uses a highly viscous binder, it’s filled by SS bins for both the binder and powder
using an elevator, the mixer doesn’t dry and after granulation its products are taken to the FBE for drying. It comprises of lid tighten clamps, bowl lid, agitator, chopper, binder/material charge port, air vent, neoprene gasket, discharge port, chopper motor cover, plat form, control panel and view window. The agitator helps uniform mixing, and a high speed chopper slices the lumps to form smaller granules. Some of the raw materials used here include those of lumefantrine and Efavirenz Fluid Bed Equipment This is used for granulation, drying, mixing and also coating of pellets. The raw material for granulation is fed into the FBE by an evacuator pipe from IPCs after it has been re-verified (label, weight, batch, texture). Hot air at high pressure is let into the equipment via the inlet pipe to the lower plenum and then through the bowl sieve to the product container, and causes free flow of the powders, the powders are first mixed and pre-heated ( up to 36-400C) to ensure uniform mixing with the other inactive and create conditions for adding of binder for approximately 5 minutes, after a peristaltic pump pumps a less viscous binder from a can and it passes through a spray gun with 1mm nozzles and it continuously wets the powder as mixing is continuously done. The fluidized material is kept within the expansion chamber by the help of a finger bag which allows only air to pass through and increases the surface area for mixing, drying is effected by heat exchange between the hot air and the wet granules. The FBE has inflatable gaskets that ensure that pressure is not lost to the outside during operation, exhaust and product temperature is monitored throughout the process every after 10 minutes, if it is low it means that the material is wet thus after binder spraying has been done, the material is dried. The material is sampled through the sampling port (at specified temperature) and analyzed for loss on drying in intervals. If LOD is in specified limits then drying is stopped and the formed granules are removed. The material is then sized and milled and sent to blending after it has been re-weighed. Some of the parts include; inlet air ducting, expansion chamber, lower plenum, explosion flap duct, product container, spring tension, bowl sieve, SS supports, pneumatic control panel, inflatable gaskets, neoprene gaskets, bull eye windows, filter bag assembly, spray gun, view window, control panel and the peristaltic pump.
Vibrator sifter This helps in material sifting, uses vibratory and gyratory motion as it causes vibration and the particles of different sizes pass through the sieve from the upper hopper to the lower hopper and re-collected. Depending on the material, sieves of different mesh sizes are used. The sizes of sieves used are determined by the number of holes per linear inch. Determining of the sieve integrity is one first essential step done before sifting using a dyner scan. It has various parts including, sifter body, and wheel lid, upper hopper, lower hopper, and stainless steel clamp, sifter hood, holding ring, neoprene gasket, sieves, control panel, electric cable and main body. The neoprene gasket helps in the reduction of noise when vibrating. PURPOSE OF SIFTING  obtain uniform particle size powder of desired range  check for any foreign matter which may come along with raw material  magnetic screens are provided at outlet of sifter to check and hold metal particles as most of bulk drugs are synthesized, processed in mild steel reactors thus chances of steel, rust particles  Raw materials from sifting area are then sent to granulation hall via pass box. Here binder preparation occurs. Multmill Helps in the sizing of clamps of powders and granules that can’t pass through the sifter it has various parts including ; pulley housing and cover, blade stud, wing nuts rotor, size reduction chamber, hopper, base plate, gasket, control panel, electric cable, agitator and wheels. The cleaning of the machine is similar to that of the vibrator sifter. Roll compactor This machine is used for dry granulation. It has a sieve in it and it only compacts and sifts at the same time to make granule that pass through the sieve and collected through the lower hopper. It’s made of two rolls rotating in different directions which allows for compression of the sifted powder particles in between the rolls and this coupled with a vacuum pressure which leads to flake formation.
Steam kettle. This is used in preparation of the binder. Octagonal blender It rotates and mixes the contents using shear mixing. It has got baffles to aid this process. Its speed is controlled using a programmable logic controller. Its main function is to blend and lubricate Weighing balance This is used to tare cans, measure granules and also verify weights of raw materials before they are granulated. The balance is calibrated by to forms IN-PROCESS CHECKS AT GRANULATION These include;-  Tap density- use of tap density apparatus/tester to determine bulk and tap density.  Moisture content- done using IR moisture analyzer  Percentage fines-using a sieve shaker.  Loss on drying CLEANING PROCEDURE FOR EQUIPMENTS Generally flush with portable water then apply detergent then rinse with portable water, flush with purified water and finally dry using compressed air. 5.4 COMPRESSION Compression is a process of tablet formation from granules with aid of compression force through the usage of compression machine. The tools used for compression are Punches and dies (kept in tool room). The die determines the diameter of the tablet. Machinery classification is dependent on the following accepts Rotation; single rotation and double rotation. The machine used is called a double rotary machine.
Illustration of set up of compression apparatus The components of the double rotary compression machine include;  Feed frame /force feeder; Holds the granule on turret so they fill the die bore.  Cam tracks; Lift upper punch and lower punch during cycle as required.  Pre compression blades; Give granules an initial tamping force to remove as much air as possible before final compression.  Main compression rollers; Apply the full pre the set pressure on punches for final compression of tablets.  Take off blade; Is fitted in front of the feeder frame to scrap the tablet off lower punch tip  Ejection cam; Guides the lower punch upwards during the ejection stage. It is adjustable to ensure smooth ejection without damaging tablets.  Hopper; this is where the granules are introduced into the machine. Compression process The compression process involves a series of stages. Filling The filling stage of the tablet compression process involves transfer of raw materials into position for tablet compression. These raw materials have undergone prior processing by wet granulation, dry granulation (roller compaction), sizing, or other processes. The final formulation is then blended to yield a homogeneous blend. The blend then flows to the compressing machine punch-die cavity. The punch-die cavity is composed of punch die and lower punch. The position of the lower punch within the die determines the volume of the punch-die cavity. This volume must be appropriately sized for the weight of granulation to be compressed into tablets. The granulation is overfilled on the die table (turret) to ensure complete filling of the punch-die cavity volume. compression machine deduster metal detector MIPC
Metering The metering stage of the tablet compressing process involves removal of excess granulation from the compressing machine. This stage enables the exact weight (volume) of granulation to be compressed into tablets. The exact weight of granulation is controlled by the height of the lower punch in the die. The height of the lower punch is controlled by the metering cam (also called the dosage cam). The lower punch is raised to the appropriate level in the die to provide the exact weight of granulation in the punch-die cavity. The excess granulation is scraped from the surface of the die table. The metering stage is similar to the method used to measure flour when baking a cake. A measuring cup is first over-filled with flour; then a knife is used to scrape off the excess. The exact amount of flour is then left in the measuring cup. Compression The compression stage of the tablet compressing process forms the tablet. This stage involves bringing together the upper and lower punches under pressure within the die to form the tablet. As the punches enter the compressing stage, the upper and lower punches move between two large wheels called pressure rolls. These pressure rolls push the punches together to form the tablet. The distance between the upper and lower punches determines the thickness and the hardness of the tablet. When the punches are close together, a thin and hard tablet is created. When the punches are farther apart, the tablet made is softer and thicker. The proper balance of thickness and hardness determines the optimum roll distance for any specific product. These adjustments are made while keeping the tablet weight constant. Ejection The ejection stage of the tablet compressing process involves removal of the tablet from the lower punch-die station. In this stage, the upper punch retracts from the die cavity and rises above the turret table. Then the lower punch rises in the die, which in turn pushes the tablet upward to the top surface of the die table and out of the die cavity. A scraper (also called takeoff scraper or tablet rake-off) then pushes the tablet off the die table away from the compressing machine into the collection container. TYPES OF TOOLING AND STATIONS;
Machinery classification is dependent on the following accepts Rotation; single rotation and double rotation Tooling refers to the diameter of the punches. B-type is for small tablets and is used to compress LUMARTEM tablets and D- type which has a larger diameter of about 16mm and is used for DUOVIR-N, DUOVIR and EFAVIR. STATIONS. This classification consists of the number of punches the machine has. The forms include 37, 45, 49, 55, 65 stations. In case the machine is double rotary then this means it compresses twice the number of tablets per rotation i.e. 37 station produces 37 x 2 = 74 tablets per rotation Tooling refers to the diameter of the punches .B –type is for compressing lumartem tablets whilst D-type for Duovir-N, Duovir, Effavir. Type Die diameter Punch diameter machine Stations D-tooling 38.1mm 25.4mm Cadpress iv 45 B-tooling 30.1mm 19mm Cadpress iv 55 BB-tooling 24mm 19mm Cadpress ii 45 TABLET PROBLEMS DURING COMPRESSION Tablet defects POSSIBLE CAUSES TOOLING RELATED PRESS RELATED FORMULATION RELATED Weight variation Inconsistency working height of the Lower punch. Jammed Lower punch. Granules not flowing freely.
Thickness variation Inconsistency working height of the Lower punch. Inconsistency of the Upper punch working height. Pressure roller jumping. Capping Air entrapment. Incorrect ejection setting. Use of pre-compressed granules. Sticking and picking Poor finish on punch cavity. Picking bore zones on embossing. Sticking formula. High moisture content. IN-PROCESS CHECKS CARRIED OUT DURING COMPRESSION AND INSTRUMENTS  punch size the diameter  upper punch description circular and has an embossing of UG  lower punch description plane and circular  Standard Compression weight should be within limits  Hardness carried on tablets from both sides of the machine i.e. right and left side TESTS CARRIED OUT DISINTERGRATION TEST This test is used to mimic the conditions in the human stomach where the time taken for a tablet to completely disintegrate is noted .the instrument used is the disintegration tester and the drug is expected to have disintegration time less than 15 minutes. The apparatus is set at 37◦C and the time taken to disintegrate is read off from the timer display. The water in the water bath is changed weekly. HARDNESS TEST
This is done to determine the hardness of a tablet by use of the ERWEKA HARDNESS TESTER. This instrument can also determine the diameter and thickness of the tablet . First switch on tester then zero it. Select measure option on LCD, place the tablets in the stations provided then the analysis process begins and results for thickness, diameter and hardness are displayed on the screen. Enter product details and start. Then view results FRIABILITY TEST This instrument is used to determine the friability of a drug .This test is used to determine how well a drug can sustain impaction forces during the process of transportation from one place to another. WEIGHING BALANCE This instrument is used for group weights, individual weights. Individual weights are taken for 50 tablets from each side of the machine (Left Hand Side and Right Hand Side). VERNIER CALLIPER, This instrument is used to determine thickness, width and length .The digital Vernier caliper is connected to the online recording system. MACHINES USED IN COMPRESSION These include  Tablet press-works on principle of particle compaction.  Deduster-operates on principle of spiral vibration and size exclusion. Has a mortar that vibrates creating a suction force that enables powder dust to separates from tablet.  Metal detector-works on principle of magnetic attraction. A large magnetic field is set up through which tablets are passed. Each tablet containing a metal component is attracted and is not released due to eddy currents. Metal components detected include SS, ferrous and nonferrous.
5.5 COATING Coating is the process of enclosing the tablet core with a polymer film or a sugar base. This is the addition of a surface coat on the tablet. Common pharmaceutical technique of applying a thin polymer based film to a tablet. Major techniques include sugar-coating, film-coating, enteric –coating. IMPORTANCES OF COATING  Tablets are coated for different reasons which include;  Masking the bitter test and bad smell of the active ingredient.  For functional purposes such as controlled release of the drug.  Provide physical and chemical protection for the drug from atmospheric effects such as temperature, humidity and light.  Protect drug from gastric environment of stomach with acid resistant coating.  To incorporate another drug or formula adjuvant in the coating.  Improve appearance by use of special colors... There are different types of coating which include; Sugar coating. Steps in sugar coating; Multiple applications of syrup containing colour are required, water-soluble dyes or water- insoluble lakes are used. Finally wax is applied in rolling pans. Film coating
Preferred method which applies a thin, uniform coating on tablets. Steps in film coating The Suspension is prepared according to the SOP, and depending on the product to be coated, then checking and setting of spray pattern of the machine. Tablet loading are loaded by the operators in the machine. This is followed by preheating of tablets for five minutes before spray is turned on. Tablets are sprayed using the coating suspension a defined rate as per SOP. Tablets are dried after the specified period of coating. Finally unloading of tablets by the operators in the MIPCs. Functional coating. This can include coating for slow release, enteric coating. NOTE: Sugar coating involves use of a sucrose based solution while film and functional coating involves use of suitable polymer which forms a thin film around the tablet core. At Ciplaqcil, some of the tablets are film coated. Components of a film coat  Solvent; IPA, Methylene Chloride  Plasticizers; poly ethylene glycol  Opacifier  Film former; methyl cellulose  Colorants  Opadry a raw material that contains all the required materials may be used. Equipment for coating;  Neocota machine  GCsmart pam Glatt PREPARATION OF COATING SOLUTION
Opardy yellow powder (1kgs) is placed in SPV, then a known amount of purified water is added and mixture thoroughly mixed for 45 minutes. Final solution is sieved to remove solid particles that did not dissolve. Film-coating is a single stage automated process highly adaptable to GMP. A suitable polymer is used to form a thin film around tablet core. Film coated tablets retain contour of original core in case the coating is translucent, have 2-3% weight increase, logo or break lines. Coating occurs by a spray process. Tablets on perforated coating pan are sprayed with coating suspension whilst pan is rotating. Baffles ensure each is coated. Parameters checked include product and exhaust temperature, spray rate, spray pattern, atomization. In –process checks done include disintegration test, appearance of coated tablets, group weight /individual rise, thickness test, loss on drying. In process checks include  Appearance  Group weight and individual weight variation  Loss on Drying  Disintegration time COATING DEFECTS Reject Cause Solution Tablet to tablet color variation Migration of coloured components within tablet core into the coating use a coating in which the components of the tablet core are insoluble Cracking Insufficient plasticizer Increase plasticizer Edge chipping/erosion Low mechanical strength Increase the compression pressure Core erosion Pan speed is too high Optimize speed of pan.
Orange peel roughness Viscosity is too high Increasing the spray rate and decreasing the air temperature Peeling Low mechanical strength Increase compression pressure Twinning Spray rate too high Reduction of spray rate Picking/sticking Inadequate drying Proper drying
6 ENGINEERING This department is located outside the facilities main building and its main purpose is to manage and control the utilities used by the facility. It consists of various equipment aimed at providing the optimal working condition. It helps to control the temperature and relative humidity inside the facility premises. This is very important because the environmental conditions required during the different stages of production vary depending on the type of product. The different machinery found in this department include, Air compressor, Boilers, Chillers. The Engineering department has the following sections.  Boiler room  Air compressor room  Chillers  Service floor (HVAC)  Effluent Treatment Plan (ETP)  Engineering Offices and Workshop AIR COMPRESSOR; For formation of purified air that is used in various processes during production like during functioning of the FBE. Types of the air compressors.  Piston air compressors.  Screw air compressors. The latter is preferred in the pharmaceutical industries because is oil free hence no incidences of production of moisture that can interfere with the production process. Procedure for purification
6.1 BOILERS Boilers are pressure vessels designed to heat water or produce steam, which can then be used to provide space heating and/or service water heating to a building. In most commercial building heating applications, the heating source in the boiler is a natural gas fired burner. Oil fired burners and electric resistance heaters can be used as well. Steam is preferred over hot water in some applications, including absorption cooling, kitchens, laundries, sterilizers, and steam driven equipment. Boilers have several strengths that have made them a common feature of buildings. They have a long life, can achieve efficiencies up to 95% or greater, provide an effective method of heating a building, andin the case of steam systems, require little or no pumping energy. How Boilers Work Oil fired boilers use controlled combustion of the fuel to heat water. The key boiler components involved in this process are the burner, combustion chamber, heat exchanger, and controls. The burner mixes the fuel and oxygen together and, with the assistance of an ignition device, provides a platform for combustion. This combustion takes place in the combustion chamber, and the heat that it generates is transferred to the water through the heat exchanger. Controls regulate the ignition, burner firing rate, fuel supply, air supply, exhaust draft, water temperature, steam pressure, and boiler pressure. Hot water produced by a boiler is pumped through pipes and delivered to equipment throughout the building, which can include hot water coils in air handling units, service hot water heating equipment, and terminal units. Steam boilers produce steam that flows through pipes from areas of high pressure to areas of low pressure, unaided by an external energy source such as a pump. Steam utilized for heating can be directly utilized by steam using equipment or can provide heat through a heat exchanger that supplies hot water to the equipment. Pressure vessel integrity, checking of safety relief valves, water cutoff devices and proper float operation, gauges and water level indicators are inspected. The boiler’s fuel and airfrom environment filtration low pressure area intercooler high pressure compartmentafter coolerdrierstorage tank to different areas at different velocity
burner system requires proper inspection and maintenance to ensure efficient operation, heat transfer and correct flame detection. 6.2 CHILLER Provide cold water from the chillers used in the cold water coil and the air from the compressor. They are used to provide cold water which is used in reducing temperature of a cubicle through HVAC system. When there is a change is relative humidity and temperature the level of cold water given is changed to fit the conditions required i.e. increased cold water when lower temperatures are required. Operation A vapor-compression chiller consists of four primary components of the vapor-compression refrigeration cycle. They include a compressor, evaporator, condenser and a metering device. Vapor-compression chillers typically utilize HCFC or CFC refrigerants to achieve a refrigeration effect. Compressors are the driving force in a vapor-compression chiller and act as a pump for the refrigerant. Compressed refrigerant gas is sent from the compressor to a condenser unit that rejects the heat energy from the refrigerant to cooling water or air outside of the system. The transfer of heat allows the refrigerant gas to condense into a liquid which is then sent to a metering device. The metering device restricts the flow of liquid refrigerant which causes a drop in pressure. The drop in pressure causes the warm refrigerant liquid to change phase from liquid to gas and in doing so absorbs heat from the water to be cooled due to adiabatic flash evaporation. The metering device is positioned so that the expanding refrigerant gas is contained within the evaporator, transferring the heat energy from the water to be cooled into the refrigerant gas. The warm refrigerant gas is then sent back to the compressor to start the cycle over again and the newly chilled water in the separate loop can now be used for cooling. 6.3 HVAC system While there are many functions that a HVAC system serves, the primary function is to maintain a comfortable temperature in every room. This is done by the regulation of humidity, air flow, as well as temperature so that these parameters stay within acceptable limits. While this makes staying indoors comfortable, it also ensures that inhabitants do not suffer from health risks that
reside in the categories of excessive fatigue, draining out, heat strokes and hypothermia. HVAC, as the name suggests, has three primary functions, they are:  Heating: HVAC serves the function of heating, this really could be the difference between life and death. When it is literally freezing outside, you need a system that keeps you warm and if it does it in a uniform manner, then all the more better and an HVAC system does. Heating can be achieved through local as well as central heaters.  Central heating systems tend to be more cost effective and are made up of furnaces, heating pumps, and radiators.  Ventilation: The V in HVAC stands for ventilation which pertains to the movement of air in the home. Controlling the air flow allows the cleansing of the atmosphere indoors so that unnecessary carbon dioxide can be carted out and the oxygen let in. Not only does this aid breathing but it also aids in the prevention of air borne diseases and allergies  Air Conditioning: An air conditioning system may be one comprising of several window machines or one central system. Dirty air ducts will need to be cleared immediately so that no pathogens thrive and are living in it 6.4 ETP a process to convert wastewater - which is water no longer needed or suitable for its most recent use - into an effluent that can be either returned to the water cycle with minimal environmental issues or reused. Waste from any industry should be treated before being released to the environment. Waste from industries such as pharmaceutical industries can cause harm to the environment if let out untreated. There wastes contain toxic substances which when released contaminate or pollute both water and air. The main use of the ETP system is to treat waste released by the facility. The ETP is located outside the facility approximately 400 meters to prevent contamination .There are two types of waste treated by the ETP, which are domestic waste which contains water from wash rooms, kitchen and industrial waste which contains waste that was in direct contact with the product. After treatment the water is tested for different parameters before releasing it to the Environment. 6.5 WATER TREATMENT Water quality affects every operational aspect for manufacturers of pharmaceuticals. The raw water obtained by the facility passes through multiple stages in the process of purification .The
purification is used to remove contaminants like; inorganic compounds, .organic compounds, solids, gases, microorganisms. The source of raw water is borehole and NWSC (National water and Sewerage Corporation). The types of water used at QCIL are purified and portable water. The main source of raw water is national water and sewerage cooperation which supplies the portable water. The portable water undergoes the following stages in order to achieve purity. STAGES OF WATER TREATMENT AND PURIFICATION The pretreatment unit consists of;  MGF – for filtration  Softener –Removes hardness  Ultra filtration –Reduces the SDI (silt density index)  SMBS (sodium metabisulphite) - to neutralize free chlorine. Chlorine dosing done using sodium hypochlorite (3ppm). MGF consists of sand media, gravels, pebbles, corax, silex, fine corax and fine silex. The softener removes hardness. Ultra filtration reduces SDI.Ultra filtration tank dosed with SMB which neutralizes free chlorine. Permanent hardness is removed by backwashing / ion exchange. Dosing with chlorine.  Chlorine kills off all the susceptible microorganisms.  Filtration.  This is done using a multi-grade filter.  The filter aids the removal of particulate matter. SOFTENER UNIT RAW WATER PRETREATMENT GENERATION STORAGE AND DISTRIBUTION
A water-softening system removes calcium and magnesium ions from hard water and replaces them with sodium ions. Calcium and magnesium ions interfere with the action of household soaps and detergents, but sodium does not. The water-softening process thus helps detergents to more effectively remove dirt and oils from clothing and dishes. The pump house contains several cubic feet of porous plastic resin covered with molecules that attract and bind to positive ions dissolved in the water. Normally, sodium positive ions coat the resin, but as water flows over the resin the naturally occurring calcium and magnesium positive ions that exist in hard water stick to the resin. This releases sodium ions into the water in order to maintain a balance of electrical charge on the resin. Gradually, most of the sodium ions are released into the plant water, and the resin becomes saturated with calcium and magnesium ions. Every few days, the unit must renew the resin by rinsing it with a concentrated solution of saltwater (sodium chloride), usually in the middle of the night. The high concentration of sodium ions in the salty water displaces the calcium and magnesium ions the resin, and the resin becomes once again covered with sodium ions. The salty rinse water, calcium and magnesium ions are flushed down the drain, and the system resumes normal operation. (Every so often it is necessary to add a bag of sodium chloride salt to the softener unit to prepare this salty rinse water.) ULTRAFILTRATION UNIT This unit is used to filter off particulate matter, colloidal impurities, silt and microbes and to reduce the silt density index to <3. Consists of membrane of 0.02μ,5μ cartridge pre-filter which polishes the water particulate matter which cannot be removed by MGF , a plate type heat exchanger which ensures transferred water is NMT 25OC to avoid damaging the RO membrane. Backwash is done every 1hour while disinfection is done after every 30 cycles using sodium Hypochlorite. Monitored parameters: pressure, temperature, flow rate, SDI. REVERSE OSMOSIS In reverse osmosis water moves from an area of low water concentration to a region of high water concentration under a pressure gradient across a semi permeable membrane. All other molecules except water are retained on the side of lower water concentration. RO membrane is
0.01micron pore size and is sensitive to temperature and chlorine. It is made of polyamide. RO is in series to-ensure efficiency of the RO process in addition to minimizing wastage. ELECTRODE –IONISATION (EDI) Electrode ionization uses an electric field to remove ions and polar species from an aqueous stream. EDI is used with reverse osmosis to replace ion exchange resin-mixed beds, which require onsite or offsite chemical regeneration. By eliminating resin regenerating chemicals, EDI delivers significant economic and environmental benefits. In addition, EDI’s continuous process improves water quality by reducing spikes and upsets. Monitored parameters: pressure, conductivity, temperature, voltage STORAGE AND DISTRIBUTION The storage and distribution unit consists of a 2000 liter tank, and S&D pump, a U.V unit and a recirculating pipe line. U.V unit consists of a U.V lamp that is enclosed in a transparent quartz sleeve. As water passes through the flow chamber the microbes are exposed to the U.V rays which damage their DNA structure hence preventing their reproduction and multiplication. Increased intensity of rays increase the kill of the microorganisms. Monitored parameters include UV Intensity, temperature, conductivity, flow rate.
7 LESSONS LEARNT The time I spent at CIPLAQCIL I learnt a lot .these include  The knowledge about the process of the manufacture of medicines.  All manufacturing facilities follow current good manufacturing practices(cGMPs)  The uses of a chemical engineer in a pharmaceutical  The need for controlled environment in a facility  Team work .I improved on my networking skills .for instance I was challenged to seeing faces I had never and had to make friends so that the training would go on smoothly. 8 CHALLENGES  Identifying places for industrial training was difficult since some institutes were not in need of trainees.  The university does not define the characteristics of places for industrial training. This would lead to trainees diverting to other fields.  Operation of Some equipment at the factory required more training. This limited our practical activity in the field.  Some departments were allocated less time so it was a challenge learn everything.  Some information at the factory was limited to only specified personnel making quest for information hard. 9 CONCLUSIONS The training was highly motivating. Usage of SOPs, cGLPs, cGMPs was highly emphasized. Most of the objectives in the industry were achieved but some of them couldn’t be achieved due to the time allocated to us by the industry. I have learned how science and engineering can interact in useful ways and how remarkable research can occur even when it is ‘profit driven’; at CiplaQCIL creativity is not limited and true innovation occurs. The company gave me to chance to study the loss of primary packaging material on Lumartem 24s blister packing. I was lucky enough to work with a group of enthusiastic and communicative people, who were passionate about what they are doing in the industry.
The atmosphere at CiplaQCIL is unique and hope that it stays that way. It has been a unique opportunity and one that I will not soon forget. My time there has been eye opening especially in the departments of Engineering, Quality Control and Production. I thoroughly recommend the experience to any other student who is thinking of applying. Despite the success achieved there are a few challenges which I hope can be addressed progressively given more opportunity? 10 RECOMMENDATIONS  The university should identify potential areas for placement in order to avoid students going to place where their course does not fit.  The university should improve the industrial training policy by my making agreements with certain industries and agreeing on the number of students to be sent to the industries.  The industry should identify the period needed for certain departments instead of giving them equal time.  Capacity building for handling complex equipment and this required another chance for placement to be negotiated by the university 11 REFERENCES  David J. am Ende, 2011, CHEMICAL ENGINEERING IN THE PHARMACEUTICAL INDUSTRY John Wiley & Sons, Inc.  http://www.ciplaqcil.co.ug  USP 36-Nf 31 2013 (3 Vol Set) (U.S. Pharmacopoeia: National Formulary)  British Pharmacopoeia 2014978-9380501246  2014/2015 Uganda National Development Plan National development Plan  Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 908), Annex 4.  CiplaQCIL 2014 Komboa newsletter volume 10

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report

  • 1. KYAMBOGO UNIVERSITY TITLE: INDUSTRIAL TRIANING REPORT NAME OF STUDENT: OMAGOR NICHOLAS REG. NO: 13/U/7251/CHE/PE YEAR OF STUDY: YEAR II ACADEMIC YEAR: 2014/2015 PROGRAM OF STUDY: BACHELOR OF SCIENCE IN CHEMICAL ENGINEERING NAME OF INDUSTRY: CIPLA QUALITY CHEMICALS INDUSTRIES LTD
  • 2. i DECLARATION I OMAGOR NICHOLAS a student of KYAMBOGO UNIVERSITY declare that I have written this report myself as an academic requirement. All the material contained in this report is an original record of the work and activities I was involved in during my industrial training at CIPLA QUALITY CHEMICAL INDUSTRIES LIMITED (CiplaQCIL). …………………………………
  • 3. ii APPROVALS This is to certify that OMAGOR NICHOLAS had his industrial training for eight weeks here at CiplaQCIL and that this report is a true record of the work he did under our supervision. Signature……………………………….. Date…………………………………… Mr. JOHN KAMILI INDUSTRIAL SUPERVISOR Signature………………………………… Date……………………………………. Mr. MANANO JOHN ACADEMIC SUPERVISOR
  • 4. iii DEDICATION This document is dedicated to my dear parents Mr. and Mrs. Enginyu, lecturers of Kyambogo University, the staff of CiplaQCIL and to my fellow class mates. It is most especially dedicated to those who directly or indirectly assisted during my training at CiplaQCIL.
  • 5. iv ACKNOWLEDGEMENTS It is always a pleasure to remind the fine people at CIPLAQCIL for the sincere guidance I received to uphold my practical as well as theoretical skills in engineering. Firstly, I would like to thank CIPLAQCIL for convincing me on the saying that “Whatever is imagined, can be achieved”, treating me as an employee of their own and guiding me to the real flavour of engineering discipline. Secondly, I would like to thank the staff at CIPLAQCIL for the positive attitude they should for my work, always allowing me to question them and giving prompt replies for my uncertainties in all the fields including educational, social and managerial to labor work. Thirdly I would like to thank Ms. Achen Irene of Department of quality assurance and Mr. Kamili John regulatory affairs executive for extending their friendship towards me and making a pleasure-training environment at the factory. A paper is not enough for me to express the support and guidance I received from them almost for all the work I did there. Mr. Manano John our academic supervisor for checking on us at the factory and giving us support on how to go about with the training. Opening our minds on some areas we didn’t raise queries in the training. I thank all the trainees who underwent training with me the mutual support I received from them. Department of chemistry Kyambogo is much thanked for allowing me to have my training in CIPLAQCIL. I also would like to thank my family for the support they gave to me during this whole internship period making sure I turn up on time and all that I can’t mention. Finally I apologize all other unnamed who helped me in various ways to have a good training Knowledge is power and unity is strength.
  • 6. v ABBREVIATIONS; ACF-ACTIVATED CARBON FILTER AHU-AIR HANDLING UNIT API- ACTIVE PHARMACEUTICAL INGREDIENT ARV-ANTI RETROVIRAL BMR-BATCH MANUFACTURING RECORD BPR-BATCH PACKAGING RECORD CAPA- CORRECTIVE AND PREVENTIVE ACTION cGLP- current GOOD LABORATORY PRACTICES cGMP – current GOOD MANUFACTURING PRACTICES CiplaQCIL –CIPLA QUALITY CHEMICALS INDUSTRIES LIMITED DT-DISINTERGRATION TIME EDTA- ETHYLENE DIAMINO TETRA ACETIC ACID EFV- EFAVIRENZ ETP- EFFLUENT TREATMENT PLANT FAT-FACTORY ACCEPTANCE TEST FBE-FLUIDIZED BED EQUIPMENT FIFO/FEFO-FIRST IN FIRST OUT /FIRST EXPIRY FIRST OUT GC-GAS CHROMATOGRAPHY GMP-GOOD MANUFACTURING PRACTICES GRN- GOODS RECEIVED NOTE
  • 7. vi HDPE- HIGH DENSITY POLYETHENE HPLC-HIGH PERFOMANCE LIQUID CHROMATOGRAPHY HVAC-HEATING, VENTILATION AND AIR CONDITIONING SYSTEM IPA-ISOPROPYL ALCOHOL IPQC-IN PROCESS QUALITY CHECKS IRS – INFRA RED SPECTROSCOPY LAF-LAMINAR AIR FLOW MGF-MULTIGRADE FILTER MIPC-MACHINERY IN PROCESS CONTAINER NDA-NATIONAL DRUG AUTHORITY NMT-NOT MORE THAN NWSC-NATIONAL WATER AND SEWAGE COOPERATION PVC-POLYVINYL CHLORIDE QA-QUALITY ASSURANCE QCIL-QUALITY CHEMICALSINDUSTRIES LIMITED QC-QUALITY CONTROL R&D- RESEARCH AND DEVELOPMENT RH-RELATIVE HUMIDITY RMG-RAPID MIXER AND GRANULATOR RO-REVERSE OSMOSIS SAT-SITE ACCEPTANCE TEST
  • 8. vii SCA-SUBAROUD CHLORAMPHENICOL AGAR SCDA-SOYA BEAN CASEIN DIGEST AGAR SDI-SLIT DENSITY INDEX SMB-SODIUM METABISULPHATE SMG-SAIZONER MIXER, GRANULATOR SOPs- STANDARD OPERATING PROCEDURES SPV-SOLUTION PREPARATION VESSEL SS-STAINLESS STEEL TRIPS -TRADE RELATED INTELLECTUAL PROPERTY RIGHTS. UV-ULTRA VIOLET VMP-VALIDATION MASTER PLAN
  • 9. viii ABSTRACT Industry training started on the 1st June for 8 weeks. Industrial training for undergraduates in Uganda universities is widely practiced. It provide hands-on experience and up-to-date information to the graduates who are about to enter the competitive job market. The report identifies specific approaches used for collecting the data on daily basis. It points out areas of experience gained from observations, interactions, hands on practice and analysis of data. The document highlights main findings of the training in the domain of management, unit operations, marketing, packing and storage that at all levels insured quality. However the report mentions some key challenges that could be useful in future review of field tools for chemical engineering students and recommends actions for future improvements. In conclusion, the report points out good practices in the industry, a linkage between theoretical exposure from the university and practical experience at the industry.
  • 10. 1 Contents DECLARATION................................................................................................................................ i APPROVALS................................................................................................................................... ii DEDICATION................................................................................................................................. iii ACKNOWLEDGEMENTS................................................................................................................iv ABBREVIATIONS............................................................................................................................v ABSTRACT...................................................................................................................................viii 1 INTRODUCTION AND BACKGROUND...................................................................................1 1.1 INTRODUCTION...............................................................................................................1 1.2 BACKGROUND.................................................................................................................1 1.3 OBJECTIVES OF TRAINING.............................................................................................2 1.4 TRAINING METHODOLOGY............................................................................................2 2 QUALITY ASSURANCE...........................................................................................................3 2.1 ROLES OF QA ...................................................................................................................3 2.2 GOOD MANUFACTURING PRACTICES. (GMP)..............................................................4 2.3 PHARMACEUTICAL QUALITY SYSTEM........................................................................4 2.4 cGMP .................................................................................................................................5 2.5 SELF INSPECTION:...........................................................................................................7 2.6 COMPLAINTS AND RECALLS:........................................................................................8 2.7 VALIDATION....................................................................................................................8 2.8 QUALIFICATION;...........................................................................................................10 2.9 DOCUMENTATION;........................................................................................................12 3 STORES...................................................................................................................................13 3.1 RECEIVING BAY AREA..................................................................................................14 3.2 RAW MATERIAL QUARANTINE AREA.........................................................................14 3.3 SAMPLING AREA. ..........................................................................................................14 3.4 APPROVED RAW MATERIAL AREA. ............................................................................15 3.5 DISPENCING...................................................................................................................15 3.6 PACKAGING MATERIAL STORES.................................................................................15
  • 11. 3.7 FINISHED GOODS STORE..............................................................................................16 4 QUALITY CONTROL..............................................................................................................17 4.1 WET CHEMISTRY...........................................................................................................22 4.2 WEIGHING SECTION......................................................................................................22 4.3 TITRATION and STANDARD AREA ...............................................................................23 4.4 WASHING AREA.............................................................................................................23 4.5 MICROBIOLOGY SECTION............................................................................................23 5 PRODUCTION.........................................................................................................................27 5.1 PRODUCTS OF CIPLAQCIL............................................................................................27 5.2 GRANULATION..............................................................................................................28 5.3 BLENDING......................................................................................................................32 5.4 COMPRESSION...............................................................................................................35 5.5 COATING ........................................................................................................................41 6 ENGINEERING........................................................................................................................45 6.1 BOILERS..........................................................................................................................46 6.2 CHILLER.........................................................................................................................47 6.3 HVAC system...................................................................................................................47 6.4 ETP ..................................................................................................................................48 6.5 WATER TREATMENT.....................................................................................................48 7 LESSONS LEARNT.................................................................................................................52 8 CHALLENGES ........................................................................................................................52 9 CONCLUSIONS.......................................................................................................................52 10 RECOMMENDATIONS.......................................................................................................53 11 REFERENCES......................................................................................................................53
  • 12. 1 1 INTRODUCTION AND BACKGROUND 1.1 INTRODUCTION Kyambogo University like any other university would like to maintain standards and integrity in the employment market so as their students are attractive to the future employeers.it is on this perspective the university emphasizes on both theoretical and practical training for their students .As for the program of bachelor of science in chemical engineering, usually at the end of semester two of your second or third year, one is granted the opportunity to take part in industrial training as part of the academic requirement. This is done under the supervision of the university and the factory technical personnel. 1.2 BACKGROUND According to the national development plan (2014/2015) the policy of the country prioritises on promotion of science and technology hence the need to support the training of science students especially engineers in order to reduce the human resource gap in economic development. In response to this government thru ministry of Education has made provisions for science students to go to university through student’s loan scheme and government sponsorship. The country relies more on imported human resource for its highly trained labour market .Kyambogo university is one of the beneficiaries among the public university. It is traditionally renowned for its competent engineers because of its emphasis on practical skills, partnership with local industries and institutions. In chemical engineering, there are number of chemical based industries which are in partnership with the university. They have state of the art modern facilities suitable for industrial training. Most of the industries are in support of the industrial training of students to increase potential source of labour. Potential industries in need of the chemical engineers include pharmaceuticals, food processing plants, oil refineries, breweries and mineral processing plants just to mention but a few. The university has therefore encouraged students to apply to any of the industries for placement, because they provide more knowledge, skills and practices for effective modelling of students for future employers. It is in view of this, I was fortunately selected by Cipla Quality Chemical Industries Limited (CiplaQCIL) against competing demands from other universities.
  • 13. BRIEF INFORMATION ABOUT THE COMPANY: Cipla Quality Chemical Industries Limited (CiplaQCIL) is a state of the art pharmaceutical manufacturing plant located in Kampala, specializing in manufacturing Anti-retroviral drugs (ARVs) and Artemisinin-based Combination Therapies (ACTs) to combat HIV/AIDS and Malaria respectively. The company was founded in June 2005 as a joint venture between Quality Chemicals Limited (QCL), a Ugandan company dealing in the importation and distribution of pharmaceutical drugs, and Cipla Ltd, a leading Indian pharmaceutical company. The joint venture then attracted Capitalworks Investments of South Africa at 14.4% and TLG Capital Investment of United Kingdom at 12.5% leaving Cipla and QCIL at 36.55% each with a vision to become a center of pharmaceutical manufacturing excellence in the region. QCIL sold more shares to Cipla Ltd. in 2013 to facilitate more pharmaceutical production and technology transfer. Cipla now owns 51.05% of the shareholding with QCIL holding onto 22.05%. CiplaQCIL is designed to meet the world’s most stringent pharmaceutical regulatory standards and is pre-qualified by the World Health Organization (WHO) as an additional contract manufacturing site for Cipla Ltd antiretroviral and anti-malaria 1.3 OBJECTIVES OF TRAINING The objectives are based on identified training needs from students and employers. They specifically include:  To gain practical work experience and to be able to see theory in practice.  To learn accepted safety practices in the industry.  To develop personality and communication skills for future roles as leaders in the scientific and technological world.  To improve the student’s manual skills associated with scientific and technological operations in the manufacturing industry. 1.4 TRAINING METHODOLOGY The industrial training considers a range of methods for collecting data and analyzing it which informed the field report writing. Specific methods included
  • 14.  Data collection forms from the university and industry.  The industry provided a checklist on what was to be learnt in each department  Orientation was done in two days from both the outside and inside of the facility. It was done on rotational basis from one department to another.to allow everybody to know what happens in every unit.  Reading documentation like SOPs which were available in all the rooms in the facility for safety and quality assurance purposes.  In order to gain deeper understanding of the industrial training, discussions with supervisors were done. Academic and industrial supervisors were also tracking the performance to ascertain we are in the right direction.  Some activities such as sifting, packing, in process checks, validation were done practically so as to gain confidence. 2 QUALITY ASSURANCE With regard to pharmaceuticals, quality assurance can be divided into major areas: development, quality control, production, distribution, and inspections. With regard to pharmaceuticals, quality assurance can be divided into major areas: development, quality control, production, distribution, and inspections. 2.1 ROLES OF QA  Responsible for all quality management systems of the facility  Approving or rejecting all components, drug product containers, closures, in-process materials, packaging material, labelling and drug products.  Review production records.  Ensure that if errors have occurred, that they have been fully investigated.  Approving or rejecting drug products manufactured, processed, packed or held under contract by another company.  Approving or rejecting procedures or specifications  QA ensures all activities involved in all the above departments are done the right way as stipulated in the SOPS and cGMP is followed.
  • 15. The QA department is made up of the following areas;  QA office  Document room ,were records are kept  Training Centre were training takes place from. It operates on the following principles;  Quality safety and effectiveness must be designed and built into a product  Quality isn’t tested it’s made.  Responsibility for quality is a collective one is all individuals involved.  Quality aims at continuous improvement of systems  Each step of manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications hence process validation. 2.2 GOOD MANUFACTURING PRACTICES. (GMP) GMP protects patients. GMP ensures that they receive medicinal products of uncompromised high quality. Compliance with these quality standards is imperative during the manufacture, processing, packaging and storage of medicinal products. Manufacturing authorization will be denied to any company that fails to comply with GMP regulations. This is governed all over the world by acts of law, regulations and guidelines issued by government bodies, ministries and international organizations. Their goal is to put safe and effective medicinal products on the market with no harm to the patients. 2.3 PHARMACEUTICAL QUALITY SYSTEM The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. To achieve this quality objective reliably there must be a comprehensively designed and correctly implemented pharmaceutical quality system (PQS) incorporating GMP and QRM Quality management is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. Quality management, therefore, incorporates
  • 16. GMP and other factors, including those outside the scope of this guide, such as product design and development. 2.4 cGMP GMP applies to the life-cycle stages from the manufacture of investigational medicinal products, technology transfer, and commercial manufacturing, through to product discontinuation. Components of cGMP PREMISES.  The rooms are designed and constructed to minimize risks of errors and cross contamination while promoting easy cleaning and maintenance.  Proper arrangement of a room and design will promote quality of final product since it will be minimizing cross contamination. This can be seen on the epoxy floors used in the facility which promote easy cleaning.  The design of the production area allows for unidirectional flow.  Double skinned windows in production area and all utility fixtures are fitted in to the wall and ceiling. There is also a walk able ceiling used to do maintenance work like on lighting.  The floor in production area is made of epoxy and the walls are painted with white poly urethane coat that has antifungal properties.  There are no corners in the rooms or curved wall joints for easy cleaning. PERSONNEL. The element of personnel comprises majorly of hygiene, medical checkups, gowning procedures and training of the workers in the facility .Since the workers are likely to get into contact with the materials and products in the manufacture of drugs .The following procedures were followed in the facility.  The facility has got an adequate number of qualified people with practical experiences that are given initial training in GMP and continuous training.
  • 17.  There is restricted access to the production area.  Heads of production and quality control are independent of each other.  All personnel prior to and during employment undergo health examination. Before moving from one area to another all personnel thoroughly disinfect their hands. Adequate changing facilities with washrooms are available and a standard operating procedure is followed. EQUIPMENT This aspect comprises of the machines and equipment that are used in the drug manufacture. Characteristic properties that the material they are made of include:  Generally the equipment are made of materials that are generally non corrosive, non- absorptive and nonabrasive in nature e.g. SS 316.  All the equipment are located, designed, constructed, adapted and maintained to suit the operations to be carried out.  The design of the equipment allows for easy cleaning.  Moving parts of the machines are enclosed.  Equipment used for production is made of SS 316 for contact parts that has a mirror finish and SS 304 for non-contact parts. MATERIALS The materials used in production are purchased from approved and certified suppliers. Before use QC has to carry out tests to confirm their identity and quality standards. The materials are stored in the required conditions as specified by the manufacturer. Material personnel contact is minimized by laminar air flow unit during sampling and dispensing .The use of lifts also limits personnel contact to the materials. The storage of the materials involves labels and status boards for identity. All raw materials are procured from approved vendors and are quarantined immediately after receipt until released by QC. There are adequate facilities for storage of the raw materials and are segregated .A provision is available for cold storage.
  • 18. 2.5 SELF INSPECTION: Self-inspection is basically a method of objective overall review of operation on aspects that may have on quality effect on quality assurance. In general, self-inspection aims at identifying deficiencies in cGMP whether of critical, major or minor nature. Self-inspection is conducted by designated competent persons from the company. Self-inspection program is conducted in order to monitor the implementation and compliance with current GMP principles and to ensure that the necessary corrective measures are taken. Coverage of Self inspection: The Self inspection team should carefully study every point in the GMP guidelines and drive questionnaires fitted to the company needs. The following items should undergo self-inspection so as to ensure GMPs in the premises as per WHO requirement.  Personnel  Premises and Equipment  Maintenance  Storage of starting and finished products  Production and in-process controls  Quality control  Documentation  Sanitation and Hygiene  Validation and revalidation program  Distribution  Product complaint and recall  Calibration of instruments  Labels control  Results of previous self-inspection and corrective action taken Corrective Action:  Should be appropriate to correct deficiency  Must prevent re-occurrence  Must be completed in a timely manner
  • 19.  It should be documented and records maintained  Must be monitored 2.6 COMPLAINTS AND RECALLS: A complaint is an expression of dissatisfaction conveyed to an organization about a product, written, electronic or oral communication that alleges deficiencies related to the identity, quantity, durability, safety, effectiveness or performance of a drug after it is released for distribution. CHANGE CONTROL Any change has to go through a clear approval by the QA manager. Change may be; Major (majorly affect other processes), Moderate (may or may not affect any process. Minor (impact no change on process). The change may be process related or product related. Change control goes through stages which include Initiation, approval, and implementation. 2.7 VALIDATION Involves establishing evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. Validation generally implies that a process, product or machine does what it’s supposed to do .Validations are done after finalizing a formula for a product, processes, before or after new drug application approval for example for a new drug product three batches are validated before applying for marketing authorization. The major aim of carrying out this process is to assure that products have identity, strength, quality, and purity they are represented to possess (purport). TYPES OF VALIDATION:  Process validation: ensures that a given process is capable of producing products that are of the required standard  Prospective validation: which is done prior to distribution of the products  Concurrent validation: generation of validation data with normal production
  • 20.  Retrospective validation: validation which is done to products already in distribution  Cleaning validation; done to verify the effectiveness of cleaning procedure for removal of the product residues, degradation products, preservatives, excipients and or cleaning agents so that analytical monitoring may be reduced to a minimum in the routine phase. DOCUMENTATION IN VALIDATION: Validation MasterPlan: It’s a document that summarizes the firms overall philosophy, intentions and approach to be used for establishing performance adequacy. It is a clear concise reflection of the key elements of the Validation program contains at least;-  A validation policy  Organizational structure of validation activities  Summary of facilities, systems, equipment and processes validated and to be validated  Documentation format (e.g. protocol and report format)  Planning and scheduling  Change control  References to existing documents. The uses of the VMP include:  To know what validation program involves with respect to time, people and money and to understand the necessity of the program  Helps Validation team to know their tasks and responsibilities  Helps GMP inspectors to understand a firm's approach to validation and the set up and organization of all validation activities.  Capacity planning. Validation protocol: a written plan stating how validation process will be conducted including the test parameters, product characteristics, production equipment and the acceptance criteria.
  • 21. Validation report: a written report on the validation activities, validation data and conclusions drawn. 2.8 QUALIFICATION; It’s like validation but applies to systems, equipment and facility area. Is an action of providing documentation that premises, systems and equipment’s are properly installed, and/or work correctly and lead to the expected results. Qualification is part of Validation process only that it is always used for the equipment’s, utilities and system. It is also the initial step of validation process. Validation is used for the processes. Qualification has been divided into the following parts; Designqualification (QC) Installation qualification (IQ) Performance qualification (PQ) Operation qualification (OQ) Qualification has got stages that include the following; In case of new machines a process is passed through a process that involves a machine certifying that a machine that is suitable for its function. IQDQ PQOQ GMPcertification DQURS SATFAT OQIQ PQ
  • 22. User Requirement Specification: The Company makes URS that includes description of equipment, GMP aspects, parts, capacity, speed, location suitability, details of utilities. DesignQualification: Evidence that the equipment and process have been designed in accordance with requirements of GMP. After manufacturer has received the user requirement specifications, he sends a document with the design of the machine he can manufacture depending on design sent. Factory Acceptance Test: When the user has seen that the design can work for required purpose, he sends a factory acceptance note to manufacturer, giving him a go ahead to manufacture machine .Before machine taken to premises it’s then tested from the factory under strict supervision by the company purchasing. The FAT is issued if it’s perfect and machine is shipped. SAT: Site Acceptance Test prepared by the company to ensure that the FAT, utilities required for the equipment if any and prove that equipment meets requirement. This is done to ensure that the machine is functioning properly at site of the user. Installation qualification; provides documented evidence that premises, supporting utilities and equipment have been built and installed in compliance with their specification. Operation qualification: provides documented evidence that the operation of a machine complies with the required specification. After installation the machine, it is first run on dry runs, to check for its operation as specified by the manufacturer. It’s qualified for operation. Performance qualification: Process/ equipment will consistently produce a product meeting its predetermined specification and its quality attributes. A hand over certificate conducted during the 1st three batches using placebo batch and product in the following combinations:  All three batches of placebo  One batch of placebo and two batches of the same product  One batch of placebo and two batches of different products (commercial)  Three batches of different products  The documents that are used in validations include
  • 23. STANDARD OPERATING PROCEDURE Logical sequence of events in instructional form of how, when, where and by whom an activity is to be carried out .In the facility SOPs where found in all the cubicles hanged on the walls. SOP consist of the following;  Examples of SOPs  SOP of SOPs  SOP of complaint handling and record  SOP of deviation handling  SOP of annual product quality review  SOP of recall procedure.  Etc. 2.9 DOCUMENTATION; It’s an important aspect of cGMP. Importance of documentation is given below;  Ensure that there are specifications for all materials and methods of manufacture and control.  Ensure all personnel know what to do and when to do it.  Ensure that authorized persons have all information necessary for release.  Provide audit trail.  To provide history of manufacture of a product. TYPES OF DOCUMENTATION.  Labels, specifications and master formulae.  Batch processing and BPR.  SOPs.
  • 24. 3 STORES How goods move in facility Production starts at stores and ends at stores. Before raw materials are bought .they source the manufacturers who are to supply the factory with the materials. The approved manufacturers are then placed on a list. The list is then sent to procurement to decide who to purchase from. Before the use of materials they are stored in well configured areas for inspection and approval .The storage of these materials is a responsibility of the stores department. The function of this department is the reception of procured materials and finished materials. The materials are stored in a way to ensure that there is no cross contamination .Before production or packing the various departments send BMR or BPR respectively. These contain a description of how much is needed for the activity to take place. If a certain material is out or almost out of stock. A requisition is made and sent to procurement which spearheads the purchase of the material. STORES ALSO HAS CERTAIN PRACTICES TO ENSURE cGMP: They include the following  Storing items on mobile racks. RECIEVING BAY QUARANTINE GOODS STORE SAMPLING AREA BY QC APPROVED GOODS STORE DISPENSING STORE PRODUCTION FINISHED GOODS STORE DOCUMENT REVIEW BATCH RELEASE CERTIFICATE DISPATCH
  • 25.  Preventing the items from getting into contact with the ground using the racks  Cleaning the floor regularly  Having separate sampling and dispensing rooms for both active and inactive ingredients  Documentation of the activities done.  Monitoring the conditions of the rooms since certain items require specific conditions.  Following the correct gowning procedures for activities like sampling and dispensing  Displaying SOPs around the different store areas  Using trolleys to carry materials instead of man  Control access is limited to most areas using a thumbprint, padlocks  Using double seal locks  Dispensing and sampling rooms have laminar air flows to prevent cross contamination Stores is divided into 6 areas which include; 3.1 RECEIVING BAY AREA Materials that have been purchased enter the facility through the receiving bay .The receiving bay is divided into two areas .The packaging material and raw material receiving bay .each receiving bay has a change room of its own. The doors at entrance to receiving bays have air curtains to prevent mixing of inside and outside air. 3.2 RAW MATERIAL QUARANTINE AREA. Before materials are used, they are quarantined for sampling tests .in order to determine their quality. Tests include assay, if they pass the physical and chemical tests at QC. This area has a sampling area for both active and inactive raw materials. The materials under tests are labeled with an UNDER TEST label (yellow) and those awaiting reanalysis have REANALYSIS label (red). The room is kept at a temperature of (2-25) º C and RH of 45%-60%. The pressure is also monitored using manometer, while temperature and humidity monitored by a hygrothermometer. The active materials and inactive materials include 3.3 SAMPLING AREA. This area is used by QC department for the sampling process done for materials under test. Whereas QC uses this area stores maintains it. The sampling areas include the inactive and active
  • 26. sampling area. Each sampling area has its own change room .the materials are received into the sampling areas through raw material pass box .The sampling unit is a class 5 ISO classified .It is made of a laminar air flow unit .Sampling is done in the laminar air flow unit prevention of cross contamination between the sampler and the material is achieved due to the unidirectional air flow. 3.4 APPROVED RAW MATERIAL AREA. When the material has passed the test carried out during sampling, it is given a PASSED LABEL (green). These materials are then taken to the raw material approved area .They are then kept in this area before dispensing. The materials are kept on a mobile rack system and the temperature and humidity measured by hygrothermometer and pressure measured by nanometer. Some Materials which require cool conditions are kept in cool walk in chamber .When excess material was in the approved room due to the less space in the quarantine room, the yellow rope is removed and replaced by a green rope. The materials are kept separated segregated batch wise as pallets / item wise as pallets / shelf. 3.5 DISPENCING Dispensing is done under ISO class 5 Reverse Laminar Air flow booth. Active and inactive are dispensed separately. This is done after a requisition has been made by the department in need 3.6 PACKAGING MATERIAL STORES This store is divided into two; primary packaging material store and tertiary, secondary store .The tertiary and secondary material are stored in the same cubicle which has no ISO classification. The packing materials in this area are kept off the floor on pallets and in a mobile rack system PRIMARY PACKING MATERIAL. Primary packing material are material directly attached to drug .This cubicle contains a laminar air flow unit and a mobile rack system. The materials are kept off the flow on mobile racks. There are a variety of primary packing materials which include;  PVC ACLAR  FOIL
  • 27.  HDPE bottles  Caps Procedure of receipt. Has sections; - primary, secondary, and tertiary packing material store. After receipt of these materials each is kept in its respective store where it’s first quarantined until it passes QC tests then they are passed. Primary packing material must be sampled and dispensed under a lamina air flow cabinet. SECONDARY PACKING MATERIAL  Cartons  Enclosures  literature  Cotton  Silica gel  Labels TERTIARY PACKING MATERIALS  Shippers  BOPP Tapes  Fitments  Labels 3.7 FINISHED GOODS STORE. The finished pharmaceutical products are stored here before dispatch. Before dispatch the store must first issue a batch release certificate. This area is involved in the storage of the finished goods temporarily until the QC and QA tests are complete. If passed, the goods are then ready for distribution. The finished goods are kept on a mobile rack system off the ground batch wise. They are also kept on SS pallets together as a batch .The temperature and humidity are monitored using a hygrothermometer and pressure using a manometer .temperature (19-25) º C and RH (45-60) %. The goods can be attached with UNDER TEST and PASSED status boards.
  • 28. 4 QUALITY CONTROL Quality control is divided into two main departments’ chemistry and microbiology. Chemistry department mainly deals with the active ingredients and some other tests like packaging materials. Microbiology deals with the inactive and microbiological organisms this department ensures that manufactured products, materials or performed services adhere to a defined set of quality criteria or meets the requirements of client and also detect defects. The department carries out chemical and physical analyses of different samples like  Water.  Air  Primary packaging materials  Raw materials.  Finished products The instruments found in QC include; Analytical Balance an analytical balance is used to measure mass to a high degree of precision and accuracy. To some the analytical balance may simply be known as a set of scales, but an analytical balance is able to measure down to the ten thousandth of a gram. An analytical balance, also known as a precision balance, it most often found in a laboratory setting and is used only with the most meticulous of measurements. They require a draft-free location on a solid bench that is free of vibrations. Some modern balances have built-in calibration masses to maintain accuracy. pH Meter a pH meter is an electronic instrument used for measuring the pH (acidity or alkalinity) of a liquid (though special probes are sometimes used to measure the pH of semi-solid substances). A probe is placed in a liquid, and it generates an electrical voltage that is converted to a logarithmic pH reading. The pH scale range is 1 to 14. Polarimeter a polarimeter is a scientific instrument used to measure the angle of rotation caused by passing polarized light through an optically active substance. Anisotropic crystalline solids, and samples containing an excess of one enantiomer of a chiral molecule, can rotate the orientation of plane-
  • 29. polarized light. Such substances are said to have optical activity. Measurement of this change in polarization orientation is called polarimetry, and the measuring instrument is called a polarimeter. These measurements are useful for studying the structure of anisotropic materials, and for checking the purity of chiral mixtures. • Isolating and identifying unknowns crystallized from various solvents or separated by high performance liquid chromatography (HPLC). • Evaluating and characterizing optically active compounds by measuring their specific rotation and comparing this value with the theoretical values found in literature. • Investigating kinetic reactions by measuring optical rotation as a function of time. • Monitoring changes in concentration of an optically active component in a reaction mixture, as in enzymatic cleavage. • Distinguishing between optical isomers. IR Moisture Balance: A high performance compact, dependable Infra-red Moisture Balance for measurement of moisture content of material not affected by radiation while losing water under of moisture exposure to Infra-red radiation. IR moisture balance is an accurate method for moisture content and dry weight analysis of a wide range of products and materials. KF Titrator Karl Fischer titration is a classic titration method in analytical chemistry that uses coulometric or volumetric titration to determine trace amounts of water in a. KF titration - is highly specific and precise - covers a wide concentration range: from ppm up to 100%. - has short determination times. IR Spectrophoto Meter It is used to measure the maximum absorption of infrared spectrum compound and the determination of IR radiation. Ultraviolet-Visible spectrophotometer Ultraviolet–visible spectroscopy or ultraviolet-visible spectrophotometry (UV-Vis) refers to
  • 30. absorption spectroscopy or reflectance spectroscopy in the ultraviolet-visible spectral region. This means it uses light in the visible and adjacent (near-UV and near-infrared (NIR)) ranges. UV/Vis spectroscopy is routinely used for the quantitative determination of different analytes, such as transition metal ions, highly conjugated organic compounds, and biological macromolecules. Determination is usually carried out in solutions. • Solutions of transition metal ions can be colored (i.e., absorb visible light) because d electrons within the metal atoms can be excited from one electronic state to another. The colour of metal ion solutions is strongly affected by the presence of other species, such as certain anions or ligands. For instance, the colour of a dilute solution of copper sulfate is a very light blue; adding ammonia intensifies the colour and changes the wavelength of maximum absorption (λmax). • While charge transfer complexes also give rise to colours, the colours are often too intense to be used for quantitative measurement. Particle counter a particle counter is an instrument that detects and counts particles. By its very nature a particle counter is a single particle counter, meaning it detects and counts particles one at a time. The nature of particle counting is based upon either light scattering or light obscuration. A high energy light source is used to illuminate the particle as it passes through the detection chamber. The particle passes through the light source (typically a laser) and if light scattering is used, then the redirected light is detected by a photo detector. Or if light blocking (obscuration) is used the loss of light is detected. The amplitude of the light scattered or light blocked is measured and the particle is counted and tabulated into standardized counting bins. The image to the right shows a light scattering particle counter diagram. Dissolution test apparatus In the pharmaceutical industry, drug dissolution testing is routinely used to provide critical in vitro drug release information for both quality control purposes, i.e., to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and drug development, i.e., to predict in vivo drug release profiles. The designs of the dissolution apparatuses and the ways of operating dissolution apparatuses have huge impacts on the hydrodynamics, thus the performances. Disintegration test apparatus it is used to measure the tablet disintegration time and subsequent drug dissolution.
  • 31. Friability Test Apparatus Tablet friability test apparatus are used for determination of durability of tablets at the time of production. The apparatus is designed to provide the precise value of rate of abrasion and impact hardness of the tablets. Friability is important since it affects in particle size distribution of granules affecting compressibility into tablet, tablet weight variation, granule flowability. Friability is determined carrying out Tumbler Test or using Friability Tester (RocheFriabilator) and % loss is determined. Hardness test facilities It is to measure the hardness the tablet and it is essential to determine the disintegration and dissolution of drug and efficient of drug. High-performance liquid chromatography (HPLC) High-performance liquid chromatography HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in quality control chemistry to identify, quantify and purify the individual components of the mixture. HPLC typically utilizes different types of stationary phases contained in columns, a pump that moves the mobile phase and sample components through the column, and a detector to provide a characteristic retention time for the analyte and an area count reflecting the amount of analyte passing through the detector. HPLC is really the automation of traditional liquid chromatography under conditions which provide for enhanced separations during shorter periods of time, utilizing
  • 32. very small particles, small column diameters, and very high fluid pressures HPLC is accomplished by injection of a small amount of liquid sample into a moving stream of liquid (called the mobile phase) that passes through a column packed with particles of stationary phase. Separation of a mixture into its components depends on different degrees of retention of each component in the column. The extent to which a component is retained in the column is determined by its partitioning between the liquid mobile phase and the stationary phase. In HPLC this partitioning is affected by the relative solute/stationary phase and solute/mobile phase interactions These instruments are calibrated regularly monthly and annually using standard weights The factors which influence the HPLC performance  Internal diameter of column  the smaller in diameter, the higher in sensitivity  Pump pressure  the higher in pressure, the higher in separation  Sample size
  • 33.  The polarity sample, solvent and column  Temperature  the higher in temperature, the higher in separation  To control the drug stability  Quantity of drug determination from pharmaceutical dosage forms  Quantity of drug determination from biological fluids, ex: blood glucose level DEPARTMENTS OF QC 4.1 WET CHEMISTRY The equipment used includes: Dissolution tester; Materials Lumartem, Duovir-N 4.2 WEIGHING SECTION The following instruments were seen in this section.  Analytical balance; for weighing material  Karl Fischer auto Titrator example Nevirapine, Lumartem tablets. .HOT ZONE AREA. Chemicals used here include;  Fuming chemicals for example HCl, H2SO4, HNO3, glacial acetic.  Triethtlemine GR-adjust pH of HPLC water. Equipment used include;  Vacuum oven-drying of substances in absence of air  Muffles furnace-determine sulfated ash-corn starch.  Precision hot air oven-analysis of ox-disable substances in H2O.  Ultrasonic cleaner-dissolving substances.
  • 34.  Fuming hood –for safety from dangerous acids through absorption of fumes by use of active carbon holding acids.  Heating mentle-boiling point 4.3 TITRATION and STANDARD AREA This area consists the following instruments;  pH meter-determine pH purified water  Bio-containment work station –prepare a compensate sample.  Magnetic stirrer-dissolving substances  Conductivity meter-determines water conductivity 4.4 WASHING AREA  Glassware drying oven –drying  Water purification system –purifies water for HPLC.  Water bath-heating, evaporation and warming. 4.5 MICROBIOLOGY SECTION Microbiology is under responsible for determining the microbial contamination in an environment, raw materials and finished products. It’s divided into five areas: Preparatory area. This is where activities are done in preparation for analysis. For example, sterilization of equipment, media preparation among others. Sterilization: this is done to kill all micro-organisms on the equipment to be used in the lab for analysis. There are two types of sterilization that are mainly used at Cipla QC. Steam sterilization;
  • 35. It is carried out using an autoclave. It’s carried out at 1210C for approximately 20 minutes. Materials sterilized using this method are sensitive to high temperatures for example Glass apparatus and equipment, dressings and fabrics and Plastic and rubber closures Dry heat sterilization; It uses a laboratory oven at 1600C for 2 hours. This method uses high temperatures and a high penetrating power. Materials sterilized by this method are not sensitive to high temperatures and include Glassware (sterilized up to 250° for 2 hours to effect depyrogenation) Media preparation; The process of preparation includes weighing the required amount and then adding a specified volume of water. Equipment present in the preparatory room includes;  Autoclave: For sterilization of media and other equipment used in the microbiology lab. It’s also used for destruction of media before it’s released to the environment.  Weighing balance: for weighing media during media preparation.  pH meter: for measuring the pH of the media.  Oven: For sterilization of instruments sensitive to moist heat.  Incubator  Refrigerator  Hot air oven: for drying. The types of analysis that occur in the microbiology laboratory include; Water analysis: To identify or quantify any microorganisms present for example pseudomonas aeroginosa, E.Coli, Salmonella, etc. Micro testing room: The area has laminar air flow. Hers a pass box foe passage of materials to and from the micro testing room. Incubation area:
  • 36. Various incubators are present and they incubate different microorganisms. The incubators are at different temperatures to favor growth of specific microbes for example:  40oC to 45oC for E.Coli.  35 to 37oC for pathogens.  25oC for fungi. Culture handling room: there is a bio containment work station where procedures are carried out from. It has vertical laminar airflow to protect personnel. It has a pass box where materials are passed to avoid cross contamination. Activities done in this area include; water analysis which is done under laminar air flow and dispensing of culture media. TYPES OF MEDIA AND THEIR USES. There are two types of media present in the microbiology section at Cipla QC; that is liquid media (broth) and solid media (agar). Examples of media present in the lab include; Media Use deoxycholate citrate Agar Selective for salmonella & shigella species EMB Agar (Levine) Isolation enumeration & differentiation of Columbian Agar Detect clostridium sporogenes from pharmaceuticals Bismuth sulphate Agar medium Selective isolation of salmonella from faces ,urine Brilliant green agar base Selective isolation of salmonella other than s. typhi Nutrient broth medium Sterility testing for aerobes Pseudomonas agar (for fluorescing ) Fluorescein production by pseudomonas SCM (Broth medium) General purpose medium for microbes Reinforced clostridia agar Sterility testing for moulds & lower bacteria clostridia & other aerobes. Sabourand dextrose Agar Cultivation of yeast moulds & acidified microorganism
  • 37. Triple sugar iron agar Identification of gram negative enteric bacilli on the basis of dextrose, lactose & sucrose, fermentation &H2S production Yeast maltose broth Acidify for selective medium Vogel Johnson agar base yeast, mould, & aciduric MOs staph aureus Yeast maltose agar Isolation & cultivation of yeasts, moulds & other aciduric micro organism
  • 38. 5 PRODUCTION After the dispensing of materials from the raw material approved room in response to the work order, they are taken to the production department. Production department is made of granulation, compression, coating and packing sections. The flow of materials in production is uni-flow from granulation, compression, and coating and finally to packing section .The production department is completely involved in the drugs manufacturing process .During the process manufacture IPQC checks are carried out to ensure quality in process of production and prevent batch failure. When raw materials are required in the production of drugs, the production department makes an order to the stores department which them dispenses off the material. In case of excess raw materials. The materials are returned. In case of less raw materials an extra material memo is made .the following products are produced 5.1 PRODUCTS OF CIPLAQCIL ARVS DRUG ACTIVE INGREDIENTS Effavir 600 Efavirenz 600mg Duovir Zidovudine USP 300mg, Lamivudine USP 150mg Duovir-N Zidovudine USP 300mg, Lamivudine USP 150mg, Nevirapine USP 200mg Nevimune Nevirapine USP 200mg Duomune Tenofovir DisoproxilFumarate 300mg Lamivudine USP 300mg Trioday Lamivudine 300mg Tenofovir DisoproxilFumarate 300mg Efavirenz 600mg Texavir Tenofovir 300mg
  • 39. ACTs DRUG ACTIVE INGREDIENTS Lumartem Lumefantrine 120mg ArtmetherPhint 20mg 5.2 GRANULATION Granulation is the process of forming granules from powder particles. The small powder particles are made to adhere to make bigger granules .The powder particles are made to adhere for many reasons which include Tablets are the most common drug dosage form today, and thus granulation, which allows primary powder particles to adhere and form granules, is one of the most important unit operations in drug manufacturing. Understanding granulation grows more complex each year. Particle-bonding Mechanisms a) Adhesion and cohesion forces in immobile films. If sufficient liquid is present in a powder to form a thin, immobile layer, there will be an increase in contact area between particles. The bond strength between particles will increase, as the Van der Waals forces of attraction are proportional to the particle diameter and inversely proportional to the square of the distance of separation. b) Interfacial forces in mobile liquid films. During wet granulation, liquid is added to the powder mix and distributed as films around and between the particles. There are three states of water distribution between particles. At low moisture levels, the pendular state, particles are held together by surface tension forces of the liquid/air interface and the hydrostatic suction pressure in the liquid bridge. When all the air has been displaced from between the particles, the capillary state is reached, and the particles are held by capillary suction at the liquid/air interface. The funicular state represents an intermediate stage between the pendular and capillary states. Moist granule tensile strength increases about three times between the pendular and the capillary state. These wet bridges are,
  • 40. however, a prerequisite for the formation of solid bridges formed by adhesives present in the liquid, or by materials that dissolve in the granulating liquid. Solid bridges can be formed in two ways: Hardening binders. When an adhesive is included in the granulating solvent it forms liquid bridges, and the adhesive will harden or crystallize on drying to form solid bridges to bind the particles. Crystallization of dissolved substances. The solvent used to mass the powder during wet granulation may partially dissolve one of the powdered ingredients. When the granules are dried, crystallization of this material will take place and the dissolved substance then acts as a hardening binder. c) Attractive forces between solid particles. In the absence of liquids and solid bridges formed by binding agents, there are two types of attractive force that can operate between particles in pharmaceutical systems, electrostatic forces and Van der Waals forces. Van der Waals forces are about four orders of magnitude greater than electrostatic and add to the strength of granules produced by dry granulation. Mechanisms of Granule Formation a) Nucleation. Granulation starts with particle-particle contact and adhesion due to liquid bridges. A number of particles will join to form the pendular state. Further agitation densifies the pendular bodies to form the capillary state, and these bodies act as nuclei for further granule growth. b) Transition. Nuclei can grow in two possible ways: either single particles can be added to the nuclei by pendular bridges, or two or more nuclei may combine. The combined nuclei will be reshaped by the agitation of the bed. This stage is characterized by the presence of a large number of small granules with a fairly wide size distribution.
  • 41. c) Ball Growth. If agitation is continued, granule coalescence will continue and produce an unusable, over-massed system, although this is dependent upon the amount of liquid added and the properties of the material being granulated. There are four possible mechanisms of ball growth, which are illustrated in the illustration  Coalescence. Two or more granules join to form a larger granule.  Breakage. Granules break into fragments which adhere to other granules, forming a layer of material over the surviving granule.  Layering. When a second batch of powder mix is added to a bed of granules, the powder will adhere to the granules, forming a layer over the surface and increasing the granule size.  Abrasion Transfer. Agitation of the granule bed leads to the attrition of material from granules. This abraded material adheres to other granules. Granulation Methods Dry Granulation. This requires two pieces of equipment, a machine for compressing the dry powders into compacts or flakes, and a mill for breaking up these intermediate products into granules. The dry method may be used for drugs that do not compress well after wet granulation, or those which are sensitive to moisture/water. Wet Granulation. In this method, the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required. Because direct compressing is not the best technology for many active substances, wet granulation is still a preferred method. Even if the active substance is sensitive to hydrolysis, modern equipment (e.g., a fluidized bed) eliminates all problems in wet granulation. Factors Affecting Granulation Methods  Liquid Requirement. High-shear mixers may exhibit a narrow margin between the liquid required to obtain granule growth and the amount that results in an over-wetted mass. Because of the intensive wet massing and densification of the granules, less liquid is
  • 42. normally required with high- than with low-shear mixers .In addition, impeller rotation speed influences the liquid requirements, as does evaporation of the solvent, usually water, in the binder solution. Especially with high-shear mixers, intense agitation results in a temperature rise and loss of solvent by evaporation. Effects of Raw Material Properties. The following properties influence granule formation and growth:  Contact angle of the binder liquid to the solids  Solubility of the particles in the binder liquid  Mean particle size and size distribution of the solids  Particle shape and surface morphology  Packing properties of the solids  Raw materials must have good wetting properties if there is to be uniform liquid distribution and, hence, controlled granule growth. The smaller the particle size of the raw material, the more binder liquid required. Binder Properties Binder Concentration. The binder forms an internal matrix; consequently, the granule strength and tablet strength increase as binder concentration increases. Mechanical Properties of Binder. The mechanical properties of the binder determine binder strength and deformation behavior of the binder matrix. Properties of Drug and Other Excipients in the Formulation Wet granulation depends upon wetting of powder by the binder solution, surface tension of lenticular bridge films formed and solution viscosity. Binder Distribution. The distribution influences the binder’s ability to produce strong and non-friable granules. The processing method used to distribute the binder influences binder efficiency.  To improve the particle size distribution so as to improve the compressibility.  Prevent segregation of the constituents of the mix  Improve flow properties of the mix
  • 43.  Reduce hazard of toxic materials associated with handling.  Reduce possibility of caking with hygroscopic material  Improve drug release properties.  It makes occupation of less volume per weight, hence easy handling. CONDITIONS The granulation area is a critical area, with the temperatures and relative humidity monitored and kept within the required limits .Temperature (19-22 ºc) and relative humidity (45- 60%).Deviations from the required limits can lead to reduced quality of the end product. It is mainly applied to heat labile and moisture sensitive materials like Duovir (Lamivudine and Zidovudine). The granulation section has three granulation cubicles, granulation I, II, III. Each cubicle is divided into a binder solution preparation room, washing area and an area were sifting, sizing and granulation occur. 5.3 BLENDING This is done using an octagonal blender after line clearance has been done. Manufacturing process containers are first re-weighed and then attached to the blender mouth. The blender is then rotated 180◦ to load the granules into the octagonal blender a process known as charging, after the blender is rotated back to its normal position and the MIPC is disconnected. This is repeated until all the granules have been loaded to the maximum capacity of the blender. Lubricants such as magnesium stearate are also added. The blender is then set to rotate through 360◦ at a specified rpm. After blending, the granules are offloaded into MIPCs which are first tared and the re-weighed with the blend and stored in the bulk store according to batch in lines, where they are later picked for compression into tablets MACHINES USED IN GRANULATION Rapid Mixer Granulator Works on the principle of high shear to achieve only mixing and granulation of the powders. This mixer uses a highly viscous binder, it’s filled by SS bins for both the binder and powder
  • 44. using an elevator, the mixer doesn’t dry and after granulation its products are taken to the FBE for drying. It comprises of lid tighten clamps, bowl lid, agitator, chopper, binder/material charge port, air vent, neoprene gasket, discharge port, chopper motor cover, plat form, control panel and view window. The agitator helps uniform mixing, and a high speed chopper slices the lumps to form smaller granules. Some of the raw materials used here include those of lumefantrine and Efavirenz Fluid Bed Equipment This is used for granulation, drying, mixing and also coating of pellets. The raw material for granulation is fed into the FBE by an evacuator pipe from IPCs after it has been re-verified (label, weight, batch, texture). Hot air at high pressure is let into the equipment via the inlet pipe to the lower plenum and then through the bowl sieve to the product container, and causes free flow of the powders, the powders are first mixed and pre-heated ( up to 36-400C) to ensure uniform mixing with the other inactive and create conditions for adding of binder for approximately 5 minutes, after a peristaltic pump pumps a less viscous binder from a can and it passes through a spray gun with 1mm nozzles and it continuously wets the powder as mixing is continuously done. The fluidized material is kept within the expansion chamber by the help of a finger bag which allows only air to pass through and increases the surface area for mixing, drying is effected by heat exchange between the hot air and the wet granules. The FBE has inflatable gaskets that ensure that pressure is not lost to the outside during operation, exhaust and product temperature is monitored throughout the process every after 10 minutes, if it is low it means that the material is wet thus after binder spraying has been done, the material is dried. The material is sampled through the sampling port (at specified temperature) and analyzed for loss on drying in intervals. If LOD is in specified limits then drying is stopped and the formed granules are removed. The material is then sized and milled and sent to blending after it has been re-weighed. Some of the parts include; inlet air ducting, expansion chamber, lower plenum, explosion flap duct, product container, spring tension, bowl sieve, SS supports, pneumatic control panel, inflatable gaskets, neoprene gaskets, bull eye windows, filter bag assembly, spray gun, view window, control panel and the peristaltic pump.
  • 45. Vibrator sifter This helps in material sifting, uses vibratory and gyratory motion as it causes vibration and the particles of different sizes pass through the sieve from the upper hopper to the lower hopper and re-collected. Depending on the material, sieves of different mesh sizes are used. The sizes of sieves used are determined by the number of holes per linear inch. Determining of the sieve integrity is one first essential step done before sifting using a dyner scan. It has various parts including, sifter body, and wheel lid, upper hopper, lower hopper, and stainless steel clamp, sifter hood, holding ring, neoprene gasket, sieves, control panel, electric cable and main body. The neoprene gasket helps in the reduction of noise when vibrating. PURPOSE OF SIFTING  obtain uniform particle size powder of desired range  check for any foreign matter which may come along with raw material  magnetic screens are provided at outlet of sifter to check and hold metal particles as most of bulk drugs are synthesized, processed in mild steel reactors thus chances of steel, rust particles  Raw materials from sifting area are then sent to granulation hall via pass box. Here binder preparation occurs. Multmill Helps in the sizing of clamps of powders and granules that can’t pass through the sifter it has various parts including ; pulley housing and cover, blade stud, wing nuts rotor, size reduction chamber, hopper, base plate, gasket, control panel, electric cable, agitator and wheels. The cleaning of the machine is similar to that of the vibrator sifter. Roll compactor This machine is used for dry granulation. It has a sieve in it and it only compacts and sifts at the same time to make granule that pass through the sieve and collected through the lower hopper. It’s made of two rolls rotating in different directions which allows for compression of the sifted powder particles in between the rolls and this coupled with a vacuum pressure which leads to flake formation.
  • 46. Steam kettle. This is used in preparation of the binder. Octagonal blender It rotates and mixes the contents using shear mixing. It has got baffles to aid this process. Its speed is controlled using a programmable logic controller. Its main function is to blend and lubricate Weighing balance This is used to tare cans, measure granules and also verify weights of raw materials before they are granulated. The balance is calibrated by to forms IN-PROCESS CHECKS AT GRANULATION These include;-  Tap density- use of tap density apparatus/tester to determine bulk and tap density.  Moisture content- done using IR moisture analyzer  Percentage fines-using a sieve shaker.  Loss on drying CLEANING PROCEDURE FOR EQUIPMENTS Generally flush with portable water then apply detergent then rinse with portable water, flush with purified water and finally dry using compressed air. 5.4 COMPRESSION Compression is a process of tablet formation from granules with aid of compression force through the usage of compression machine. The tools used for compression are Punches and dies (kept in tool room). The die determines the diameter of the tablet. Machinery classification is dependent on the following accepts Rotation; single rotation and double rotation. The machine used is called a double rotary machine.
  • 47. Illustration of set up of compression apparatus The components of the double rotary compression machine include;  Feed frame /force feeder; Holds the granule on turret so they fill the die bore.  Cam tracks; Lift upper punch and lower punch during cycle as required.  Pre compression blades; Give granules an initial tamping force to remove as much air as possible before final compression.  Main compression rollers; Apply the full pre the set pressure on punches for final compression of tablets.  Take off blade; Is fitted in front of the feeder frame to scrap the tablet off lower punch tip  Ejection cam; Guides the lower punch upwards during the ejection stage. It is adjustable to ensure smooth ejection without damaging tablets.  Hopper; this is where the granules are introduced into the machine. Compression process The compression process involves a series of stages. Filling The filling stage of the tablet compression process involves transfer of raw materials into position for tablet compression. These raw materials have undergone prior processing by wet granulation, dry granulation (roller compaction), sizing, or other processes. The final formulation is then blended to yield a homogeneous blend. The blend then flows to the compressing machine punch-die cavity. The punch-die cavity is composed of punch die and lower punch. The position of the lower punch within the die determines the volume of the punch-die cavity. This volume must be appropriately sized for the weight of granulation to be compressed into tablets. The granulation is overfilled on the die table (turret) to ensure complete filling of the punch-die cavity volume. compression machine deduster metal detector MIPC
  • 48. Metering The metering stage of the tablet compressing process involves removal of excess granulation from the compressing machine. This stage enables the exact weight (volume) of granulation to be compressed into tablets. The exact weight of granulation is controlled by the height of the lower punch in the die. The height of the lower punch is controlled by the metering cam (also called the dosage cam). The lower punch is raised to the appropriate level in the die to provide the exact weight of granulation in the punch-die cavity. The excess granulation is scraped from the surface of the die table. The metering stage is similar to the method used to measure flour when baking a cake. A measuring cup is first over-filled with flour; then a knife is used to scrape off the excess. The exact amount of flour is then left in the measuring cup. Compression The compression stage of the tablet compressing process forms the tablet. This stage involves bringing together the upper and lower punches under pressure within the die to form the tablet. As the punches enter the compressing stage, the upper and lower punches move between two large wheels called pressure rolls. These pressure rolls push the punches together to form the tablet. The distance between the upper and lower punches determines the thickness and the hardness of the tablet. When the punches are close together, a thin and hard tablet is created. When the punches are farther apart, the tablet made is softer and thicker. The proper balance of thickness and hardness determines the optimum roll distance for any specific product. These adjustments are made while keeping the tablet weight constant. Ejection The ejection stage of the tablet compressing process involves removal of the tablet from the lower punch-die station. In this stage, the upper punch retracts from the die cavity and rises above the turret table. Then the lower punch rises in the die, which in turn pushes the tablet upward to the top surface of the die table and out of the die cavity. A scraper (also called takeoff scraper or tablet rake-off) then pushes the tablet off the die table away from the compressing machine into the collection container. TYPES OF TOOLING AND STATIONS;
  • 49. Machinery classification is dependent on the following accepts Rotation; single rotation and double rotation Tooling refers to the diameter of the punches. B-type is for small tablets and is used to compress LUMARTEM tablets and D- type which has a larger diameter of about 16mm and is used for DUOVIR-N, DUOVIR and EFAVIR. STATIONS. This classification consists of the number of punches the machine has. The forms include 37, 45, 49, 55, 65 stations. In case the machine is double rotary then this means it compresses twice the number of tablets per rotation i.e. 37 station produces 37 x 2 = 74 tablets per rotation Tooling refers to the diameter of the punches .B –type is for compressing lumartem tablets whilst D-type for Duovir-N, Duovir, Effavir. Type Die diameter Punch diameter machine Stations D-tooling 38.1mm 25.4mm Cadpress iv 45 B-tooling 30.1mm 19mm Cadpress iv 55 BB-tooling 24mm 19mm Cadpress ii 45 TABLET PROBLEMS DURING COMPRESSION Tablet defects POSSIBLE CAUSES TOOLING RELATED PRESS RELATED FORMULATION RELATED Weight variation Inconsistency working height of the Lower punch. Jammed Lower punch. Granules not flowing freely.
  • 50. Thickness variation Inconsistency working height of the Lower punch. Inconsistency of the Upper punch working height. Pressure roller jumping. Capping Air entrapment. Incorrect ejection setting. Use of pre-compressed granules. Sticking and picking Poor finish on punch cavity. Picking bore zones on embossing. Sticking formula. High moisture content. IN-PROCESS CHECKS CARRIED OUT DURING COMPRESSION AND INSTRUMENTS  punch size the diameter  upper punch description circular and has an embossing of UG  lower punch description plane and circular  Standard Compression weight should be within limits  Hardness carried on tablets from both sides of the machine i.e. right and left side TESTS CARRIED OUT DISINTERGRATION TEST This test is used to mimic the conditions in the human stomach where the time taken for a tablet to completely disintegrate is noted .the instrument used is the disintegration tester and the drug is expected to have disintegration time less than 15 minutes. The apparatus is set at 37◦C and the time taken to disintegrate is read off from the timer display. The water in the water bath is changed weekly. HARDNESS TEST
  • 51. This is done to determine the hardness of a tablet by use of the ERWEKA HARDNESS TESTER. This instrument can also determine the diameter and thickness of the tablet . First switch on tester then zero it. Select measure option on LCD, place the tablets in the stations provided then the analysis process begins and results for thickness, diameter and hardness are displayed on the screen. Enter product details and start. Then view results FRIABILITY TEST This instrument is used to determine the friability of a drug .This test is used to determine how well a drug can sustain impaction forces during the process of transportation from one place to another. WEIGHING BALANCE This instrument is used for group weights, individual weights. Individual weights are taken for 50 tablets from each side of the machine (Left Hand Side and Right Hand Side). VERNIER CALLIPER, This instrument is used to determine thickness, width and length .The digital Vernier caliper is connected to the online recording system. MACHINES USED IN COMPRESSION These include  Tablet press-works on principle of particle compaction.  Deduster-operates on principle of spiral vibration and size exclusion. Has a mortar that vibrates creating a suction force that enables powder dust to separates from tablet.  Metal detector-works on principle of magnetic attraction. A large magnetic field is set up through which tablets are passed. Each tablet containing a metal component is attracted and is not released due to eddy currents. Metal components detected include SS, ferrous and nonferrous.
  • 52. 5.5 COATING Coating is the process of enclosing the tablet core with a polymer film or a sugar base. This is the addition of a surface coat on the tablet. Common pharmaceutical technique of applying a thin polymer based film to a tablet. Major techniques include sugar-coating, film-coating, enteric –coating. IMPORTANCES OF COATING  Tablets are coated for different reasons which include;  Masking the bitter test and bad smell of the active ingredient.  For functional purposes such as controlled release of the drug.  Provide physical and chemical protection for the drug from atmospheric effects such as temperature, humidity and light.  Protect drug from gastric environment of stomach with acid resistant coating.  To incorporate another drug or formula adjuvant in the coating.  Improve appearance by use of special colors... There are different types of coating which include; Sugar coating. Steps in sugar coating; Multiple applications of syrup containing colour are required, water-soluble dyes or water- insoluble lakes are used. Finally wax is applied in rolling pans. Film coating
  • 53. Preferred method which applies a thin, uniform coating on tablets. Steps in film coating The Suspension is prepared according to the SOP, and depending on the product to be coated, then checking and setting of spray pattern of the machine. Tablet loading are loaded by the operators in the machine. This is followed by preheating of tablets for five minutes before spray is turned on. Tablets are sprayed using the coating suspension a defined rate as per SOP. Tablets are dried after the specified period of coating. Finally unloading of tablets by the operators in the MIPCs. Functional coating. This can include coating for slow release, enteric coating. NOTE: Sugar coating involves use of a sucrose based solution while film and functional coating involves use of suitable polymer which forms a thin film around the tablet core. At Ciplaqcil, some of the tablets are film coated. Components of a film coat  Solvent; IPA, Methylene Chloride  Plasticizers; poly ethylene glycol  Opacifier  Film former; methyl cellulose  Colorants  Opadry a raw material that contains all the required materials may be used. Equipment for coating;  Neocota machine  GCsmart pam Glatt PREPARATION OF COATING SOLUTION
  • 54. Opardy yellow powder (1kgs) is placed in SPV, then a known amount of purified water is added and mixture thoroughly mixed for 45 minutes. Final solution is sieved to remove solid particles that did not dissolve. Film-coating is a single stage automated process highly adaptable to GMP. A suitable polymer is used to form a thin film around tablet core. Film coated tablets retain contour of original core in case the coating is translucent, have 2-3% weight increase, logo or break lines. Coating occurs by a spray process. Tablets on perforated coating pan are sprayed with coating suspension whilst pan is rotating. Baffles ensure each is coated. Parameters checked include product and exhaust temperature, spray rate, spray pattern, atomization. In –process checks done include disintegration test, appearance of coated tablets, group weight /individual rise, thickness test, loss on drying. In process checks include  Appearance  Group weight and individual weight variation  Loss on Drying  Disintegration time COATING DEFECTS Reject Cause Solution Tablet to tablet color variation Migration of coloured components within tablet core into the coating use a coating in which the components of the tablet core are insoluble Cracking Insufficient plasticizer Increase plasticizer Edge chipping/erosion Low mechanical strength Increase the compression pressure Core erosion Pan speed is too high Optimize speed of pan.
  • 55. Orange peel roughness Viscosity is too high Increasing the spray rate and decreasing the air temperature Peeling Low mechanical strength Increase compression pressure Twinning Spray rate too high Reduction of spray rate Picking/sticking Inadequate drying Proper drying
  • 56. 6 ENGINEERING This department is located outside the facilities main building and its main purpose is to manage and control the utilities used by the facility. It consists of various equipment aimed at providing the optimal working condition. It helps to control the temperature and relative humidity inside the facility premises. This is very important because the environmental conditions required during the different stages of production vary depending on the type of product. The different machinery found in this department include, Air compressor, Boilers, Chillers. The Engineering department has the following sections.  Boiler room  Air compressor room  Chillers  Service floor (HVAC)  Effluent Treatment Plan (ETP)  Engineering Offices and Workshop AIR COMPRESSOR; For formation of purified air that is used in various processes during production like during functioning of the FBE. Types of the air compressors.  Piston air compressors.  Screw air compressors. The latter is preferred in the pharmaceutical industries because is oil free hence no incidences of production of moisture that can interfere with the production process. Procedure for purification
  • 57. 6.1 BOILERS Boilers are pressure vessels designed to heat water or produce steam, which can then be used to provide space heating and/or service water heating to a building. In most commercial building heating applications, the heating source in the boiler is a natural gas fired burner. Oil fired burners and electric resistance heaters can be used as well. Steam is preferred over hot water in some applications, including absorption cooling, kitchens, laundries, sterilizers, and steam driven equipment. Boilers have several strengths that have made them a common feature of buildings. They have a long life, can achieve efficiencies up to 95% or greater, provide an effective method of heating a building, andin the case of steam systems, require little or no pumping energy. How Boilers Work Oil fired boilers use controlled combustion of the fuel to heat water. The key boiler components involved in this process are the burner, combustion chamber, heat exchanger, and controls. The burner mixes the fuel and oxygen together and, with the assistance of an ignition device, provides a platform for combustion. This combustion takes place in the combustion chamber, and the heat that it generates is transferred to the water through the heat exchanger. Controls regulate the ignition, burner firing rate, fuel supply, air supply, exhaust draft, water temperature, steam pressure, and boiler pressure. Hot water produced by a boiler is pumped through pipes and delivered to equipment throughout the building, which can include hot water coils in air handling units, service hot water heating equipment, and terminal units. Steam boilers produce steam that flows through pipes from areas of high pressure to areas of low pressure, unaided by an external energy source such as a pump. Steam utilized for heating can be directly utilized by steam using equipment or can provide heat through a heat exchanger that supplies hot water to the equipment. Pressure vessel integrity, checking of safety relief valves, water cutoff devices and proper float operation, gauges and water level indicators are inspected. The boiler’s fuel and airfrom environment filtration low pressure area intercooler high pressure compartmentafter coolerdrierstorage tank to different areas at different velocity
  • 58. burner system requires proper inspection and maintenance to ensure efficient operation, heat transfer and correct flame detection. 6.2 CHILLER Provide cold water from the chillers used in the cold water coil and the air from the compressor. They are used to provide cold water which is used in reducing temperature of a cubicle through HVAC system. When there is a change is relative humidity and temperature the level of cold water given is changed to fit the conditions required i.e. increased cold water when lower temperatures are required. Operation A vapor-compression chiller consists of four primary components of the vapor-compression refrigeration cycle. They include a compressor, evaporator, condenser and a metering device. Vapor-compression chillers typically utilize HCFC or CFC refrigerants to achieve a refrigeration effect. Compressors are the driving force in a vapor-compression chiller and act as a pump for the refrigerant. Compressed refrigerant gas is sent from the compressor to a condenser unit that rejects the heat energy from the refrigerant to cooling water or air outside of the system. The transfer of heat allows the refrigerant gas to condense into a liquid which is then sent to a metering device. The metering device restricts the flow of liquid refrigerant which causes a drop in pressure. The drop in pressure causes the warm refrigerant liquid to change phase from liquid to gas and in doing so absorbs heat from the water to be cooled due to adiabatic flash evaporation. The metering device is positioned so that the expanding refrigerant gas is contained within the evaporator, transferring the heat energy from the water to be cooled into the refrigerant gas. The warm refrigerant gas is then sent back to the compressor to start the cycle over again and the newly chilled water in the separate loop can now be used for cooling. 6.3 HVAC system While there are many functions that a HVAC system serves, the primary function is to maintain a comfortable temperature in every room. This is done by the regulation of humidity, air flow, as well as temperature so that these parameters stay within acceptable limits. While this makes staying indoors comfortable, it also ensures that inhabitants do not suffer from health risks that
  • 59. reside in the categories of excessive fatigue, draining out, heat strokes and hypothermia. HVAC, as the name suggests, has three primary functions, they are:  Heating: HVAC serves the function of heating, this really could be the difference between life and death. When it is literally freezing outside, you need a system that keeps you warm and if it does it in a uniform manner, then all the more better and an HVAC system does. Heating can be achieved through local as well as central heaters.  Central heating systems tend to be more cost effective and are made up of furnaces, heating pumps, and radiators.  Ventilation: The V in HVAC stands for ventilation which pertains to the movement of air in the home. Controlling the air flow allows the cleansing of the atmosphere indoors so that unnecessary carbon dioxide can be carted out and the oxygen let in. Not only does this aid breathing but it also aids in the prevention of air borne diseases and allergies  Air Conditioning: An air conditioning system may be one comprising of several window machines or one central system. Dirty air ducts will need to be cleared immediately so that no pathogens thrive and are living in it 6.4 ETP a process to convert wastewater - which is water no longer needed or suitable for its most recent use - into an effluent that can be either returned to the water cycle with minimal environmental issues or reused. Waste from any industry should be treated before being released to the environment. Waste from industries such as pharmaceutical industries can cause harm to the environment if let out untreated. There wastes contain toxic substances which when released contaminate or pollute both water and air. The main use of the ETP system is to treat waste released by the facility. The ETP is located outside the facility approximately 400 meters to prevent contamination .There are two types of waste treated by the ETP, which are domestic waste which contains water from wash rooms, kitchen and industrial waste which contains waste that was in direct contact with the product. After treatment the water is tested for different parameters before releasing it to the Environment. 6.5 WATER TREATMENT Water quality affects every operational aspect for manufacturers of pharmaceuticals. The raw water obtained by the facility passes through multiple stages in the process of purification .The
  • 60. purification is used to remove contaminants like; inorganic compounds, .organic compounds, solids, gases, microorganisms. The source of raw water is borehole and NWSC (National water and Sewerage Corporation). The types of water used at QCIL are purified and portable water. The main source of raw water is national water and sewerage cooperation which supplies the portable water. The portable water undergoes the following stages in order to achieve purity. STAGES OF WATER TREATMENT AND PURIFICATION The pretreatment unit consists of;  MGF – for filtration  Softener –Removes hardness  Ultra filtration –Reduces the SDI (silt density index)  SMBS (sodium metabisulphite) - to neutralize free chlorine. Chlorine dosing done using sodium hypochlorite (3ppm). MGF consists of sand media, gravels, pebbles, corax, silex, fine corax and fine silex. The softener removes hardness. Ultra filtration reduces SDI.Ultra filtration tank dosed with SMB which neutralizes free chlorine. Permanent hardness is removed by backwashing / ion exchange. Dosing with chlorine.  Chlorine kills off all the susceptible microorganisms.  Filtration.  This is done using a multi-grade filter.  The filter aids the removal of particulate matter. SOFTENER UNIT RAW WATER PRETREATMENT GENERATION STORAGE AND DISTRIBUTION
  • 61. A water-softening system removes calcium and magnesium ions from hard water and replaces them with sodium ions. Calcium and magnesium ions interfere with the action of household soaps and detergents, but sodium does not. The water-softening process thus helps detergents to more effectively remove dirt and oils from clothing and dishes. The pump house contains several cubic feet of porous plastic resin covered with molecules that attract and bind to positive ions dissolved in the water. Normally, sodium positive ions coat the resin, but as water flows over the resin the naturally occurring calcium and magnesium positive ions that exist in hard water stick to the resin. This releases sodium ions into the water in order to maintain a balance of electrical charge on the resin. Gradually, most of the sodium ions are released into the plant water, and the resin becomes saturated with calcium and magnesium ions. Every few days, the unit must renew the resin by rinsing it with a concentrated solution of saltwater (sodium chloride), usually in the middle of the night. The high concentration of sodium ions in the salty water displaces the calcium and magnesium ions the resin, and the resin becomes once again covered with sodium ions. The salty rinse water, calcium and magnesium ions are flushed down the drain, and the system resumes normal operation. (Every so often it is necessary to add a bag of sodium chloride salt to the softener unit to prepare this salty rinse water.) ULTRAFILTRATION UNIT This unit is used to filter off particulate matter, colloidal impurities, silt and microbes and to reduce the silt density index to <3. Consists of membrane of 0.02μ,5μ cartridge pre-filter which polishes the water particulate matter which cannot be removed by MGF , a plate type heat exchanger which ensures transferred water is NMT 25OC to avoid damaging the RO membrane. Backwash is done every 1hour while disinfection is done after every 30 cycles using sodium Hypochlorite. Monitored parameters: pressure, temperature, flow rate, SDI. REVERSE OSMOSIS In reverse osmosis water moves from an area of low water concentration to a region of high water concentration under a pressure gradient across a semi permeable membrane. All other molecules except water are retained on the side of lower water concentration. RO membrane is
  • 62. 0.01micron pore size and is sensitive to temperature and chlorine. It is made of polyamide. RO is in series to-ensure efficiency of the RO process in addition to minimizing wastage. ELECTRODE –IONISATION (EDI) Electrode ionization uses an electric field to remove ions and polar species from an aqueous stream. EDI is used with reverse osmosis to replace ion exchange resin-mixed beds, which require onsite or offsite chemical regeneration. By eliminating resin regenerating chemicals, EDI delivers significant economic and environmental benefits. In addition, EDI’s continuous process improves water quality by reducing spikes and upsets. Monitored parameters: pressure, conductivity, temperature, voltage STORAGE AND DISTRIBUTION The storage and distribution unit consists of a 2000 liter tank, and S&D pump, a U.V unit and a recirculating pipe line. U.V unit consists of a U.V lamp that is enclosed in a transparent quartz sleeve. As water passes through the flow chamber the microbes are exposed to the U.V rays which damage their DNA structure hence preventing their reproduction and multiplication. Increased intensity of rays increase the kill of the microorganisms. Monitored parameters include UV Intensity, temperature, conductivity, flow rate.
  • 63. 7 LESSONS LEARNT The time I spent at CIPLAQCIL I learnt a lot .these include  The knowledge about the process of the manufacture of medicines.  All manufacturing facilities follow current good manufacturing practices(cGMPs)  The uses of a chemical engineer in a pharmaceutical  The need for controlled environment in a facility  Team work .I improved on my networking skills .for instance I was challenged to seeing faces I had never and had to make friends so that the training would go on smoothly. 8 CHALLENGES  Identifying places for industrial training was difficult since some institutes were not in need of trainees.  The university does not define the characteristics of places for industrial training. This would lead to trainees diverting to other fields.  Operation of Some equipment at the factory required more training. This limited our practical activity in the field.  Some departments were allocated less time so it was a challenge learn everything.  Some information at the factory was limited to only specified personnel making quest for information hard. 9 CONCLUSIONS The training was highly motivating. Usage of SOPs, cGLPs, cGMPs was highly emphasized. Most of the objectives in the industry were achieved but some of them couldn’t be achieved due to the time allocated to us by the industry. I have learned how science and engineering can interact in useful ways and how remarkable research can occur even when it is ‘profit driven’; at CiplaQCIL creativity is not limited and true innovation occurs. The company gave me to chance to study the loss of primary packaging material on Lumartem 24s blister packing. I was lucky enough to work with a group of enthusiastic and communicative people, who were passionate about what they are doing in the industry.
  • 64. The atmosphere at CiplaQCIL is unique and hope that it stays that way. It has been a unique opportunity and one that I will not soon forget. My time there has been eye opening especially in the departments of Engineering, Quality Control and Production. I thoroughly recommend the experience to any other student who is thinking of applying. Despite the success achieved there are a few challenges which I hope can be addressed progressively given more opportunity? 10 RECOMMENDATIONS  The university should identify potential areas for placement in order to avoid students going to place where their course does not fit.  The university should improve the industrial training policy by my making agreements with certain industries and agreeing on the number of students to be sent to the industries.  The industry should identify the period needed for certain departments instead of giving them equal time.  Capacity building for handling complex equipment and this required another chance for placement to be negotiated by the university 11 REFERENCES  David J. am Ende, 2011, CHEMICAL ENGINEERING IN THE PHARMACEUTICAL INDUSTRY John Wiley & Sons, Inc.  http://www.ciplaqcil.co.ug  USP 36-Nf 31 2013 (3 Vol Set) (U.S. Pharmacopoeia: National Formulary)  British Pharmacopoeia 2014978-9380501246  2014/2015 Uganda National Development Plan National development Plan  Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 908), Annex 4.  CiplaQCIL 2014 Komboa newsletter volume 10