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1 ISSN: X CODEN: IJPTFI Available through Online Review Article A REVIEW ON GOOD MANUFACTURING PRACTICE FOR PHARMACEUTICAL INDUSTRY Sowjanya Mallampalli*, M.Muthukumaran*, B.Krishnamoorthy, Amreen Nishat. Montessori Siva Sivani Institute of Science & Technology College of Pharmacy, Mylavaram, Vijayawada, Andhrapradesh sowjanyabujji7000@gmail.com Received on Accepted on Abstract: Good Manufacturing Practice (GMP) is a set of regulations, codes, and guidelines for the manufacture of drug substances and drug products, medical devices, in vivo and in vitro diagnostic products, and foods. GMP term that is recognized worldwide for the control and management of manufacturing and quality control testing of pharmaceutical products. Most requirements were put in place as responses to tragic circumstances and to prevent future tragedies. The concept of a total quality control system is not limited in scope in the terms of analytical methods of assay, to provide specific guidelines and concepts, which can serve as checks for critical operations within the entire organization so that a total quality system may be achieved. Each requirement loosely generalized in GMP, regulations is enlarged upon and made more specific to include measures, which the authors believe necessary for good control. Keywords: Good Manufacturing Practice, manufacturing and quality control, future tragedies. Introduction What is GMP? GMP requires that the manufacturing process is fully defined before it is initiated and that all necessary facilities are provided. In practice, this means that personnel must be adequately trained, suitable premises and equipment used, correct materials used, approved procedures. Why it is required? Raw materials used in the manufacture of pharmaceuticals are authentic, of prescribed quality and are free from contamination. The manufacturing process is as has been prescribed to maintain the standards. IJPT Jan-2013 Vol. 4 Issue No Page 2363

2 World Health Organization (WHO) GMP GMP covers all aspects of the manufacturing process: defined manufacturing processes; critical manufacturing steps; suitable premises, storage, transport; qualified and trained production and quality control personnel; adequate laboratory facilities; approved written procedures and instructions; records to show all steps of defined procedures have been taken. [1] GMP REQUIREMENTS FOR PREMISES AND MATERIALS FOR PHARMACEUTICAL PRODUCTS 1. GENERAL REQUIREMENTS 1.1. Location and surroundings The factory building(s) for manufacture of drugs shall be so situated and shall have such measures as to avoid risk of contamination from external environment including open sewage, drain, and public lavatory Buildings and premises The building(s) used for the factory shall be designed, constructed, adapted and maintained to suit the manufacturing operations so as to permit production of drugs under hygienic conditions. They shall conform to the conditions laid down in the Factories Act, 1948 (63 of 1948). 1.3 Water system There shall be validated system for treatment of water drawn from own or any other source to render it potable in accordance with standards specified by the Bureau of Indian Standards. 1.4 Disposal of waste The disposal of sewage and effluents (solid, liquid and gas) from the manufactory shall be in conformity with the requirements of Environment Pollution Control Board. All bio-medical waste shall be destroyed as per the provisions of the Bio-Medical Waste. 2. WAREHOUSING AREA Receiving and dispatch bays shall protect materials and products from adverse weather conditions. Printed packaging materials shall be stored in safe, separate and secure areas. IJPT Jan-2013 Vol. 4 Issue No Page 2364

3 3. PRODUCTION AREA The production area shall be designed to allow the production preferably in uni-flow and with logical sequence of operations. Working and in-process space shall be adequate to permit orderly and logical positioning of equipment and materials and movement of personnel to avoid cross-contamination. 4. QUALITY CONTROL AREA Quality Control Laboratories shall be independent of the production areas. Separate areas shall be provided each for physico-chemical, biological, microbiological or radio-isotope analysis. 5. HEALTH, CLOTHING AND SANITATION OF WORKERS All employees shall be instructed to report about their illness or abnormal health condition to their immediate supervisor so that appropriate action can be taken. 6. SANITATION IN THE MANUFACTURING PREMISES The manufacturing areas shall not be used for storage of materials, except for the material being processed. It shall not be used as a general thoroughfare. 7. RAW MATERIALS The licensee shall keep an inventory of all raw-materials to be used at any stage of manufacture of drugs and maintain records as per Schedule U. Smoking, eating, drinking, chewing or keeping plants, food, drink and personal medicines shall not be permitted in production, laboratory, storage and other areas where they might adversely influence the product quality. 8. EQUIPMENT The parts of the production equipment that come into contact with the product shall not be reactive, additive or adsorptive to an extent that would affect the quality of the product. To avoid accidental contamination, wherever possible, non-toxic/edible grade lubricants shall be used. 9. DOCUMENTATION AND RECORDS Its aim is to define the specifications for all materials, method of manufacture and control, to ensure that all personnel concerned with manufacture know the information necessary to decide whether or not to release a batch of a drug for sale and to provide an audit trail that shall permit investigation of the history of any suspected defective batch. IJPT Jan-2013 Vol. 4 Issue No Page 2365

4 10. QUALITY CONTROL SYSTEM Quality control shall be concerned with sampling, specifications, testing, documentation, release procedures which ensure that the necessary and relevant tests are actually carried and that the materials are not released for use, nor products released for sale or supply until their quality has to be satisfactory. Every manufacturing establishment shall establish its own quality control laboratory managed by qualified and experienced staff. 11. VALIDATION AND PROCESS VALIDATION Validation studies shall be an essential part of Good Manufacturing Practices and shall be conducted as per the predefined protocols. These shall include validation of processing, testing and cleaning procedures. 12. COMPLAINTS AND ADVERSE REACTIONS Reports of serious adverse drug reactions resulting from the use of a drug along with comments and documents shall be forthwith reported to the concerned Licensing Authority. [2] 13. SELF INSPECTION AND QUALITY AUDITS [3-12] The purpose of self-inspection is to evaluate the manufacturer s compliance with GMP in all aspects of production and quality control. ITEMS FOR SELF-INSPECTION: (a) Personal, (b) Storage. GMP IN THE MANUFACTURING OF PHARMACEUTICALS 1. STERILE DOSAGE FORMS (PARENTERAL & OPHTHALMIC) 1. Buildings And Civil Works The building shall be built on proper foundation with standardized materials to avoid cracks in critical areas like aseptic solution preparation, filling and sealing rooms. 2. Air Handling System (Central Air-Conditioning) The filter configuration in the air handling system shall be suitably designed to achieve the Grade of air as given in Table No 1. Typical operational activities for clean areas are highlighted in Table No 2 and Table No 3. IJPT Jan-2013 Vol. 4 Issue No Page 2366

5 Table-1: Air Borne Particulate Classification for Manufacture of Sterile Products. Grade At rest In Operation Maximum number of permitted particles per cubic meter equal to or above 0. 5 m 5 mini 0. 5 m 5 m A B 35, ,52,000 2,930 C 3,52,000 2,930 35,20,000 29,300 D 35,20,000 29,300 Not defined Not defined Table-2: Types of Operations to Be Carried Out In the Various Grades for Aseptic Preparations. Grade A Types of operations for aseptic preparations. Aseptic preparation and filling. B Background room conditions for activities requiring Grade A. C D Preparation of solution to be filtered. Handling of components after washing. Table-3: Types of Operations to Be Carried Out In the Various Grades for Terminally Sterilized Products. Grade Types of operations for terminally sterilized products. A Filling of products, which are usually at risk. B Placement of filling and sealing machines, preparation of solutions, when usually at risk. Filling of product when unusually at risk. IJPT Jan-2013 Vol. 4 Issue No Page 2367

6 C Maudling, blowing (pre-forming) operations of plastic containers, Preparations of solutions and components for subsequent filling. 4. Garments The garments shall be made of non-shedding and tight weave material. Cotton garments shall not be used. 5. Equipment The special equipment required for manufacturing sterile products includes component washing machines, steam sterilizers, dry heat sterilizers, membrane filter assemblies, manufacturing vessels, blenders, liquid filling machines, powder filling machines, sealing and labeling machines, vacuum testing chambers, inspection machines. 6. Water and Steam Systems Potable water meeting microbiological specification of not more than 500 cfu/ml and indicating absence of individual pathogenic micro-organisms. Escherichia coli, Salmonella, Staphylococcus aureus and Pseudomonas aeruginosa per 100 ml sample shall be used for the preparation of purified water. 7. Manufacturing Process Manufacture of sterile products shall be carried out only in areas under defined conditions. Each lot of finished product shall be filled in one continuous operation. In each case, where one batch is filled in using more than one operation, each lot shall be tested separately for sterility and held. 8. Sterilization (Autoclaving) Periodic bio-burden monitoring of products before terminal sterilization shall be carried out and controlled to limits specified for the product in the Master Formula. [13] 2. ORAL SOLID DOSAGE FORMS (TABLETS & CAPSULES) GENERAL The processing of dry materials and products creates problems of dust control and cross-contamination. Special attention is, therefore, needed in the design, maintenance and use of premises and equipment in order to overcome these problems. IJPT Jan-2013 Vol. 4 Issue No Page 2368

7 Sifting, mixing and granulation Unless operated as a closed system, mixing, sifting and blending equipments shall be fitted with dust extractors. Compression (Tablets) Each tablet compressing machine shall be provided with effective dust control facilities to avoid cross contamination. Unless the same product is being made on each machine, or unless the compression machine itself provides its own enclosed air controlled environment, the machine shall be installed in separate cubicles. Coating (Tablets) Air supplied to coating pans for drying purposes shall be filtered air and of suitable quality. The area shall be provided with suitable exhaust system and environmental control (temperature, humidity) measures, which shall minimize the risk of microbial growth. Their preparation and use shall be documented and recorded. Filling of Hard Gelatin Capsule Empty capsules shells shall be regarded as 'drug component' and treated accordingly. (a) Printing (Tablets and Capsules) Special care shall be taken to avoid product mix-up during any printing of tablets and capsules. Where different products, or different batches of the same product, are printed simultaneously, the operations shall adequately be segregated. (b) Packaging (Strip and Blister) Care shall be taken when using automatic tablet and capsule counting, strip and blister packaging equipment to ensure that all 'rogue' tablets, capsules or foils from packaging operation are removed before a new packaging operation is commenced. [14] 3. ORAL LIQUIDS (SYRUPS, ELIXIRS, EMULSIONS AND SUSPENSIONS) (a).building And Equipment The premises and equipment shall be designed, constructed and maintained to suit the manufacturing of Oral Liquids. The layout and design of the manufacturing area shall strive to minimize the risk of cross- contamination and mix-ups. It shall be made fly proof by use of ' fly catcher' and / or 'air curtain'. IJPT Jan-2013 Vol. 4 Issue No Page 2369

8 (b).purified Water The chemical and microbiological quality of purified water used shall be specified and monitored routinely. The microbiological evaluation shall include testing for absence of pathogens and shall not exceed 100 cfu/ml. (c).manufacturing Manufacturing personnel shall wear non-fiber shedding clothing to prevent contamination of the product. [15] 4. EXTERNAL PREPARATIONS (CREAMS, OINTMENTS, PASTES, EMULSIONS, LOTIONS, SOLUTIONS, DUSTING POWDERS AND IDENTICAL PRODUCTS) (a).the entrance to the area where topical products are manufactured shall be through a suitable airlock. Outside the airlock, insectocutors shall be installed. (b).a separate packing section may be provided for primary packaging of the products. [16] 5. METERED DOSE INHALERS (MDI) a. General Manufacture of Metered-Dose-Inhalers shall be done under conditions which shall ensure minimum microbial and particulate contamination. Assurance of the quality of components and the bulk product is very important. b. Building and civil works The building shall be located on a solid foundation to reduce risk of cracking walls and floor due to the movement of equipment and machinery. c. Environmental Conditions Where products or clean components are exposed, the area shall be supplied with filtered air of Grade C. d. Manufacture There shall be approved master formula records for the manufacture of metered dose inhalers. The humidity of the compressed air shall be controlled as applicable. [17] Quality systems requirements for national GMP inspectorates 1. Introduction 2. Documentation 3. Records IJPT Jan-2013 Vol. 4 Issue No Page 2370

9 4. Quality Manual 1. Introduction These requirements are applicable to quality systems for the operation of inspection services within competent authorities concerned with GMP inspection 2. Documentation The current versions of the appropriate documentation are available at all relevant locations 3. Records It must comply with the relevant obligations under national legislation and demonstrate that the quality system is operating satisfactorily. 4. Quality Manual The information contained in the quality manual and procedures should include: (a) Quality policy statement (b) Details of testing of samples (c) The control of non-conforming products. [18] Scope In this Guide manufacturing is defined to include all operations of receipt of materials, Production, packaging, repackaging, labeling, relabeling, quality control, release, storage and Distribution of APIs and the related controls. For the purposes of this Guide, the terms current good manufacturing practices and good manufacturing practices are equivalent. Conclusion The quality and purity of the pharmaceutical product depends on the Condition maintained during the manufacturing process. The Good Manufacturing Process (GMP) concept strictly adheres to stringent specifications followed during the manufacturing process. This assures the quality of the final product. References 1. The Good Manufacturing Practices for pharmaceutical products 2. GMP requirements for premises and materials for pharmaceutical products IJPT Jan-2013 Vol. 4 Issue No Page 2371

10 3. Quality assurance of pharmaceuticals volume2, second updated edition Provisional guidelines on the inspection of pharmaceutical manufacturers. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992 (WHO Technical Report Series, No. 823), Annex Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Volume2. Good manufacturing practices and inspection. Geneva, World Health Organization, Recommendations on quality system requirements for GMP inspectorates of PIC Contracting States. Geneva, Pharmaceutical Inspection Convention, 1994 (unpublished Document PH 7/94; this document forms the basis of the publication Recommendations on quality system requirements for pharmaceutical inspectorates. Geneva, Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operation Scheme (PIC/S, 2000 (PI 002-1); available from PIC/S Secretariat, PO Box 5695, 1211 Geneva 11, Switzerland). 6. Quality management and quality assurance standards guidelines for selection and use. International Standard ISO Geneva, International Organization for Standardization, Quality systems-model for quality assurance in design/development, production, Installation and servicing. International Standard ISO Geneva, International Organization for Standardization, Quality systems-model for quality assurance in production, installation and servicing. International Standard ISO Geneva, International Organization for Standardization, Quality systems-model for quality assurance in final inspection and test. International Standard ISO Geneva, International Organization for Standardization, Quality management and quality system elements-guidelines. International Standard ISO Geneva, International Organization for Standardization, General criteria for certification bodies operating quality systems certification. European Standard EN Brussels, European Committee for Standardization, 1989(available from CEN Central Secretariat, 36 rue de Sassier, B-1050 Brussels, Belgium). 12. Good manufacturing practices: authorized person-role, functions and training. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fifth report. Geneva, World Health Organization, 1999 (WHO Technical Report Series, No. 885), Annex 4. IJPT Jan-2013 Vol. 4 Issue No Page 2372

11 13. Good Manufacturing Practice (GMP) Guidelines/Inspection Checklist. 14. Dosage Form Drug Manufacturers cgmps (10/93) Companion volume to a HANDBOOK OF DRUG LAWS by M.L. 17. Mehra FDA guidelines for industry, Global programme for vaccines supply and quality written by Gillian Chaloner Larsson, Roger Anderson and Anik Egan. Corresponding Author: Sowjanya Mallampalli*, sowjanyabujji7000@gmail.com IJPT Jan-2013 Vol. 4 Issue No Page 2373