Amin Pharmaceutical Company

Transcription

1 Title: Amin Chemical & Pharmaceutical SITE MASTER FILE Page 1 of 57 Revised Revision No.: 04 Amin Pharmaceutical Company Prepared by Confirmed by Approved by

2 Page 2 of 57 Revised Revision No.: 04 Prepared by Dr. M. Mokhtarianpour Responsible of documentation Ph.D. Analytical Chemistry Approved by Dr. M.M. Hoghoughi Dr. F. Heidarnejad Qualified Person Managing Director pharm. D pharm. D Revision Number 04 Review Date September 2016 Number of Pages 57

3 Page 3 of 57 Revised Revision No.: 04 Sr.No Title Page No 1. GENERAL INFORMATION ON THE MANUFACTURER Contact information on the manufacture Name and official address of the manufacture Name and exact address of the site Geographic location system Short description of the building Location and immediate environment Size of Site and area Authorized pharmaceutical manufacturing activities Valid manufacturing authorization Type of actual products manufactured on the site List of GMP inspection of the site Other manufacturing activities at the site QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER The Quality Management System of the manufacturer Short description of the Quality Management System of the 14 firm responsible for manufacture Quality policy 14

4 Page 4 of 57 Revised Revision No.: Responsibility of Quality Assurance function Information of activities for certifying the site Release procedure of finished products Detailed description of authorised persons responsible for releasing procedures General description of batch certification Management of suppliers and contractors Brief description of the qualification system of contractor Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis Quality Risk Management (QRM) Product Control Review (PQR) PERSONNEL Organization chart for Quality Management Qualification and experience of key personnel Arrangement of basic and in-service training and records maintaining Health requirements for personnel engaged in production Personnel hygiene requirements including clothing Employees Details PREMISES AND EQUIPMENT Premises 29

5 Page 5 of 57 Revised Revision No.: Simple plan of manufacturing areas Nature of construction Storage area Special areas for handling of highly toxic, hazardous and sensitizing materials Brief description of heating, ventilation and conditioning (HVAC) systems Classification of production department Brief Description of Water System Brief Description of Waste water treatment system Brief description of other relevant utilities Steam system Compressed air Nitrogen Equipment List of major production equipment and analytical instruments Brief description of equipment Cleaning and sanitation Qualification, Calibration and Validation Maintenance of premises and equipment DOCUMENTATION 39-41

6 Page 6 of 57 Revised Revision No.: Description of documentation system The existing documents Other documentation related to the product quality PRODUCTION Type of production Process validation Toxic or hazardous substances handled Controlled and specific materials and products Material management and warehousing Arrangements for handling material and product Arrangements for handling rejected materials and products QUALITY CONTROL (QC) DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS Distribution Arrangements and recording system for distribution Arrangements of handling of complaints Product Recalls SELF INSPECTION 57

7 Page 7 of 57 Revised Revision No.: 04 Tables Tables No Title 1 Name and exact address of the site 2 Size of Site and area 3 Employees Details

8 Page 8 of 57 Revised Revision No.: 04 APPENDICES Appendix NO Title 1 Map of factory 2 List of the manufactured products on the site 3 List of the manufactured products for contract manufaturing 4 GMP and ISOs inspection 5 Contact information of important contractor laboratory 6 Organization chart of Quality Management 7 The plan of production and storage areas 8 Information of HVACs 9 Layout of classification in production part 10 Schematic diagram of water purification system 11 Schematic diagram of waste water system 12 List of major production equipment 13 List of major analytical instruments of Quality Control Laboratory 14 List of major analytical instruments of R &D 15 Layout of materials flow 16 Layout of personnel flow

9 Page 9 of 57 Revised Revision No.: GENERAL INFORMATION ON THE MANUFACTURER 1.1. Contact information on the manufacture Name and responsibility of the manufacture AMIN PHARMACEUTICAL COMPANY- ESFAHAN-IRAN Responsibility: Manufacturing of FPPs Name and exact address of the site Site address: Baharan Town, Abrisham Town, Zobe Ahan Highway, Isfahan, Iran., Table 1 Telephone Managing Director (Tehran Office) Operator Commercial Department Fax Numbers Managing Director info@aminpharma.com

10 Page 10 of 57 Revised Revision No.: There is no geographic location system like as GPS detail, Short description of the building Location and immediate environment Amin pharmaceutical company was built in 1984 near Baharan city, 23 km south-west of Isfahan on an area of 32 hectares of land at the foot of Iran Kooh, a range of Zagross Mountains. A map of factory area is attached in Appendix 1. There are no companies or factories except the ones that are far away in the immediate environment. So, the company is not threatened by sources of pollution The plant is comprised of: Independent manufacturing area for liquid and solid products. Primary and secondary packaging area. Warehouse area (Separate area for storing quarantine, approved and rejected materials of raw materials, packaging materials and finished products). Engineering area (maintenance, water purification system, HVAC systems, Boiler, Chiller and alternative power generating system (Diesel Generators). Quality control laboratory including microbiology section having major sophisticated instruments like HPLCs, GC with auto sampler, FTIR, UV spectrophotometer etc.

11 Page 11 of 57 Revised Revision No.: 04 Quality Assurance office. Administrative offices The area covered for each department / section is given below: Table 2 Sr. No. Department / Section Area in Sq. meters. 1 Management and administration 943 m 2 Liquid manufacturing plant Production department 442 m 2 Packaging department m 2 3 granulation units m 2 2 Production plant Capsule and 3 capsule filing rooms 94.9 m 2 tablet 3 tablet pressing rooms m 2 manufacturing plant 1 coating room m 2 packaging lines m 2 2 quarantines m 2 3 Starting material stores m 2 4 Packaging material stores m 2 5 Finished product stores m 2 6 Laboratories m 2 7 Utility building m 2

12 Page 12 of 57 Revised Revision No.: Authorized pharmaceutical manufacturing activities of the site Valid manufacturing authorization Amin pharmaceutical company is registered in IRAN and activities are licensed by the national authority that has a valid Manufacturing License (MfgL), No issued by Ministry of Health of IRAN. The following pharmaceutical dosage forms that are validated by national authority: Tablets Hard capsules Soft Gelatin Capsules Oral solutions, syrups and oral drops Type of actual products manufactured on the site Non- sterile products including oral liquid dosage forms (Syrups & Drops) and solid dosage forms (Capsules and Tablets) is produced in Amin pharmaceutical company. List of the manufactured products on the site is attached in Appendix 2. Also the name of company and products list of Iranian and foreign contracted manufacturer such as Servier (France), Apotex (Canada), Cipla (India), Vitabiotecs (India), Vitane Pharma (India), Koushan Pharmed, Arena Life Science, Behin Tamin Rouzamad, Vana Darou Gostar, Darou Darman Sepehr, Soha and is attached in Appendix 3.

13 Page 13 of 57 Revised Revision No.: List of GMP inspection of the site Amin has been inspected by MOH of Iran for GMP certificate annually. Also, foreign companies such as Servier, Apotex, Cipla, Vitabiotecs, Vitane Pharma have inspected Amin Co. before contract manufacturing. The copy of GMP and ISO inspection is attached in Appendix Other manufacturing activities at the site Apart from manufacturing activities as mentioned in other activities like formulation development and analytical development are carried out at the site. This facility does not manufacture products falling under the following categories; B- lactam antibiotics Penicillin group products Cytotoxic products Site does not manufacture wound dressing surgical dressing, drug substances, other chemicals, cosmetic and toilet preparations, household cleaning products, disinfactants, agricultural, horticultural and pesticide products.

14 Page 14 of 57 Revised Revision No.: QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER 2.1. The Quality Management System of the manufacturer Quality Management System is performed in accordance with ISO 9001:2008, ISO 14001:2007, OHSAS 18001:2004 and ISO 17025: Short description of the Quality Management System of the firm responsible for manufacture Quality policy Amin Quality policy is To provide products that satisfy customers. The management and staff at Amin Co. limited their committed to manufacture and deliver pharmaceutical products of quality that comply with national and international standards by strict adherence to GMP, Quality Management System (QMS) and Good laboratory practices (GLP) by continuous training and effective communication. Each employee can be proactive in supporting continuously improve products and processes. Amin senior management is committed to this policy and will provide the leadership resources and training to support it.

15 Page 15 of 57 Revised Revision No.: Responsibility of Quality Assurance function QA Head is reporting to the Managing Director and all personal involved in the quality related operations have written responsibilities. Quality manual is the top tier document in the quality management system. Ensure effective functioning of the quality management system at their respective sites. Preparation of SMF/Quality Manual/ Validation Master Plan. Review and authorize of all Master Manufacture Formula, BMRs. Ensure that the production and quality control laboratory are using validation methods, software and qualified equipments. Deviation records, failure investigations, change control records, OOS investigation records are evaluated to ensure the product quality. To ensure that the finished product meets the regulatory requirements of the intended market. To ensure that the engineering drawings approved by appropriate experts meets the functional and cgmp requirements. To ensure that the functional requirement are design specification of any new or modification in the existing facility, utility and equipment the requirement of cgmp. Conducting self audits, Vendor audits for meeting the cgmp requirements.

16 Page 16 of 57 Revised Revision No.: 04 Recommending management to recall of product based on the market complain investigation. Providing support to marketing and purchase functions to comply with the cgmp requirements To approve or reject any request to rework or reprocess. Self-inspection program are done to ascertain the compliance with the GMP requirements. Procedure for product development is according to GMP, GLP and GSP requirements. Quality Management at Amin pharmaceutical company encompasses the organizational structure, procedures, processes and resources, as well as the activities necessary to ensure confidence that the finished products meet their intended specifications for quality. All activities are clearly defined in the respective department SOPs in the form of work instructions. If any changes are undertaken at any stage of the manufacturing process, all critical manufacturing processes are reported initially and corrective action taken for it. A vendor certification system for raw materials and packing materials suppliers / manufacturers exists in the company and is mainly carried out through questionnaires followed by actual visit to the supplier / manufacturer's site of operation.

17 Page 17 of 57 Revised Revision No.: 04 All the raw materials, packaging materials, intermediates and finished products are stored as per GMP guidelines, regarding storage conditions like temperature and humidity, as applicable. The entire manufacturing process is carried out under expert technical supervision and a well developed in-process Quality Control system is in force to ensure that the processes are in a state of control. All raw materials, packaging materials, in-process materials and finished products are analyzed by validated test methods and released for distribution only after approval. Raw material and packing material are received as per SOP. They are quarantined and provided with Under test label. Sampling plans are done according to the SOP and analyzed as per Pharmacopoeia standards and in - house specification. If the material complies with the specifications, QC Department releases the approval of the materials by affixing a status label APPROVED to the raw and packing material containers. If the batch fails, it is kept under HOLD and the related investigation is carried out. All manufacturing processes are clearly defined in the Batch Records, which are regularly reviewed for compliance.

18 Page 18 of 57 Revised Revision No.: Information of activities for certifying the site Training on good laboratory practices (GLP) and current good manufacturing practices (cgmp) is carried out initially and at regular frequency as scheduled. The maintenance of the department, premises and equipment is specified and carried out. Each person is assigned to observe personal hygiene. The vendors of starting materials and equipment are monitoring for purchasing. All of analytical apparatus, instruments and equipment are calibrated. All of equipment and utility are qualified. Starting materials, packaging materials, and intermediate, bulk, and finished products will be approved or rejected. The storage conditions for materials and products are monitoring. The analytical methods are validating. The compliance to GMP requirements is monitoring. The monitoring and control of the manufacturing environment are carrying out. The inspection and investigation in order to monitor factors that may affect product quality is carrying out. All necessary testing is carried out. Sampling instructions, specifications, test methods and other quality control procedures are approved.

19 Page 19 of 57 Revised Revision No.: Release procedure of finished products Detailed description of authorised persons responsible for releasing procedures All stages, from weighting of raw materials to the amount of packing materials of the products, have been specified in Batch records. All steps must be performed according to instruction and finally Production Manager must confirm the Master Formulae. The QC Department evaluates each Batch Master Formulae before the release of the finished product. This department pays close attention to the accuracy of each component batch number, the amount of each component in the formulation, in-process control documents and conformity of the test results with the product specifications. After the completion of the batch packing by the packaging department, the product is transferred to the FINISHED PRODUCT QUARANTINE. The results of all the analysis which are done on the raw materials, packaging materials and finished products, would be written on the specified certificates of analysis. Then, they will be studied carefully by the QC Manager. Based upon the results, the QC Manager makes a decision on approving or rejecting them. The quality assurance department checks the batch manufacturing, batch packaging records and analytical records along with all data relevant to the quality, efficacy and safety of the product, before authorizing the batch for sales and distribution. Qualified Person checks all the documents of that batch and gives RELEASE to the finished product for the distribution and sales.

20 Page 20 of 57 Revised Revision No.: General description of batch certification Batch Record document includes of: Batch sheet of weighted raw materials. Completed and confirmed Master Formula by Production and Quality Control Department. Certificate of Analysis (COA) of intermediate products. COA of finished product. COA of packing stage. Report about quality of packing. Brochure and carton of product. Green sheet. One blister of product (for solid products). Check list of cleaning Management of suppliers and contractors Brief description of the qualification system of contractor Supplying chain: Setup of management and personnel of materials purchasing, testing, storage and distribution.

21 Page 21 of 57 Revised Revision No.: 04 Purchasing depart follows the order of production, and chose the qualified supplier for purchasing contacting, and make sure it meets all the requirement of product, process, specification, etc. Receiving, testing, releasing, storaging of material by warehousing and quality department. The materials will be stored in its suitable conditions waiting for using application. External audit: For all material suppliers, the company will do the paper audit work based on the procedure during the first purchasing agreement, and sign the quality contract. For key materials, QA person will do the external audit based on the procedure, and renew the supplier list according to report. Evaluation criteria for supplier companies, pharmaceutical ingredients and packaging materials: Having ISO 9001 Certificate. Having ISO Certificate. Having OHSAS Certificate. According to GMP. Having result of Health Ministry. Comment of Production manager during the consumption of raw materials. Record sales.

22 Page 22 of 57 Revised Revision No.: 04 Having a representative office in Iran. If the company wants to purchase from a contractor for the first time, that contractor is identified and evaluated. Only after obtaining approved score, business relationship will begin with them. The task of education is responsible for training capability. Director of Engineering and Technical Company is responsible for evaluating technical contractor. Commercial Manager is responsible for evaluation criteria of supplier companies, pharmaceutical ingredients and packaging materials Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis In Amin, we do not have contract manufacturers and all our procedure for production and packaging are done in Amin Co. site. Our QC facilities are self sufficient and well equipped. List of some assistance from the following Government-approved public testing laboratories is listed in appendix Quality Risk Management (QRM) These documents are providing according to Quality Risk Management Implementation of ICH Q9 in the pharmaceutical field an example of methodology from PIC/S.

23 Page 23 of 57 Revised Revision No.: 04 All the QRM activities cover the whole product life by the ways of before and after efficiency consideration. The process includes access, control, review, etc. The potential effects from deviations, complaints, regulatory, marketing, audits, computerization, preventation, maintenance, etc Product Quality Review (PQR) Brief description of the management procedure of annual quality reviews as follows: Content of product quality reviews: the annual product quality reviews include all the aspects of supply chain: active pharmaceutical ingredients and excipients, packing materials, process, process circumstance and finished products, etc. General information of product: name, code, specification, packing specification, validity period Review period: one year Reviews of the active pharmaceutical ingredients and excipients: including the suppliers, the arrived batches, the qualified batches and unqualified batches in review period, the test items and reasons of the unqualified batches and the final handling suggestion.

24 Page 24 of 57 Revised Revision No.: PERSONNEL 3.1.Organization chart for Quality Management Organization chart is attached in Appendix Qualification and experience of key personnel Education: Pharm. D Designation: Managing Director Experience: 35 years Name: Dr. M. M. Hoghooghi Education: Pharm. D Designation: Qualified Person Experience: 17 years Name: Dr. Sh. Hashemi Education: Pharm. D Designation: QC Manager Experience: 14 years

25 Page 25 of 57 Revised Revision No.: 04 Name: Dr. Sh. Haji Shamsi haghi Education: Pharm. D Designation: Production Manager Experience: 9 years Name: Mr. R. Shahpari Education: Electronic engineering, BSc Designation: Engineering Manager Experience: 9 years 3.3. Arrangement of basic and in-service training and records maintaining All new employees undergo an induction program for introduction to the company, policies on health and safety regulations, long term and short term goals, products and the concepts of GMP as well as GLP. Due to regulatory requirements, some basic safety training is typically performed before the employee can start work in the manufacturing or laboratory environment. GMP training is also carried out annually for all the personnel. Training is imparted through in-house programs involving classroom sessions and external training programs also.

26 Page 26 of 57 Revised Revision No.: 04 Efficacy of training is assessed through post evaluation of the classroom training by the use of questionnaires with the topic related queries. Each personnel have a folder with detailed training documentation, which outlines a summary of their education and experience, and the training courses they have passed to now. The training records include: The date of training Name of trainer and/or sponsoring organization Subject covered Exercises taken to ensure trainee comprehension Certificates issued by related authority If the training assessment shows that it is not enough, retraining course is carried out again. Post evaluation report from the classroom trainers also serve as indicators for retraining of employees Health requirements for personnel engaged in production The industrial hygiene section of the company is responsible for taking decisions regarding the physical ability and health requirements of the employees to do the jobs assigned to them.

27 Page 27 of 57 Revised Revision No.: 04 The company takes the responsibility for a complete checkup of new personnel to be sure that they have no medical problems. So, the following examinations are done in the first week of each employee s arrival: General health condition Blood, urine and stool test Chest X-ray Ear and eye test If medical condition of personnel is good, they will be allowed to start their work. Employees health check up according to organized programmed. All the staffs who work in Amin are examined once a year to ensure their health condition, but the ones who work in the production departments are examined twice a year. If the infections disease is recognized or suspected in a person, s/he will not be allowed to work in the production department or any other critical areas until a medical certificate will ensure that his/her health is completely restored. Based upon the test results, the factory skillful physicians make decisions on allowing or not allowing the sick employee to start working again Personnel hygiene requirements including clothing and environment The company has provided suitable washing, changing and rest areas for employees and visitors.

28 Page 28 of 57 Revised Revision No.: 04 The relevant staffs of production are obliged to wear protective garments such as hats/uniforms/slacks/masks or disposable gloves/shoes/respirators/masks/boots etc. As production operations are carried out in controlled clean rooms, personnel should change their cloth again and wash hands before entering solid and liquid departments. Eating, drinking, smoking, resting and use of jewelers and makeup are forbidden in the production areas. Separate place is provided for tea breaks. For lunch and dinner, there is a restaurant completely separate from the production areas. 3.6.Employees Details Table 3 Sr. No. Department personnel 1 Quality assurance 8 2 Production Quality control 36 4 Engineering 35 5 Storage 13 6 R&D 12 Total of personnel in Amin pharmaceutical 315

29 Page 29 of 57 Revised Revision No.: 04 4.PREMISES AND EQUIPMENT 4.1.Premises Simple plan of manufacturing areas: The premise is designed considering cgmp, safety and manufacturing capacity. Premises and equipment s are located, designed, constructed, adapted and maintained to suit the operations to be carried out. The layout and design is in such a way that it is aimed to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination and any adverse effect on the quality of products. The layout of Production area and storage is given as Appendix # Nature of construction The building is constructed of brick, masonry cement and main ceiling is made of bricks and constructional steel. In production department and stores the false ceiling is made of tiles, (Tiles are made of galvanized steel covered with powder coated painting). The flooring of the manufacturing areas, primary packaging areas, stores, are made of reinforced cement, covered with epoxy paint. The warehouses floors are covered with stones and mosaics.

30 Page 30 of 57 Revised Revision No.: 04 Material of construction of the doors and windows is suitably painted aluminum with glass, designed so as to have a minimum number of joints and bends. The vision panels in the walls are provided with painted constructional steel and double side glass. All corridors and classification areas are provided with airlock systems. All ducting, electrical lines and utility are either located above the false ceiling or concealed within the walls and floor. All the luminaries are flush with the false ceiling. Illumination in the manufacturing areas has been designed to suit the operation. All lights used in production department have been specially developed for pharmaceutical clean room application. Pass boxes are installed to avoid mix- ups during man material movement in new production part. All entry points to the plant are provided with air locks. Adequate inprocess storage areas have been provided Storage area Outer entrance doors are made of painted steels. Warehouse security is ensured by providing iron shutters at the entry point. The foundation of the warehouse is raised to ease loading and unloading activities.

31 Page 31 of 57 Revised Revision No.: 04 There is separate storage area available for raw materials (quarantine/ approved / rejected), packaging materials (quarantine/ approved / rejected) and finished goods. Air locks are installed to avoid mix-ups during personnel and material movement. The raw material storage area is located on the ground floor of the facility in the same block, so that material movement and handing is minimized. The plan of storage areas with special areas for the storage and handling of sensitizing materials is attached in Appendix Special areas for handling of highly toxic, hazardous and sensitizing materials Poisons and narcotics are kept in locked safes. Organic solvents as well as utility gases are stored in separate areas outside the buildings. Such materials are handled only in the QC laboratory. Solids are collected in separate containers Brief description of heating, ventilation and conditioning (HVAC) systems There is an integrated central ventilation system for warming and cooling the air and also filtrating dust and powder particles existed in the air and maintain pressure relationships between spaces. Differential pressure is positive from corridors against solid departments.

32 Page 32 of 57 Revised Revision No.: 04 Differential pressure is positive from liquid production department against corridors. Details of air change rate, filter types, room temperature, humidity, differential pressure between corridor and rooms, type of air, percentage of fresh air and maximum allowed pressure drop for changing filters are attached in Appendix 8. Differential pressure is maintained in the process area to restrict the contamination in respective processing area. Percentage of fresh and circulated air differs from room to room according to U. R. S. The Pre- filters are cleaned according to the frequency mentioned in the standard operating procedure. Integrity of HEPA filters are checked once a year. If any of the HEPA filters are failing in the Integrity testing, these should be replaced. The D. O. P. is performed to check HEPA filters integrity. The Pre-filters are cleaned according to the frequency mentioned in the SOP Layout of classification in production departments is attached in Appendix Brief Description of Water System Schematic diagram of water purification system is attached in Appendix 10. Wells water is used as feed water for processing to deionized water. The hardness of water is about PPM. Capacity of water purification systems is 10 m 3 /hr.

33 Page 33 of 57 Revised Revision No.: 04 Material of construction of vessels and pipes is PVC. Size of filter hole before RO system is 0.5 μ. Size of filter hole after mix bed and UV sanitizer is 0.2 μ. Sanitation of pipes and tanks is performed with deionized water at 25 C and chlorination method every 6 month. Sampling points in the manufacturing areas comprise of the user points and also from the deionized water storage tanks. Frequency of sampling and testing is scheduled on daily and weekly basis. The plant uses 50 m 3 of purified water every day. BOD and COD test performs on produced water. Purified water complies with pharmacopeia specifications- EP & BP Brief Description of Wastewater treatment system Schematic diagram of wastewater treatment system is attached in Appendix 11. Deodorant is addition to entrance of sludge. In aerator pool, organic material changed to inorganic material by aerobic bacteria. In rotor clarifier sludge and waste water were separated. Chlorination is done in pool of waste water and used for agricultural use. Analysis test are done by online system. Soda is added to sludge pool.

34 Page 34 of 57 Revised Revision No.: 04 Filter press system is used for drying and compacting sludge Brief description of other relevant utilities Steam system Capacity of steam production is 5 ton/hr. Average temperature of steam is 125 C. Steam pressure in steam pipes is 2 bar. Material of construction of vessels and pipes is seamless. Steam uses in granulation department, coating room, liquid department and bottle washing Compressed air Capacity of compressed air production is 276 lit/sec. Average temperature of steam is 125 C. Pressure of compressed air is about 7bar. Material of construction of vessels and pipes is seamless. Compressed air uses in compression department, coating room, capsule filling department, packing department and water system Nitrogen Plant uses nitrogen capsules for packing of some products.

35 Page 35 of 57 Revised Revision No.: 04 Pressure of Nitrogen in capsule is about 2 bar. 4.2.Equipment List of major production equipment, analytical instruments of Quality Control laboratory and R&D are showed in Appendix 12, 13 and 14 respectively Brief description of major production and laboratory equipment All the manufacturing equipment are designed, located and maintained to suit its intended purpose. The manufacturing equipment is designed as per GMP requirement with ease of cleaning and maintenance. All production equipments have been allotted distinctive identification numbers. Records for the history of maintenance of critical equipment are kept in the Engineering department. Machine parts in contact with the drugs products during processing are made of resistance covers and SS 316 which are non reactive, non- corrosive and nontoxic Cleaning and sanitation The equipment surface which is in directly contact with reagents should be cleaned by the cleaning procedure validated in our company. Generally, 75% ethanol is used as disinfectant.

36 Page 36 of 57 Revised Revision No.: 04 The cleaning validation is assessed by cleaning validation classification and worst case assessment procedure, then the general standard will be confirmed. According to the cleaning validation procedure, there should be no visible residues, chemical residues; solvent residues of cleaning use, microbiology limit should conform with the regulation. Cleaning procedure is done manually for the contact surface. SOPs for the cleaning of different processing areas and the cleaning of processing equipment are available. SOPs covering the cleaning methods for the water supply system, air handling system and dust extraction system have been provided along with their frequency of cleaning. The cleaning procedure for areas is validated by the microbiological test method. Cleaning Validation for process equipment is carried out as per protocol during product change over. Besides validation of the cleaning methods used for area and equipment, random sampling and testing is carried out to monitor its efficacy. At the end of each production operation the walls and floors and all the dusty parts are thoroughly cleaned with water and specific detergents. Some filters (0.2 micron) and UV lamps are installed on the water circulation route to prevent any contamination. Some reliable filters are also used on the air circulation route to absorb any dust or powder particles created by the recycled or fresh air.

37 Page 37 of 57 Revised Revision No.: 04 Many of the machines and apparatuses in the production areas are equipped with dust extractors to let their users remove dust or powder inside or around the machines. Dust is continuously evacuated from the premises during production time. Cleaning the production premises is done by production service personnel Qualification, Calibration and Validation Validation Master Plan has been written, clearly defining the scope of activities such as qualification of equipment, facilities and utilities, validation of processes and analytical methods. Standard formats prepared, approved and issued by QA Department, are used for Equipment Qualification and Process Validation Studies and Reports. Equipments are qualified during commissioning and installation through Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). All reference equipment and analytical instruments are calibrated by are calibrated by Government approved external agencies. Calibration certificates and reports provided by these agencies are maintained as records of equipment calibration. Every apparatus has its own specific method of calibration and also has an instrument s specifications such as name, sensibility, range, calibration background, etc are recorded.

38 Page 38 of 57 Revised Revision No.: 04 The instruments such as gauges, hydrometers, humidity meters, balances, PH meters, spectrophotometers, thermometers, melting point apparatuses, gas chromatographs, IR and HPLC and generally the critical apparatuses are precisely calibrated on the basis of international standards inside or outside of the company at regular intervals. The persons in charge of calibration in the company are trained enough to handle the job assigned to them properly Maintenance of premises and equipment Planned maintenance programmed is followed as per SOP which describes in detail the procedure for the manufacturing unit covering the schedule of maintenance and servicing of equipment and utilities. Records of PM will be carried out by the technician and kept by engineering Department. Major maintenance jobs and modifications are recorded in MIS system. Services of external agencies are undertaken on contractual agreement between the company and the concerned agency. QC instruments including HPLC, GC and UV are serviced by external contractor. Record of such preventive maintenance is maintained in the respective checklist and the reports are made known to users.

39 Page 39 of 57 Revised Revision No.: DOCUMENTATION 5.1. Description of documentation system Documentation management procedure stipulates the system management of the document drafting, approval, issuance, training, coming in to operation, revision and filing. At present all documentation are in paper and computerized manner. Standard Operating Procedure for the preparation of SOP and other technical documents specifies the format to be used for each type of document. Standard Operating Procedures (SOP's) are prepared by the related department, reviewed, controlled and issued by QA Department. The master documents are kept in charge departments and the documentation centre. Document number is specified by QA department according to the GMP documentation system and coding SOP. During use, documents should be modified when they can not meet the requirements of managements or process change or equipment replacement or new environmental, manufacturing conditions. The QA Department is responsible for distribution of the documents. Master Formula and Batch Records are prepared by the QA Department. All batch documents are filed and classified chronologically. They are all kept in the QC Department and computerized MIS.

40 Page 40 of 57 Revised Revision No.: 04 Batch records ddocuments are kept on file for at least one year after expire date of products. All of other expired documents are kept for one year. 5.2.The existing documents are as follows The main type of those files as: Quality manual, Policy document Site master file SOP procedural Work instructions Job description Master Formulae and batch record Raw material specifications Packaging component specifications Standard process instructions including manufacturing, packaging Analytical methods Release procedures SOPs PM instructions Cleaning instructions Inventories

41 Page 41 of 57 Revised Revision No.: Other documentation related to the product quality The following documents are available and in use: Equipment specifications Equipment Qualification (IQ, OQ & PQ). QC procedures Training procedures Documents of out of standards Documentation control of process deviations Calibration and test Validation Reconciliation of raw material batches and packaging components

42 Page 42 of 57 Revised Revision No.: PRODUCTION Layouts of production areas including material and personnel flows are attached in Appendix 15 and Type of production Amin pharmaceutical company is capable of producing and packaging non-sterile human pharmaceutical products both in solid dosage forms (coated / non- coated tablets, and capsules) and liquid dosage forms (oral drops / syrups). List of products including general name, brand name and dosage are showed in Appendix Process Validation Assessment of process linchpin will be carried out according to the quality risk management procedure and the key steps, parameters, starting materials, intermediates controls, etc, which need to be validated, will be confirmed. - Content should be investigated in validation: Process time, temperature, pressure ph value Yield of different process stage Storage time and period of the weighed starting materials, intermediate materials and semi finished products.

43 Page 43 of 57 Revised Revision No.: 04 The homogeneity within batch is assessed by proper sampling and testing. The important process variables should be monitored and controlled in process validation, and the results should be assessed. All the test items in product quality standard should be implemented in validation. Test results should be in accordance with the relevant quality standard or product release standard. All the batches validated should b determined whether or not to implement the stability study by risk assessment, and the type and scope for study should be confirmed. Sampling related to process validation should be carried out according to the written sampling plan, including sampling time, method, personnel, tool, sampling location and sampling quantity. The equipment related to process validation and the parameter setting range should be confirmed before validation starting. The validation scope should include the worst conditions under which it is most likely to produce product quality problems Toxic or hazardous substances handled All condition of transport, storage and use of material is in MSDS. All of personnel that work with this kind of material must cover all of body. This material kept in specific and safety area and containers.

44 Page 44 of 57 Revised Revision No.: Controlled and specific materials and products Controlled production needs some special condition for production, distribution and trade. List of controlled raw materials in Amin pharmaceutical company: Codein phosphate Phenobarbital Zolpidem Diphenoxylate Tramadol Chlordiazepoxide Pseudoefedrine Methadone List of controlled products in Amin pharmaceutical company: Diphenoxylate Tramadol Acetaminophen codein Methadon tablet and syrup These materials and products require separate and enough space for storing. Intermediate products, documents, labels instruments for controlled product are kept in special local.

45 Page 45 of 57 Revised Revision No.: 04 Warehouse of under control raw materials and products must be equipped with camera and locked system. Qualified Person, supervisor of storage and quality control are responsible for opening or sealing locks. Weighing of raw materials and finished products are done by accurate balances Material management and warehousing Arrangements for handling starting materials, packaging materials, bulk and finished products Material purchase: The supplier requirement, supplier ratification, supplier review and supplement alteration are clearly regulated in supplier management. Materials are stored on the pallets and racks under controlled conditions. Separate approved Entry/ Exit SOP's are available for warehouse and dispensing areas. The packaging materials warehouse provides for segregation and storage of materials and is classified. Printed packaging materials are kept under lock and key and are subject to a reconciliation system. Construction and finishing of the primary packaging areas is similar to that of the process areas.

46 Page 46 of 57 Revised Revision No.: 04 All the containers are placed in designed area and labeled as QUARANTINE with details of receipt NO., MFG date and expiry date. The samples are drawn as per the sampling plan sampled containers are identified with SAMPLED stickers and tested as per their respective material specifications by QC after sampling UNDER TEST labels are affixed on each container. Identification test is done on API materials upon receipt wherever applicable. Head QC / designee review the analytical data and dispose the material as APPROVED /REJECTED. Subsequently APPROVED/ REJECTED labels are affixed on the container & transferred to the designated storage area. All packaging materials are handled as per the above procedure and APPROVED/REJECTED labels are affixed accordingly. The printed packaging materials are stored securely under lock and issued in requisite number only. The dispensing of material is carried out as per the SOPs and on FIFO. For transportation of the dispensed material from warehouse to production area, the appropriate material handling devices are used such as trolleys, cages and other suitable containers. The "REJECTED" raw materials are transferred to designated place of warehouse with lock and key mechanism and handled by the authorized QA personnel only. Based on the supplier/ manufacturer.

47 Page 47 of 57 Revised Revision No.: 04 The "REJECTED" finished drug products and printed packaging materials are destroyed under the supervision of QA personnel and records are maintained for the same. Raw materials and packing materials are stored at controlled and suitable area depending upon the storage requirement of the material. The raw and packaging materials are kept in a specific quarantine warehouse and not allowed to be used unless the QC Manager confirms them by Approved label. SOPs for sampling of the raw materials and packaging materials are available and followed. The sheet of batch records for weighed raw materials is containing following information: The raw material name and specifications. The product batch number and name. Date. The name and signature of the person in charge of weighing. The name and signature of the person in charge of controlling. The damaged or improperly labeled goods referred to QC for further instructions for disposal or return.

48 Page 48 of 57 Revised Revision No.: 04 Each consignment of material after receipt is visually examined. Separate zones are earmarked for Quarantine/under test, Approved and Rejected status of raw and packing material. The batch numbers, the production and expiry dates, the type of labels, the brochures, the aluminum foils and the boxes and bottles are controlled by the head of the packaging staffs before starting the packaging operation. After granulation, tablet, coating, and capsule filling, the tablets and capsules are put into plastic bags, and then into barrels. The storage of quarantine bulk products is done in a specific area provided for this purpose. All the drug specifications have already been printed on the labels except the product batch numbers and the manufacturing / expiry dates. Intermediate and finished products are sampled by QC. Intermediate products are taken for next stages and packing, after QC release based on the results of intermediate products. The batch numbers production and expiry dates related to blisters and bottle of oral and syrup are engraved on them. The packed finished products are quarantined till approval by QC after complete analysis.

49 Page 49 of 57 Revised Revision No.: Arrangements for handling rejected materials, products and the wastes All rejected materials are identified by Red colored Rejected labels. The QC persons affix Rejected labels. For rejected material, whole purchased materials will be returned to the supplier. Fortunately it has rarely happened so far. All documents in this regard are kept on file in duplicate both in the QC Department and the commercial Department. If a bulk product is rejected, the production department tries to find technical solutions for it. If the problem is not possible to solve, the bulk product will be rejected by the QC Department and stored in an appropriate area before destruction. The QC Manager mentions the reasons of rejection. All information in this regard is kept on file. Expired products are destroyed under control of inspectors. The amount of destroyed products is recorded in details in a specific file. The wastes of different production operations are collected and stored in a secure warehouse located in a special locked area and then they will be destroyed according to ISO Standards.

50 Page 50 of 57 Revised Revision No.: 04 7.QUALITY CONTROL (QC) Description of the QC activities: QC Department functions are specified in SOPs by which all its activities are governed. SOPs, Specifications and Test Methods constitute the documents controlled, issued and used by the QC Department for the sampling, testing and approval of materials and products. Each batch undergoes individual sampling and testing prior to approval / rejection. The finished products are sampled as per SOP. These items are analyzed by Standard Test Procedures and approved on compliance to specifications. The methods of analysis used by QC Department cover physical and chemical testing, instrumental analysis by sophisticated electronic instruments e.g. UV / Visible Spectrophotometer, Gas Chromatograph (GC), High Pressure Liquid Chromatography (HPLC) Batch Production and Control Records are recorded in Batch Records, from its issue till the packaging and dispatch of the finished goods, each Batch Records is reviewed during dispensing, manufacturing, packaging and during the release of the finished product.

51 Page 51 of 57 Revised Revision No.: 04 COA is prepared on completion of testing of finished products and enclosed in the Batch Records by QC Department. The authorized personnel are responsible for sampling and testing of starting materials, raw and packaging materials, the in-process materials like blends and granules and the finished products in the packaged form. The dispatch of finished products for sale / distribution can be planned only after approval by QC Department and Qualified person. Samples store from all batches according to cgmp for sampling and testing. Following analyses are carried out in- house: Instrumental analysis, Chemical analysis, microbiological testing and packaging material analysis. To ensure consistency in results our laboratory use as far as possible methods described in USP and BP and EP. Microbiological department tests for total bacterial count, fungal count and absence of pathogens. The test results are documented and preserved as Certificate of Analysis (COA) with the raw data, as per statutory requirements up to one year beyond the expiry of finished products. Review of QC activities and responsibilities Development and approval of specifications.