AO 43 cGMP Guidelines PDF

Republic of the Philippines Department of Health OFFICE OF THE SECRETARY SAN LAZARO COMPOUND, RIZAL AVENUE, STA. CRUZ...

Republic of the Philippines Department of Health OFFICE OF THE SECRETARY SAN LAZARO COMPOUND, RIZAL AVENUE, STA. CRUZ MANILA, PHILIPPINES September 29, 1999 ADMINISTRATIVE ORDER No. 43 S. 1999 TO : ALL DRUG AND DEVICES MANUFACTURERS, TRADERS AND PARTIES CONCERNED SUBJECT : CURRENT GOOD MANUFACTURING PRACTICE GUIDELINES FOR DRUGS. The Bureau of Food and Drugs hereby adopts the 1st edition of Current Good Manufacturing Practice Guidelines and the specific GMP guidelines hereunder prescribed. PART 1. GENERAL PROVISIONS Section 1 Authority This order is issued under the authority conferred upon the Secretary of Health by virtue of section 26(a) of RA 3720 as amended. Section 2 Statement of Policies 2.1 Drugs shall be manufactured using methods, facilities and control procedures adequate to preserve their identity, strength, quality and purity. 2.2 License to manufacture drugs shall be issued only upon compliance with Current Good Manufacturing Practice guidelines. 2.3 Overall control is essential to ensure the manufacture of drugs conforming officially recognized standards of quality, efficacy and safety. 2.4 The qualities of drug products depend on the starting materials, production, quality control processes, building, equipment, and personnel involved and testing protocols. Section 3 Statement of Objectives This 1999 GMP guidelines is adopted to: 3.1 Prescribe standard guidelines in the manufacture of drug products 3.2 Ensure that no person or establishment shall manufacture drugs under substandard conditions. Page 1 of 92 Section 4 Definition of Terms For the purpose of these guidelines, the following terms shall mean: 4.1 Accuracy The nearest value obtained during measurement or analysis to the true value. 4.2 Actual Yield The quantity that is actually produced at any phase of production of a particular drug product based on the initial input. 4.3 Airlock An enclosed space with two or more doors, which is interposed between two or more rooms e.g. of different standard of cleanliness for the purpose of controlling the air flow between those rooms when they need to be entered. An airlock may be designed for and used by either people or materials; in the latter case it can be termed a “pass through hatch”. An airlock can also be the “anteroom” to a clean room in which sterile goods are handled. 4.4 Approved Supplier A supplier of all components of finished products generally approved for use by the trade and accredited by the manufacturer based on a vendor rating which include but not limited to conformance to the company or compendium material specifications. 4.5 Batch A quantity of drug product/device that is homogenous in character and quality produced during a given cycle of manufacture and from a specific manufacturing order. 4.6 Batch Number A designation in numbers or letters or combination thereof that identifies the batch, and permits the tracing of the complete history of a batch, including all stages of its production, control and distribution. 4.7 Biogenerator A contained system, such as a fermenter, into which biological agents are introduced together with other materials in order to effect their multiplication or their production of other substances by reaction with other materials. Biogenerators are generally equipped with devices for regulation, control connection, material addition and material withdrawal. 4.8 Microbiological Agents Microbiological Agents including genetically engineered microorganisms, cell cultures, as well as endoparasites, whether pathogenic or not. Page 2 of 92 4.9 Blood Whole blood collected from a single donor and processed either for transfusion or further manufacturing. 4.10 Bulk Product Any processed material which has to undergo another process including packaging operation to become a finished product. 4.11 Calibration The operations carried out to determine the accuracy of measuring instruments, of “material measures” such as masses or gauges and of measurement standards. 4.12 Cell Bank System A system whereby successive batches of a product manufactured by culture in cells derived from the same master cell bank (see Master Cell Bank). The cell bank system is validated for a passage level or number of population doubling beyond that which was achieved during routine production. 4.13 Cell Culture The in-vitro growing of cells isolated from multicellular organisms. 4.14 Clean Area An area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to minimize the introduction, generation and retention of contaminants within the area. 4.15 Compatibility Testing The in-vitro serological tests performed on donor and recipient blood samples to establish the serological matching of a donor’s blood or blood components with that of a potential recipient. 4.16 Component Any material intended to be used for the manufacture of a product whether raw or packaging materials. 4.17 Contained Area An area constructed, operated and equipped with air-handling and filtration system in order to prevent contamination of the external environment by biological agents from within the area. Page 3 of 92 4.18 Contaminants Anything that cause contamination to the product. 4.19 Controlled Area An area constructed and operated to control the introduction of potential contamination (an air supply approximately class III may be appropriate), and the consequences of accidental release of living organisms. The level of control exercise shall reflect the nature of the organism employed in the process. The area shall be maintained at a pressure negative to the immediate external environment and allow for the efficient removal of small quantities of airborne contaminants. 4.20 Cross Contamination Contaminations of a starting, intermediate product or finished product. 4.21 Cryogenic Vessel A container designed to store liquefied gas at extremely low temperature. 4.22 Cylinder A container designed to store gas at a high pressure. 4.23 Date of Manufacture The date indicating the start of processing of every batch. 4.24 Dispensing The activity of weighing, counting or measuring and checking of starting materials and issuing these to the appropriate production personnel; details of the activity being duly and properly documented. 4.25 Documentation Written recording of all procedures, instructions and processes involved in the manufacture of drug products. 4.26 Drug Product Any substance or mixture of substances in finished dosage forms that is manufactured, offered for sale, or presented for use in (1) the treatment, mitigation, cure, prevention, or diagnosis of disease, abnormal physical state, or the symptoms thereof in man or animal; or (2) the restoration, correction or modification of organic functions in man or animal; regardless of whether it is in package form. Page 4 of 92 4.27 Device Instrument, apparatus, or contrivances, including their components, parts and accessories, intended (1) for use in the diagnosis, cure, mitigation, or prevention of disease in man and animals; or (2) to affect the structure or any function of the body of man or animal. 4.28 Expiration Date A date fixed for each individual batch on or before which the batch is expected to meet the standard specifications for quality, safety and efficacy. 4.29 Facilities For Blood Products: Any area used for the collection, processing, compatibility testing, storage or distribution of blood and blood components. For Other Products (drugs, medical devices, bulk chemical material and others): This refers to the building, premises and equipment necessary in the manufacture of drugs. 4.30 Finished Product A product which has undergone all stages of manufacturing operations. 4.31 Good Manufacturing Practice (GMP) It is the system of quality assurance aimed at ensuring that products are consistently manufactured to a quality appropriate for their intended use. It is thus concerned with both manufacturing and quality control processes and procedures. 4.32 Infected ( Man or Animal ) Contaminated with extraneous biological agents and therefore capable of spreading infection. 4.33 In-Process Control Checks and tests instituted and carried out in the course of the manufacture of a drug to assure identity, strength, quality and purity. 4.34 Intermediate Product Any processed substance or mixture of substances which has to undergo one or more further stages of processing to become finished product. 4.35 Leukopheresis The process in which blood is extracted from the donor, a leukocyte concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor. Page 5 of 92 4.36 Liquefied Gases Gases that, at the specified temperature and pressure, remain as a liquid in the cylinder. 4.37 Lot A batch or any portion of batch produced by a continuos process, an amount of drugs produced in a unit of time or quantity in a manner that assures its uniformity and in either case which is identified by a distinctive lot number and has uniform character and quality within specified limits. 4.38 Lot Number See batch number 4.39 Manifold Equipment or apparatus designed to enable one or more gas containers to be filled simultaneously from the same source. 4.40 Manufacture or Manufacturing The complete set of activities to produce a drug that comprise production and quality control from dispensing of materials to the release for distribution of the finished product. 4.41 Master Cell Bank A culture of fully characterized cells filled into containers in a single operation, processed together and stored to ensure uniformity and stability. A master cell bank is normally stored at -70oC or lower. 4.42 Master Seed Lot A culture of a microorganism distributed from a single bulk into containers in a single operation to ensure uniformity, stability and to prevent contamination. 4.43 Packaging The process of packing which is that part of the production cycle applied to a bulk product to obtain the finished product. 4.44 Packaging Material Any material used in the packaging of a bulk product to obtain the finished product. 4.45 Plasma (for further manufacture) The liquid portion of blood separated and used as material to prepare another product. Page 6 of 92 4.46 Plasmapheresis The process in which blood is extracted from the donor, the plasma is separated from the formed elements and at least the red blood cells are returned to the donor. 4.47 Plateletpheresis The process in which blood is extracted from the donor, the platelet concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor. 4.48 Precision ( in analytical assay and method) The degree of variation between individual test results when the method is used separately to different samples drawn from the same batch of material. This will include variation between analysts, between days, between tests on the same prepared extract of a given sample, between different extracts and between laboratories conducting the same test. It is normally divided into two types: - Repeatability (within laboratory), and - Reproducibility (between laboratories). 4.49 Primary Containment A system of containment that prevents the dispersal of a biological agent into the immediate working environment. It involves the employment of closed containers or safety biological cabinets accompanied with secure operating procedures. 4.50 Procedures Description of the operations to be executed, the precautions to be implemented directly or indirectly related to the manufacture of a drug. 4.51 Processing The part of production cycle starting from weighing of raw materials to finished product. 4.52 Processing of Blood Any process employed after collection and before computability testing of blood. It includes the identification of a unit of donor blood, the preparation of components from such unit of donor blood, serological testing, labeling and associated record keeping. 4.53 Production All operations starting from dispensing of materials to processing, packaging, to finished product. Page 7 of 92 4.54 Quality Control All control measures taken designed to ensure that finished products consistently conform to established specification of identity, strength, purity and quality. 4.55 Quarantine An act of holding off a material for use, or a product for packaging or distribution by physically setting it apart or by system duly validated, pending a decision on release or rejection. 4.56 Raw Material All substances whether active or excipients that are employed in the processing of a finished product. 4.57 Reconciliation A resolution between the theoretical and actual yield. 4.58 Recovery The incorporation of all or part of previous batches with the required quality into another batch at a defined step of production. 4.59 Rejected The status of materials or products which are not permitted to be used for processing, packaging or distribution. 4.60 Released or Passed The status of materials or products which are permitted to be used for processing, packaging or distribution. 4.61 Representative Sample A sample representing the lot, the batch, or the total amount of materials based on a sampling plan. 4.62 Reprocessing The reworking of all or part of a batch of product of an unacceptable quality from a defined step of production in order that its quality may be rendered acceptable by one or more additional operations. 4.63 Returned Product Any finished product which is already in distribution and sent back to the manufacturer or distributor due to complaint, damage, expiration, validity or Page 8 of 92  other reasons such as the condition of the container or package which may cast doubt on the product identity, quality, strength and safety. 4.64 Sanitation All measures taken to assure suitable or adequate environmental conditions in compliance to GMP. 4.65 Secondary Containment Secondary containment is a system of containment that prevents the dispersal of a biological agent into the external environment or into other working areas. It involves the use of rooms with specially designed air handling, the existence of air locks and/or sterilizers for the exit of material. It may add to the effectiveness of primary containment (see Primary Containment). 4.66 Seed Lot System A seed lot system is a system where successive batches of product are derived from the same master seed lot at a given passage level. 4.67 Specification of Material A description of starting material, intermediate, bulk or finished product in terms of its chemical, physical and microbiological characteristics, if any. A specification shall include descriptive and or numerical clauses stating standards and tolerated deviations, whenever applicable. 4.68 Starting Materials Raw materials used in the production of a finished product (drugs). 4.69 Sterile Room or Sterile Area A room or area of defined environmental condition with controlled particulate and microbial contamination, constructed, equipped and used to eliminate the introduction, generation or retention of contaminants. 4.70 Sterilization Inactivation or reduction to an acceptable level of all viable microorganisms by a suitable process. 4.71 Theoretical Yield The quantity that is expected or planned to be obtained at any phase of production of a particular product, based on the quantity of components to be used. Page 9 of 92  4.72 Unit (of Blood) The volume of blood or one of its components in a suitable volume of anticoagulant obtained from a single collection of blood. 4.73 Validation The process of confirming by recognized appropriate means or manner, that any material, process, procedure, activity, system, equipment or mechanics used in production and control consistently achieved the desired results. 4.74 Working Cell Bank A culture of cell derived from the master cell bank and intended for use in the preparation of production of cell cultures and normally stored at - 70OC or lower. 4.75 Working Seed Lot A culture of microorganism derived from the master seed lot and intended for use in production. 4.76 Worst Case A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when, compared to ideal conditions. Such conditions do not necessarily induce product or process failure. PART 2. BASIC GMP GUIDELINES Section 1 PERSONNEL There shall be an adequate number of personnel at all levels having knowledge, skills and capabilities relevant to their assigned functions, in good mental and physical health to be able to execute their duties. 1.1 Organization, Qualification and Responsibilities 1.1.1 The organizational structure of the company shall be such that the production and the quality assurance are headed by different managers, neither of whom shall be responsible to the other. Each shall be given full authority and facilities necessary to execute his/her duties effectively. Neither shall have any interests outside the manufacturer’s organization that prevent or restrict their dedication to the assigned responsibilities or which may be considered to entail a conflict of interest. 1.1.2 The production manager shall be a PRC registered qualified pharmacist or any other related profession. He/she shall be adequately trained and shall posses good practical experience in the Page 10 of 92  field of pharmaceutical manufacture and managerial skill, which enable him/her to perform his/her function effectively. The production manager shall have full authority and responsibility to manage production of drug products. 1.1.3 The quality control manager shall be a PRC registered qualified pharmacist or any other related profession. He/she shall have adequate training and practical experience that will enable him/her to perform his/her function effectively. The quality assurance manager shall have full authority and responsibility in all quality control processes such as establishment, verification and implementation of all quality control procedures. He/she shall have the sole authority to approve starting materials, intermediates, bulk and finished products that meet the specification or to reject those which do not conform to the relevant specification or which are not manufactured in accordance with the approved procedures. 1.1.4 The quality assurance manager shall clearly define the field of work and the method of delegating responsibilities in his/her absence. 1.1.5 The quality assurance manager shall have personal and professional responsibility for ensuring that various checks and tests have been carried out. The details of this work may be delegated to an appropriately trained and experienced staff who would endorse their work. Finally, the quality assurance manager has to be satisfied directly by the proper operation of quality systems that include appropriate approvals, audits, self-inspections and spot checks that the production and testing have complied with relevant requirements. 1.1.6 The production manager and the quality assurance manager are jointly responsible to establish for the quality, strength, purity and efficacy of the finished products. 1.1.7 To support and assist the key personnel, an adequate number of qualified personnel should be available in the production and quality assurance. Each personnel shall be adequately trained with their respective assignment. 1.1.8 The duties and responsibilities of all employees shall be clearly defined, well understood and shall be within his/her capacity to perform to ensure quality products. 1.2 Training 1.2.1 All employees who are directly and indirectly engaged in the manufacturing activities shall be trained in the particular operations that the employees perform in accordance with the principles of Current Good Manufacturing Practice. 1.2.2 Training shall be conducted by qualified individuals. Special attention shall be given to training of personnel working in sterile and clean areas or with highly potent, toxic or sensitizing materials. Page 11 of 92  1.2.3 Training in Current Good Manufacturing Practice shall be on a continuing basis and with adequate frequency to assure that employees remain familiar with the Current Good Manufacturing Practice requirements relevant to their functions. 1.2.4 Training in Current Good Manufacturing Practice shall be in accordance with written program approved by the production manager and the quality assurance manager. 1.2.5 Records of personnel training in Current Good Manufacturing Practice shall be maintained and the effectiveness of training programs shall be assessed periodically. 1.2.6 After training, the consequential employees’ performance shall be appraised to determine their capability to meet the qualification requirement for the jobs. Section 2 PREMISES The premises for manufacturing shall be of suitable size, design, construction and location to facilitate proper operation, cleaning and maintenance. The individual working areas shall be adequate so that any risk of confusion, cross-contamination and other mistakes that will adversely affect the quality of drugs and devices will be avoided. 2.1 Location, Construction, Design & Lay-out 2.1.1 Premises shall be so located and protected against contamination from the environment. 2.1.2 Premises shall be constructed and maintained to protect against weather, flood, ground seepage and the access and harboring of vermin, rodents, birds, insects or other animals. 2.1.3 In determining the design and lay-out of premises, consideration should be paid to: 2.1.3.1 the compatibility of other manufacturing operations that may be carried out in the same or adjacent premises 2.1.3.2 allow the production to take place in areas connected in a logical order according to the sequence of the operations and to the requisite cleanliness levels 2.1.3.3 the adequacy of the working space, which shall allow orderly and logical placement of equipment and materials to suit the operation, efficient flow of work, effective communication and supervision to avoid crowding and disorder 2.1.3.4 avoid the use of production areas as a general traffic for personnel or materials or for storage other than the materials in process. Page 12 of 92 2.1.4 The layout of rooms, corridors, and spaces shall provide for logical movements of materials and personnel with minimal traffic for operations to be carried out in defined areas and to avoid cross contamination. The design and layout of premises shall fulfill the following requirements: 2.1.4.1 the risk of mix-up between different drugs or their components, the possibility of cross-contamination by other drugs or substances and the risk of omission of any production step shall be prevented 2.1.4.2 penicillins shall be produced only in separate buildings, with separate air handling facilities dedicated to these products using dedicated equipment, including dedicated packaging lines. 2.1.4.3 cephalosporins shall be produced in separate buildings, with separate air handling facilities dedicated to these products using dedicated equipment, including dedicated packaging lines 2.1.4.4 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods: 2.1.4.4.1 carrying out production operations in separate buildings or adequately isolating the operations by total enclosure or by making successive batches in the same or in dedicated equipment followed by validated cleaning procedures and where appropriate, fumigation 2.1.4.4.2 controlling airborne contaminants by the use of an appropriate air pressure differential in processing areas and adequate exhaust systems and filters, together with control of recirculated air 2.1.4.4.3 the setting and shielding of production equipment, and wherever possible, the use of equipment solely for one type of drug/product; 2.1.4.4.4 containment of contaminant-transfer by means of airlocks, clothing change and decontamination of containers and other articles prior to their removal from the isolated area 2.1.4.4.5 separate cleaning area for contaminated clothing Page 13 of 92  2.1.4.4.6 periodic testing of the environment around the production areas for the presence of the therapeutic substance being processed and 2.1.4.4.7 validation of cleaning procedures. 2.1.5 In all manufacturing rooms (processing and packaging), air supply and air exhaust points shall not be so close or so disposed as to restrict or negate the supply of clean air to worksites and or movement of product dust or other contaminants away from worksites. The airflow pattern within the facility and each manufacturing area and the throughput rate of air shall be selected to afford adequate protection to the products and personnel. A plan of the building(s) showing air handling facilities including key air handling equipment and showing air quality standards, flow rates, proportions re-circulated and relative air pressures shall be made available for inspection. 2.1.6 Air handling facilities for the production of cytotoxins shall be appropriate. The anteroom should operate at a positive pressure relative to the processing area but negative or lower pressure relative to the outside or adjacent room. 2.1.7 The processing of materials for drug products shall be separated from the production of non-drug products. 2.1.8 Separate space for: 2.1.8.1 Cleaning mobile equipment 2.1.8.2 Storage of cleaning materials 2.1.9 Locker/gowning room shall be directly connected to but separated from processing areas. 2.1.10 Toilets should not be opened directly to production areas and shall have adequate supply of water and ventilation. 2.1.11 Experimental animals shall be housed in a separate building.[Refer to Annex on Biological Products for further details on Animal Quarantine and Care] 2.1.12 Defined areas for the following operations are required: 2.1.12.1 gowning/change rooms for all personnel 2.1.12.2 receiving of starting materials 2.1.12.3 incoming goods quarantine 2.1.12.4 sampling room for sampling of deliveries of starting materials Page 14 of 92  2.1.12.5 storage for approved materials (chemical & packaging) 2.1.12.6 storage of reject materials 2.1.12.7 laboratories 2.1.12.8 weighing / dispensing of materials 2.1.12.9 processing operations 2.1.12.10 equipment washing 2.1.12.11 storage of cleaned, idle/non-functional equipment 2.1.12.12 major repair and maintenance activities 2.1.12.13 storage of cleaning tools and supplies 2.1.12.14 staging/storage of bulk products 2.1.12.15 packaging / labeling operations 2.1.12.16 quarantine storage for finished products 2.1.12.17 storage for approved of finished products and 2.1.12.18 distribution center 2.1.12.19 cafeteria 2.1.12.20 process water treatment 2.1.13 Interior surfaces (walls, floors and ceilings) shall be smooth, free from cracks and open joints, shall not retain or shed particulate matter, shall permit easy cleaning and disinfecting. The floor in processing areas shall be made of impervious materials, laid to an even surface, shall allow prompt and efficient removal of any spillage. Walls shall be of impervious and washable surface. The coving of junctions between walls, floors and ceilings in critical areas is necessary. 2.1.14 Drains shall be of adequate size with trapped gullies. Open channels shall be avoided where possible, but if required, they shall be shallow enough to facilitate cleaning and disinfecting. 2.1.15 Air intakes and exhausts, and associated pipework and ducting shall be installed in a way that will avoid product contamination. 2.1.16 Production areas shall be effectively lit and ventilated with air control facilities (including temperature, humidity and filtration), appropriate both to the products handled, to the operation undertaken within them and to the external environment. [refer to section 2.1.5, 2.1.6] Page 15 of 92  2.1.17 Pipework, light fittings, ventilation points and other services in production areas shall be installed in a way that will have cleanable recesses and preferably located outside the processing areas. 2.1.18 Avoid having exposed overhead roof joints, pipes and ducts. 2.1.19 Electrical power supply shall be adequate to ensure the proper functioning of production equipment and laboratory instruments. 2.1.20 The condition of buildings shall be reviewed regularly, and repaired where necessary. Special care shall be exercised to ensure that building repair or maintenance operations do not adversely affect products. 2.1.21 Storage areas shall be of adequate space, provided with suitable lighting, arranged and equipped to allow dry, clean and orderly placement of stored materials and products. 2.1.21.1 Special and secured areas shall be available for storage of flammable and explosive substances, highly toxic substances, narcotics and other dangerous drugs. 2.1.21.2 Storage areas shall be laid-out to permit effective and orderly segregation of the various categories of materials stored to allow FIFO system. 2.1.21.3 Segregated storage shall be provided for rejected, recalled or returned goods. 2.1.21.4 Storage arrangements shall permit separation of different labels, as well as other printed materials to avoid mix-up. 2.1.21.5 Materials require special storage conditions such as temperature and/or humidity controls. These conditions should be monitored and records of the monitoring retained. 2.1.22 Doors that lead from production areas directly to the outside, e.g. fire exits, shall be secured against contamination. Section 3 EQUIPMENT Equipment used in the manufacturing of drug products shall be of appropriate design and construction, adequate size and suitably located in order to assure product quality and process reproducibility and to facilitate its cleaning and maintenance. 3.1 Design and Construction The design and construction of equipment shall fulfill the following requirements: 3.1.1 the equipment surfaces coming in contact with any raw material, intermediate, bulk or finished product shall not be reactive, additive or Page 16 of 92  absorptive so as to alter safety, strength, identity, quality or purity of the drug beyond the established limits 3.1.2 equipment shall not adversely affect the product through leaking valves, lubricant drips, inappropriate repairs, maintenance, modifications or adaptations 3.1.3 materials required for specific operations, such as lubricants or coolants shall not come into contact with any in-process materials as to alter the strength, safety, identity, quality, or purity of raw material, intermediate, bulk or the finished product beyond the established limits 3.1.4 equipment shall be easily and conveniently cleanable 3.1.5 all equipment designated for use with flammable substances or chemicals shall be explosion proof 3.1.6 equipment employed for weighing, measuring, testing and recording shall be regularly checked for accuracy and calibrated according to an appropriate program and procedure; and records shall be maintained. Calibration conducted shall be traceable to a primary standard of calibration of an appropriate national government agency and other reliable agency. Records of calibration shall be provided and maintained 3.1.7 filters for liquid filtration used in the processing of products shall not release fibers or substances into such products. 3.2 Installation and Location 3.2.1 Equipment shall be suitably installed and located to eliminate cross- contamination. 3.2.2 Equipment shall be located at a sufficient distance from other equipment to avoid congestion and to ensure that products do not become admixed or confused with one another. 3.2.3 All open mechanical belts and pulleys shall be equipped with safety guards. Water, steam and pressure or vacuum lines shall be installed so as to be easily accessible during all phases of operation. These shall be adequately labeled and marked to be easily recognized. 3.2.4 Each piece of equipment shall be clearly marked with an identifying number. This number will be used on all batch directions to designate the particular unit or apparatus used in that specific batch. 3.2.5 All pipes, tanks, jackets for steam or coolant shall be properly insulated to prevent possible injury and to minimize energy loss. 3.2.6 Piping to equipment designated for use with the pressurized steam shall be properly trapped and drained. Page 17 of 92  3.2.7 Heating, ventilation, air conditioning, potable water, purified water, distilled water, clean steam, compressed air, gases and other support systems must undergo validation. 3.3 Maintenance 3.3.1 Equipment shall be subjected to regular maintenance checks at appropriate intervals to prevent malfunctions or contamination that can alter the strength, safety, identity, quality, or purity of the product beyond established limits. 3.3.2 Written procedures shall be established and followed for maintenance of equipment. The preventive maintenance program shall be structured to assure: 3.3.2.1 all equipment requiring preventive maintenance is identified 3.3.2.2 the preventive maintenance schedule allocates priorities for maintenance 3.3.2.3 the frequency for preventive maintenance for each equipment is identified 3.3.2.4 the maintenance records are kept 3.3.2.5 that a preventive maintenance activity for critical pieces of equipment exceeds the scheduled time interval for that activity, quality assurance is advised of the deviation in the maintenance schedule. 3.3.3 A written record of major equipment maintenance and use shall be included in individual equipment logs which also identifies the date, time, product, strength and batch or lot number of each batch processed. For equipment used solely for one product the record can be included in the production batch records. 3.3.4 A comprehensive program shall cover equipment calibration. Records shall be maintained and to highlight trends and/or exceptional reports. 3.4 Validation 3.4.1 Validation shall be conducted following a Validation Protocol. Equipment validation involves three distinct stages: 3.4.1.1 Installation Qualification 3.4.1.2 Operational Qualification 3.4.1.3 Performance Qualification/Product Valida- tion (sometimes referred as process validation) 3.4.2 There are a number of basic principles related to validation of new equipment. The detail and scope of an installation and operational Page 18 of 92  qualification exercises is related to the complexity of the equipment involved and the critical nature of that equipment with respect to the quality of the final product. Nonetheless, basic principles shall be adhered to whether it is the installation and operation of a simple weighing balance or an autoclave. These basic principles are: 3.4.2.1 Install the equipment in accord with an installation plan per supplier's manual or by any special purchase requirements. 3.4.2.2 The requirements for calibration, maintenance and cleaning are developed first as draft procedures, reviewed and finally issued as authorized standard operating procedures (SOP) and become part of the SOP program of the company. 3.4.2.3 Establish operating requirements and conduct test to assure equipment is operating correctly, under normal and worst case conditions. 3.4.2.4 Finalize and document operator-training requirements pertaining to new equipment. Section 4 SANITATION AND HYGIENE High level of sanitation shall be practiced in every aspect of manufacturing drug products. The scope of the sanitation and hygiene program covers personnel, premises, equipment and apparatus, production materials and containers and anything that could become a source of contamination to the product. Potential sources of contamination shall be eliminated through an integrated comprehensive program of sanitation and hygiene. In all instances, the sanitation and the hygiene procedures should be validated and periodically assessed to ensure that the effectiveness of the operation meets the requirements. 4.1 Personnel 4.1.1 All personnel, prior to and during employment, shall undergo health examinations. Operators required to undertake visual inspections shall also undergo periodic eye examination. 4.1.2 Personal hygiene shall be observed by all those concerned with the manufacturing processes. 4.1.3 Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products shall not be allowed to handle raw materials, packaging materials, in-process materials, and drug products until fit to work. 4.1.4 All employees shall be instructed and encouraged to report to their immediate supervisor any health condition that may adversely affect the product. Page 19 of 92  4.1.5 Direct contact shall be avoided between the operator and raw materials, intermediate or bulk products. 4.1.6 Personnel engaged in the manufacturing of drug products shall wear clean clothing appropriate for the duties they perform. Soiled uniforms shall not be used and be stored in closed containers until properly laundered or disposed. 4.1.7 Only authorized personnel shall enter those areas of the buildings and facilities designated as limited-access areas. 4.1.8 Personnel shall be instructed to wash their hands before entering production areas. Signs to this effect shall be posted. 4.1.9 Smoking, eating, drinking, chewing and other activities; keeping plant, food, drink, smoking material and personal medicines shall be restricted to specific areas and not permitted in production, laboratory, storage areas and other areas where they might adversely affect product quality. 4.1.10 Personal hygiene procedures including requirement of using protective clothing shall apply to all persons entering production areas, whether they are temporary or full-time employees or non-employees on company property, e.g. contractor’s employees, visitors, senior management and inspectors. 4.2 Premises Premises used for manufacturing drug products shall be suitably constructed to facilitate good sanitation. 4.2.1 Adequate, well-maintained, and properly sited facilities shall be provided. 4.2.2 Suitable locker facilities shall be provided in appropriate locations. 4.2.3 The preparation, storage and consumption of food and beverages shall be restricted to cafeteria/lounge. These facilities shall meet sanitary standards. 4.2.4 Waste materials shall not be allowed to accumulate. It shall be collected in suitable receptacles for removal to collection points outside the buildings and should be disposed off properly in a safe sanitary manner at regular and adequate intervals. 4.2.5 Rodenticides, insecticides, fumigating agents and sanitizing materials used within the premises shall not be permitted to contaminate equipment, raw and packaging materials, in-process materials or finished products. 4.3 Equipment 4.3.1 Equipment shall be cleaned according to established procedures immediately after use and shall be kept or stored in a clean condition Page 20 of 92  and be checked for cleanliness prior to each use to ensure that all products or materials from the previous batch has been removed. 4.3.2 Vacuum or wets cleaning methods are to be preferred. Compressed air and brushes shall be used with care and avoided if possible, as they increase the risk of product contamination. 4.3.3 Cleaning and storing of mobile equipment and storing of cleaning materials shall be done in rooms separated from processing areas. 4.3.4 Written procedures in sufficient detail shall be established and followed for cleaning and sanitizing equipment, and containers used in the manufacture of drug products. These procedures shall be designed to prevent equipment contamination by cleaning or sanitizing agents and shall include responsibility for cleaning schedule, method, equipment and materials used in cleaning operations, the method of disassembling and reassembling equipment as appropriate to assure proper cleaning and sterilization, removal of previous batch identification, protection of clean equipment from contamination prior to use. 4.3.5 Records of cleaning, sanitizing, sterilization and inspection prior to use shall be maintained. 4.3.6 Weighing and measuring equipment shall be calibrated regularly for accuracy and precision. Section 5 STORAGE OF STARTING AND PACKAGING MATERIALS, INTERMEDIATES, BULK PRODUCTS AND FINISHED PRODUCTS 5.1 Materials shall be stored in an orderly manner to prevent any risk of mix-up or contamination and to facilitate inspection and maintenance. Materials shall be stored off the floor and sufficiently spaced. 5.2 The materials shall be stored under suitable environmental condition. Any special storage condition shall be provided and conditions monitored. 5.3 Outdoor storage is permissible for materials in secured containers (e.g. metal drums) and whose condition will not be adversely affected by exposure to temperature or other conditions. 5.4 Storage operations shall be adequately segregated from other operations. Storage operations shall be adequately segregated from other operations. 5.5 All deliveries to storage areas, including returns, shall be properly documented. Each batch of starting and packaging materials, intermediates, bulk products and finished products in storage areas shall have an inventory system. Inventory system shall be periodically reconciled and if there is any discrepancy found it shall be verified and justified when the quantity approved for use is different from the original receipt or delivery. This shall be documented with a written explanation. Page 21 of 92 5.6 Raw materials and packaging materials shall be returned to storage areas following clearly defined operating procedures. 5.7 All raw materials, packaging materials, intermediate and bulk products returned to storage areas shall be properly documented and reconciled. 5.7.1 All raw materials and packaging materials delivered shall be checked for proper identity, condition of container and approval of quality control unit. 5.7.2 Rejected raw materials and packaging materials shall not be stored together with approved materials. They are to be stored in the assigned location for rejects. 5.7.3 Printed packaging materials shall be stored in a restrictive storage area and dispensed under strict supervision. 5.7.4 The First Expiry First Out system (FEFO) on approved raw materials shall be used. 5.7.5 Raw materials shall be re-tested for identity, strength, quality and purity as necessary e.g. after storage periods, or after exposure to air, heat or other conditions that may adversely affect their quality. 5.7.6 There shall be a written procedure or system on re- evaluation of residual raw and packaging materials before use. 5.7.7 All incoming, outgoing and remaining materials shall be recorded. The record shall contain information on suppliers, batch or lot number, quantity and number of containers, control number, date of receipt or issuance, date of release and date of expiry if any. 5.7.8 Each batch of starting materials delivered shall have assigned reference number or control number that will identify the delivery or batch throughout storage and processing. This number shall appear on the labels of the containers and permit access to records where full details of the delivery or batch to be checked. Different batches within one delivery shall be regarded as separate batches for sampling, testing and release purposes. 5.7.9 Each starting material employed prior to release for use shall be in compliance with its material specification and be labeled with the name designated in the specification. Unauthorized abbreviations, codes or names shall not be used. 5.7.10 Each delivery shall be visually checked on receipt for general condition, integrity of container(s), spillage and possible deterioration, and be sampled by personnel and methods of sampling approved by the quality control manager. The sample shall be regarded as separate batches for sampling, testing and release purposes. 5.7.11 Steps shall be taken to provide assurance that all containers in a delivery contain the correct starting materials, and to safeguard Page 22 of 92  against mislabeling of the containers by the supplier. A listing of standard names of chemical materials shall be available for reference. 5.7.12 Deliveries of starting materials shall be held in quarantine until approved and released for use on the authority of the quality control manager or his/her designate. 5.7.13 Labels indicating status shall only be attached to starting materials by persons authorized by the quality control. Such labels shall be of a nature or form which prevents confusion with any similar labels previously used by the material supplier ( e.g. they shall bear the company name or logo). As the status of the material changes, the status-labels shall be changed accordingly. 5.7.14 Stocks of starting materials shall be inspected at intervals to ensure that the containers are properly closed and labeled, and in good condition. These shall be re-sampled and re-tested and shall be initiated by the application of retest labels and/or by similarly effective documentary systems. 5.7.15 Starting materials, particularly those that may deteriorate on exposure to heat shall be stored in a strictly controlled temperature room. 5.7.16 Only an authorized person using an approved procedure shall issue starting materials. Stock record shall be maintained so that stock reconciliation can be made or equivalent. 5.7.17 Segregated dispensing areas suitably equipped to avoid cross- contamination shall be provided. Specially equipped production areas may be solely designated for the dispensing of sensitizing or highly toxic materials such as hormones, cytotoxic agents and certain antibiotics. 5.7.18 All rejected starting materials shall be conspicuously identified, placed separately under lock and key and shall be destroyed or returned to the supplier as soon as possible. 5.8 Intermediate, Bulk and Finished Products 5.8.1 Intermediates, bulk products and finished products shall be held pending quality control testing and disposition. 5.8.2 Intermediates, bulk products and finished products shall be checked to verify that the material delivered agrees with the delivery documentation. 5.8.3 Each container of intermediates, bulk products and finished products delivered to the storage area shall be checked for proper identification and condition. 5.8.4 If the identity or condition of any container of intermediates, bulk products and finished products is suspected, or does not comply with the requirements of identity or condition, that container shall be retained in the quarantine for quality control inspection and disposition. Page 23 of 92 Section 6 PRODUCTION Production shall follow defined procedures capable to provide assurance of consistently yielding drug products that conform to their specifications. 6.1 Basic manufacturing requirements: 6.1.1 Equipment shall be technically suitable, well sited (so as not to interfere with other operations), easy to clean and maintain. The design, siting and operation of equipment shall ensure that no contamination from foreign materials such as rust, lubricants, abraded particles or foreign ingredients should occur. 6.1.2 A high standard of factory sanitation and personal hygiene is necessary to achieve the objectives of protecting each product from contamination by the environment or by the operations and protecting products from cross contamination with other products. Emphasis in this important areas shall be placed on written programs to ensure that the steps have been logically thought out and validated. 6.1.3 The manufacturer shall clearly define its system of information and control. The documentation system shall: provide unambiguous sections to be followed, provide confirmation of performance, allow calculation to be checked and to allow the accountability and traceability of operators, materials and batch disposition. 6.1.4 Manufacturing facilities and methods shall be designed to prevent cross-contamination. 6.1.5 There shall be sufficient space provided to minimize clutter and untidy work practices to assure orderly material receivals, warehousing and processing activities. The layout of rooms, corridors and areas, shall provide for logical movement of materials and personnel with minimal traffic and for operations to be carried out in defined areas. 6.2 Process Validation A company should only use validated manufacturing processes. All established processes, materials or products, procedures, activities, systems, equipment or mechanism used in manufacture or control procedures may be validated utilizing a retrospective approach. 6.2.1 All production procedures shall be properly validated, validation shall be conducted in accordance with previously defined procedures and a record of the results shall be maintained. The extent and degree of validation depend on the nature and the complexity of the product and process. 6.2.2 The validation program and documentation shall provide evidence of the suitability of materials, the performance and reliability of equipment and systems and the competency of personnel. 6.2.3 When any master processing procedure is adopted, steps shall be taken to demonstrate that it is suitable for routine operation and that Page 24 of 92  the defined process, using materials and equipment specified, will consistently yield a product of the required quality. 6.2.4 Significant changes in process, equipment or materials shall be accompanied by further validation steps to ensure that the changes continue to yield consistently a product of the required quality. 6.2.5 To ensure that processes and procedures remain capable of achieving the intended results, these shall routinely undergo critical appraisal. 6.3 Contamination The presence in a drug product of any contaminant is unacceptable. The air, water, personnel and all surfaces that come in contact with the product during the manufacturing process are all potential sources of contamination. Regular monitoring of the manufacturing environments shall be instituted to assure that the risk of contamination is detected early and corrective actions are undertaken. 6.4 Batch and Lot Numbering System There shall be a system describing the details of the batch and/or lot numbering set up to ensure that each batch or lot of intermediate, bulk or finished product is identified with a specific batch or lot number. 6.4.1 A batch and/or lot numbering system applied to a processing state and to the respective packaging stage shall be related to each other. 6.4.2 The batch and/or lot numbering system shall be defined to assure that the same batch or lot numbers will not be repeatedly used. 6.4.3 Batch or lot numbers allocation shall be immediately recorded in a logbook or any other means of recording. The record shall include date of allocation, product identity and size of batch or lot. 6.5 Weighing and Dispensing Only approved materials shall be permitted into the dispensary area. The dispensary area is an area that permits a transition from “dirt” bulk storage containers to clean containers for the dispensed materials intended for manufacture. This stage is also the time when pallets constructed of plastic or some other cleanable and impervious materials are used for storage of dispensed materials and transport of bulk dispensed materials throughout the manufacturing areas. The dispensary is an example of a “gray” area that is a transition area from a black area (the warehouse) to a white area (the processing area/s) where the cleanliness level or the reduction of transfer of contaminants is achieved by a simple operation. Another example is operator change and wash procedures. 6.5.1 The methods for handling, weighing, counting and dispensing raw materials, packaging materials, intermediate products, and bulk products shall be included in written procedures. Page 25 of 92 6.5.2 All issuance of raw materials, packaging materials, intermediate products, and bulk products including those for additional materials for production orders already dispensed shall be properly documented. 6.5.3 Only raw materials, packaging materials, intermediate products and bulk products which are approved by quality control can be dispensed. 6.5.4 To avoid mix-up, cross-contamination, loss of identity and confusion, only the relevant raw materials, intermediate products and bulk products shall be within the dispensing areas. After weighing, dispensing and labeling, the raw materials, intermediate products and bulk products shall be transported and stored in a manner that will preserve its integrity until further processing. 6.5.5 Prior to weighing and dispensing, each container of raw materials shall be checked for proper labeling, including the approval from quality control. 6.5.6 Capacity of weighing and measuring equipment used shall be appropriate to the amount of materials to be weighed or measured. 6.5.7 For any weighing or measuring operation, two persons shall independently verify the correctness of the identity and amount of weighed or measured materials. 6.5.8 Weighing and dispensing areas shall be maintained in a clean condition. 6.5.9 Weighing and dispensing operations shall be carried out with clean equipment. 6.5.10 Dispensed raw materials, intermediate and bulk products shall be rechecked for identity and accuracy and signed by the production supervisor or equivalent prior to delivery to the production area. Processing 6.5.11 All materials utilized in processing shall be checked for its identity and weight against the batch record before use. The environment of an area shall be monitored and controlled to the degree required for the operation to be performed. Before any processing operation begin steps shall be taken to ensure that the work area and equipment are free from any material product or document not required for the current operation 6.5.12 All equipment employed in processing shall be checked before use. Equipment should be certified in writing as clean before use. 6.5.13 All operation shall be performed in accordance with the written procedures. Any deviation shall be justified and reported. 6.5.14 Containers and closures used for materials awaiting processing, for intermediate products and for bulk products shall be clean and of a Page 26 of 92  nature and type which prevent contamination or deterioration of the product or materials. 6.5.15 All containers and equipment holding intermediate products shall be properly labeled as to identify the material and stage of processing. Before applying the labels, all inappropriate labels or marks previously applied shall be completely removed or crossed out. 6.5.16 All intermediate and bulk products shall be properly labeled and quarantined until approved and released by quality control. 6.5.17 All in-process intermediate and bulk controls shall be accurately recorded at the time of performance. All step-wise activities in the processing operation indicated in the batch processing record shall be signed and dated at the time of completion of the activity. 6.5.18 The actual yield of each processing step of a production batch shall be recorded and checked against the theoretical yield. 6.5.19 In all stages of processing, particular attention shall be given to the possibility of cross-contamination. 6.6 Dry Materials and Products 6.6.1 To overcome problem of dust control and cross-contamination created in handling of dry materials and products, special attention is needed in the design, maintenance and use of premises and equipment. Enclosed dust collecting systems or other suitable methods shall be employed. 6.6.2 Effective dust extraction systems shall be installed with discharge points situated to avoid contamination of other products or processes. Effective filtration or other appropriate systems shall be installed to retain dust. 6.6.3 To protect the product against contamination with fragments of metal, glass or wood, special care shall be taken. Use of glass equipment is to be avoided. Screens, punches, sieves and dies shall be checked for wear or breakage before and after each use. 6.6.4 Care shall be taken to guard against tablets or capsule that may lodge and remain undetected in equipment, counters or bulk containers. 6.7 Mixing and Granulation 6.7.1 Mixing, sifting and blending equipment shall be fitted with a dust control system. 6.7.2 Critical operating parameters (e.g. time, speed and temperature) for each mixing, blending and drying operation shall be laid down in the master production document, monitored during processing and recorded in the batch records. Page 27 of 92  6.7.3 Filter bags fitted to fluid bed dryers shall be specific to one product use. 6.7.4 Solutions or suspensions shall be freshly prepared and consumed to minimize the risk of contamination or microbial growth. 6.8 Compression 6.8.1 Tablet compressing machines shall be provided with effective dust control facilities. 6.8.2 There shall be a suitable physical, procedural and labeling control to prevent mix-up for all in-process tablets. 6.8.3 Accurate weighing equipment shall be used for in-process monitoring of tablet weights. 6.8.4 Tablets removed from a compressing cubicle or station for testing or other purposes shall not be returned to the batch. 6.8.5 Rejected or discarded tablets shall be placed in containers properly identified and the quantity shall be recorded in the batch processing record. 6.8.6 Punches and dies shall be examined before each use for wear and tear. A record of their use shall be maintained. 6.9 Coating 6.9.1 Air supplied to coating pans for drying purposes shall be filtered and of suitable quality. 6.9.2 Coating solutions shall be prepared in a separate cubicle within the coating room and used immediately to prevent microbial growth. Their preparation and use shall be documented. 6.10 Hard Capsule filling 6.10.1 Empty capsule shells should be regarded as starting materials. They should be stored under appropriate conditions to prevent drying and brittleness or other effects of moisture. 6.11 Liquids, Creams and Ointments 6.11.1 Liquids, creams and ointments shall use closed system of production and transfer to protect the product from contamination. 6.11.2 Tanks, containers, pipework and pumps shall be designed and installed so that they may be readily cleaned and sanitized. In particular, equipment design should include a minimum of dead-legs or sites where residues can accumulate and promote microbial proliferation. Page 28 of 92  6.11.3 High quality stainless steel is the material of choice for parts coming into contact with product. 6.11.4 The chemical and microbiological quality of the water used shall be specified, monitored and documented. Water shall be of potable quality and have an acceptable microbial count before use. 6.11.5 Where pipelines are used for delivery of ingredients or supply of bulk products, care should be taken to ensure that such systems are easy to clean. Pipework shall be designed and installed so that it may be readily dismantled and cleaned. 6.11.6 Measuring systems shall be verified as accurate. Where dipsticks are used, they shall be used only with the particular vessel for which they have been calibrated. They shall be made of suitable non-reactive, non-absorptive material (e.g. stainless steel). 6.11.7 Care shall be taken to maintain the homogeneity of mixtures, suspensions, etc. during filling. Mixing and filling processes should be validated. Special care shall be taken at the beginning of a filling process, after stoppages and at the end of the process to ensure that homogeneity is maintained. 6.11.8 When the finished product is not immediately packaged, the maximum period of storage and the storage conditions shall be specified and adhered to. Section 7 PACKAGING The function of the packaging operation is to subdivide and control bulk product. These operations shall be performed under strict control designed to protect the identity, integrity and quality of the final package. 7.1 All packaging operations shall proceed in accordance with a SOP. Details of the operation shall be recorded on the batch packaging record. 7.2 Before a packaging operation begin, checks shall be carried out to ensure that the work area and equipment are clean and free from any products, product residues or documents not required for the operation. 7.3 Finished bulk product and packaging component shall be checked and verified for their correctness against the master packaging procedure or a specific packaging order. 7.4 Coding of Components 7.4.1 Labels, cartons and other components that require pre-coding with a batch number or lot number, expiration date, or other information specific to a given packaging order shall be strictly controlled at all stages of the process, from the time of delivery from the warehouse until they become parts of finished packages. Page 29 of 92  7.4.2 Components for coding shall be stored in sealed containers within an appropriate area for proper security and segregation. 7.11.1 Coding of components shall take place in an area isolated from other packaging operations. To avoid mix-up, only one particular printed packaging material is permitted in a single coding station at a time. Adequate segregation shall be maintained between coding stations. 7.4.3 All coded materials shall be checked before transfer to packaging. 7.4.4 Special emphasis shall be given to the control of pre-printed packaging materials particularly product labels. It is important that there be rigorous control from the draft text through artwork approval, printing, receipt and quality control, storage, verification, issue, application to the product unit and disposal or return of surplus. Pre- printed packaging materials shall be identified by a component code number as part of the component printed text. These code numbers shall be unique to each amendment of text. In addition to the code numbers, there shall be a system of bar codes that is also part of the printed text and is unique for each amendment. 7.4.5 All approved pre-printed packaging materials (including “approved” status labels) shall be stored separately in a locked area. Access to this area shall be restricted to authorized persons. 7.4.6 Pre-printed materials shall not be over-printed with a different name, dosage form or strength of the product. Labels shall be counted on receipt or at the time of issuance or on line. Where batch numbers and expiry date are added to labels off-line, this operation shall be done in a segregated, lockable area which maybe a label store. The coding process shall be documented and preceded with an area clearance check that follows the standard operating procedure. A known number of each label or pre-printed packaging material shall be issued in sealed containers for each packaging run. 7.5 Line Clearance 7.5.1 Immediately prior to the placement of materials on the packaging line, a line clearance check shall be made by a designated responsible packaging person in accordance with a written line clearance procedure to: 7.5.1.1 verify that all materials and packaged products from the previous packaging operation have been removed from the packaging line and line area 7.5.1.2 check the line and immediate area for general cleanliness and 7.5.1.3 verify that the equipment has been properly cleaned. 7.5.2 The person responsible for the line check shall initial and date the batch packaging documentation indicating completion of that check Page 30 of 92  7.5.3 All packaging and labeling materials shall be carefully checked for identity and conformity to the description in the batch documentation 7.5.4 A check shall be made of the batch number and expiry imprinted on pre-printed packaging materials at start up and regular intervals through the packaging run. The expiry date for a product should be calculated from the date of the final processing stage of the product before packaging 7.5.5 Upon completion of the packaging run unused, un-coded labels and pre-printed packaging materials shall be counted and held for destruction or be returned to the store. Damaged or defaced pre- printed packaging materials shall be counted or closely estimated. 7.5.6 A reconciliation shall be made between the issued quantities of pre- printed packaging materials and the respective numbers accounted for on product units, as samples on bulk shipper cartons and also the number destroyed or defaced. 7.6 In-Process Control 7.6.1 Written in-process control procedures shall be followed. These procedures shall describe the point of sampling, frequency of sampling, number of samples to be taken, specifications to be checked, and the limits of acceptability for each specification. 7.6.2 In addition, in-process control shall include, but not limited to, the following general procedures : 7.6.2.1 the product fill or count shall be checked at the start of a packaging run and 7.6.2.2 finished packages shall be checked throughout the run at regular intervals to assure that these fully comply with the specifications and that all components are those specified in the master packaging procedure. 7.6.3 Results of in-process tests/inspection shall be recorded, and these documents shall become a part of the batch packaging record. 7.7 Operating Practices 7.7.1 Risk of packaging errors can be minimized by the following means : 7.7.1.1 the use of roll-feed labels 7.7.1.2 on-line batch coding 7.7.1.3 use of electronic code readers and labels counters 7.7.1.4 labels and other printed materials designed with distinct marks for different products and Page 31 of 92  7.7.1.5 in addition to visual checks during the packaging run, independent quality control checks during and at the end of the run should be performed. 7.7.2 Products of similar appearance shall not be packaged in close proximity unless there is physical segregation. 7.7.3 At each packaging line the name and batch of the product being packaged shall be displayed. 7.7.4 Containers in which bulk product, partly packed product, or sub-batch is stored shall be labeled or marked with an indication of product identity, quantity, batch and status. 7.7.5 Containers to be filled shall be supplied to the packaging line or station in a clean condition. 7.7.6 All packaging personnel shall be trained to recognize in process control requirements and report any deviation they may detect while performing their specific responsibilities. 7.7.7 Packaging areas shall be cleaned at frequent intervals throughout the workday and at any time a spill of material occurs. Personnel engaged in cleaning shall be trained to avoid practices that could cause mix-up or cross-contamination. 7.7.8 Any printed packaging material found during clean up operation shall be turned over to a supervisor, and be placed in a designated container for reconciliation and destroyed at the end of a packaging run. 7.7.9 Products filled into their final containers while waiting for labeling shall be segregated and marked so as to avoid mix-up. This practice should be avoided and only be instituted in exceptional circumstances. 7.7.10 Packaging equipment whose parts do not normally come in contact with the bulk product but in which dust, debris, packaging components or product might collect and later fall into the product or otherwise become a contaminant or source of mix-up, shall be appropriately cleaned. 7.7.11 Measures shall be taken to control the spread of dust during packaging especially of dry products. Segregated packaging areas are necessary for some products e.g. potent low dose or toxic products and sensitizing agents. Compressed air shall never be used to clean equipment within an operation packaging area where there is danger of cross-contamination. 7.7.12 Brushes shall be restricted in use because of the contamination hazard of hairs or bristles and/or particles held in the brushes. 7.7.13 Personnel shall place packaging components or products in appropriate properly identified containers. Page 32 of 92  7.7.14 Essential supplies, such as lubricants, adhesive, inks, cleaning fluids, etc. shall be kept in containers that look completely different from any container that is used for product packaging and shall be clearly labeled as to their contents. 7.8 Completion of the Packaging Operation 7.8.1 On the completion of the packaging operation, the last production package shall be carefully checked to confirm that it fully agrees with the master packaging procedure. 7.8.2 Only finished goods from a single packaging operation shall be placed on a pallet. Any partial carton and the quantity contained shall be indicated on the carton. The removal of excess packaging components and bulk product, after reconciliation, shall be closely supervised to ensure that only the packaging components and bulk product permitted to be returned to the warehouse are saved and that these are properly identified. 7.8.3 A responsible person shall oversee the counting and destruction of non-returnable packaging components and bulk product. All unused coded materials shall be reconciled and destroyed. Quantities destroyed shall be recorded on the batch packaging record. 7.8.4 A responsible person shall calculate and record the net used for all packaging components and bulk product. 7.8.5 Any unexplained yield discrepancies or failure to comply with the specifications shall be thoroughly investigated, with consideration extended to other batches or other products which might also be affected. 7.8.6 After acceptable reconciliation, the finished product shall be delivered to the quarantine finished product area pending final release by the quality control department. Section 8 FINISHED PRODUCT QUARANTINE AND DELIVERY TO WAREHOUSE Finished product quarantine is the last point of control before the product enters the warehouse and becomes available for distribution to the market. Strict controls shall be exercised to ensure that the product and its packaging records meet all specified requirements before release to the warehouse. Written procedures shall describe the transfer of finished product into the quarantined area, storage while waiting approval, requirements that shall be met for approval and subsequent transfer to the finished goods warehouse. Pending release by the quality control unit, the entire packaged batch or lot shall be held in the finished goods quarantine. No material except samples for the quality control unit shall be dispensed from any product lot or batch while it is being held in the finished goods quarantine area. Page 33 of 92  Physical access to the products under quarantine shall be restricted, and only those persons actually required working in the area or who have been properly authorized to enter the area should be allowed access. Any finished product that requires special storage conditions shall be appropriately labeled to show the required storage conditions, and the material shall be stored in quarantine under the specified conditions. Final quality control release of the product shall be preceded by the satisfactory completion of the following events : 8.6.1 finished products meet quality control requirements for all processing and packaging specifications 8.6.2 retention by quality control of sufficient finished market containers as retained samples for future testing; packaging and labeling meet all require- ments as checked by quality control 8.6.3 the reconciliation of printed packaging components is acceptable and 8.6.4 marketed packages received in the finished goods quarantine area are reconciled with the amount shown on the transfer documents. 8.7 After the quality control unit has approved a batch or a lot, the material shall be removed from the finished goods quarantine area to the finished goods storage. If required by BFAD, antibiotic products should not be released without BFAD certification. 8.8 Upon receipt of the finished goods, the warehouse unit shall make entry in the corresponding inventory card or other system for the batch received. 8.9 Control record for shipment of finished products 8.9.1 A system designed to control the shipment of finished products shall assure that the first expiry material is distributed first. 8.9.2 The system shall generate records from which the distribution of each batch or lot of drug product can be readily determined to facilitate investigation or recall if necessary. 8.9.3 Written procedures describing the distribution of products (drug, devices and other products) shall be established and followed. Section 9 QUALITY CONTROL Quality Control is an essential part of Good Manufacturing Practices to provide assurance that the products will be consistently of a quality appropriate to their intended use. The involvement and commitment of all concerned at all stages are mandatory towards the achievement of this quality objective from the start of manufacturing to the distribution of the finished product. An independent quality control unit shall be established. Page 34 of 92 9.1 General Provisions 9.1.1 A quality control system shall be developed and designed so as to ensure that finished products contain the correct materials of specified quality and quantity and are manufactured under proper conditions following standard procedures, thereby they will consistently meet the established specifications for identity, strength, purity, quality and safety. 9.1.2 Quality control involves all analytical functions conducted in the laboratory, including sampling, inspecting and testing of starting materials, intermediate, bulk and finished products. It also includes stability test, environmental monitoring program, validation tests, review of batch documentation, sample retention program and establishing and maintaining current specification of materials, products and their test methods. 9.1.3 Documentation and release procedures applied by the quality control unit shall ensure that the necessary tests are carried out, and that the materials are not released for use, nor products released for distribution and sale until their quality has been determined to meet specifications. 9.1.4 The quality control unit shall have the following principal duties: 9.1.4.1 to establish and revise control procedures and specification 9.1.4.2 to prepare detailed written instructions for carrying out each inspection, test and analysis 9.1.4.3 to establish written sampling plans and sampling procedures 9.1.4.4 to maintain retained sample for future reference 9.1.4.5 to release or reject each batch of starting material, intermediate, bulk or finished product 9.1.4.6 to review all documentation relating to the batch processing, packaging and testing of each batch of finished product before authorizing release for distribution 9.1.4.7 to evaluate the stability of all finished products on an on-going basis and raw materials where necessary, and to establish instructions for the storage of materials and products within the manufacturing plant on the basis of their stability data 9.1.4.8 to establish expiration dates and shelf-life of raw materials and finished products based on their stability data and storage condition Page 35 of 92  9.1.4.9 to evaluate and approve any reprocessing procedure for products 9.1.4.10 to accredit those approved suppliers of raw and packaging materials capable of and reliable for supplying starting materials that meet the company’s established quality specifications 9.1.4.11 to take part or assist in validation program 9.1.4.12 to evaluate all complaints received or deficiencies noted about any batch, if necessary in co-operation with other units of the company, and to take appropriate corrective action 9.1.4.13 to prepare secondary reference standards as specified in the current procedure for testing and to store these standards under proper conditions 9.1.4.14 to maintain analytical records of the tests of all samples taken 9.1.4.15 to evaluate returned drug products and determine whether such products could be released or reprocessed or shall be destroyed 9.1.4.16 to participate in the self-inspection program with other units of the company and 9.1.4.17 to recommend toll manufacturing operations after evaluating the toll manufacturer’s capability to produce products that meet the company’s specified quality standards. 9.2 Control Laboratory 9.2.1 Premises 9.2.1.1 Control laboratories shall be designed, equipped and of sufficient space to suit relevant operations. 9.2.1.2 Provisions shall be made for the proper and safe storage of waste materials awaiting disposal. Toxic substance and inflammable materials shall be stored in suitably designed and storage. 9.2.1.3 The laboratories shall be physically separated from the production rooms. Biological, microbiological and chemical laboratories shall be segregated from each other. Air handling facilities for biologicals and microbiologicals should be separate from process air handling facilities. Page 36 of 92  9.2.1.4 A separate room shall be provided for instruments to protect these against electrical interference, vibration, contact with excessive moisture and other external factors or where there is need to isolate the instrument. 9.2.1.5 The design of the laboratory shall take into account the suitability of construction materials, fume prevention and ventilation. Separate air handling units shall be installed for biological, microbiological and radioisotope laboratories. 9.2.1.6 All service pipings/pipelines and devices shall be adequately marked and special attention paid to the provision of non-interchangeable connections or adaptors for dangerous gases and liquids. 9.2.1.7 A safety shower and eye-bath shall be provided in close proximity to the laboratory working area. 9.2.2 Personnel 9.2.2.1 Each individual engaged in the supervision or conduct of a laboratory operation shall have proper education, training and experience or combination thereof, to enable the individual to perform the assigned functions. Their duties and responsibilities shall be clearly defined in job descriptions or by other suitable means. 9.2.2.2 Personnel shall wear protective clothing and safety equipment such as respirators or face masks, safety glasses and acid or alkali resistant gloves appropriate to the duties being performed. 9.2.3 Equipment 9.2.3.1 Control laboratory equipment and instruments shall be