schedule M

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good manufacturing practices for pharmaceuticals


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Drugs and Cosmetics Rules 1945 Amendments 1955 1960 1962 1964 1972 1982 1986 1995 2005 Ministry of health and family welfare GOI Thursday, September 12, 2013 1 Dept. of Pharmaceutics

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Drugs and Cosmetics Act and Rules 1940 Schedule – A Licensing applications Schedule – B Fee paid to government analyst Schedule – C List of biological and immunological products Schedule – D Exemptions for import and licensing Schedule – E Labeling and other requirements for poisons Schedule – F Provisions for complying manufacture of biologicals/ recently running blood bank Schedule – G Drugs used under medical supervision Schedule – H Drugs sold under prescription of medical practitioner Schedule – J List of drugs or ailments which may not purpose to prevent or cure as stated in label Schedule – K Exemptions for not complying standards. Schedule – M Good manufacturing practices. Schedule – N Minimum requirements of equipments for running pharmacy Schedule – O Standards for disinfecting fluids Schedule – P Life, conditions of storage Schedule – Q List of coal tar colors permitted in cosmetics Schedule – R Labeling contraceptives Schedule – S Standards for cosmetics Schedule – T Requirements for manufacturing Ayurvedic, Unani, Siddha drugs Schedule – U Records Schedule – V Standards for patient, proprietary medicines, quantities of vitamins permitted Schedule – W drugs marketed under generic name only Schedule – X Psychotropic drugs Schedule – y Clinical trials Different schedules according to Drugs and Cosmetics act are 2 Dept. of Pharmaceutics

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Schedule M Schedule – M Good Manufacturing practices and requirements of Premises, Plant and Equipment for pharmaceutical products Schedule M –II – Requirements of factory premises for manufacture of Cosmetics. Schedule M – III – Requirements of factory premises for manufacture of Medical Devices. Schedule M – I Requirements of factory premises for manufacture of Homeopathic preparations . Thursday, September 12, 2013 3 Dept. of Pharmaceutics

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Part I – Good Manufacturing Practices for premises and materials. Part I A – Sterile products Part I B – Oral solid dosage forms Part I C – Oral liquid dosage forms Part I D – Topical products Part I E – Metered dosage inhalers Part I F – Bulk drug manufacturing premises. Part II – Plant and equipment requirements Parts in schedule M Thursday, September 12, 2013 4 Dept. of Pharmaceutics

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Good Manufacturing Practices for Premises and Materials Elements included in Part I are General requirements Ware housing area Production area Ancillary areas Quality control area Personnel Health, clothing, sanitation of workers Manufacturing operation and controls Sanitation in manufacturing premises Raw materials Equipment Documentation and records Labels and other printed material Quality assurance Self inspection and quality audits Quality control system Specifications Master formula records Packaging records Batch packaging records Batch processing records SOP’s and records Reference samples Reprocessing and recoveries Distribution records Validation and process validation Product recalls Complaints and adverse reactions Site master file 5

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General requirements (Area, Construction, Water supply, Waste disposal) Location and environment – Contamination from environment should be avoided. Avoid smoke, chemicals, odour, open drains. Building and premises – Designed constructed and maintained to suit Manufacturing under hygienic conditions. Water – Purified water according to Pharmacopoeial standards. Potable water for cleaning should be employed. Stored in suitable conditions. Avoid microbial contamination. Waste disposal – Sewage disposal should comply environmental control board. Biological wastes as per bio-medical waste disposal rules 1999 Toxic chemicals, flammables should be properly segregated. Thursday, September 12, 2013 6 Dept. of Pharmaceutics

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Adequate and categorized areas (raw, quarantined, samples returned, released, intermediates, finished products, machine change parts). Good storage conditions, restricted access to personnel. Separate storage for hazardous, toxic, explosive chemicals, abusive chemicals. Separate dispensaries for categorically (Steroids, Hormones, Cytotoxic substances). Aseptic maintenance, prevention of rodents, conducting regular inspections. Ware house – Raw materials – Records should be maintained according to schedule U. Immediately quarantined, stored under appropriate conditions. First in – first out principle should be followed. Damaged or received condition should be noted. Approved by QC should only be dispensed. Separate storage for quarantined, stored, rejected materials. Always stored on racks, not on bare ground/ floor. 7

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Personnel should not be allergic to chemicals handled. Should be periodically checked for cytotoxic or hormonal adverse effects. Thorough medical examination before employing, trained in personal hygiene, inform superior authorities when sick. Direct contact should be avoided, change room procedures should be followed strictly. Smoking drinking, eating are not permitted Plants which effect the quality are also not permitted. Personnel – Qualified technical staff with experience in dosage form manufactured. Quality control should be done by competent staff. Workers proportional to work load. SOP’S should be provided to staff, training should be provided. Health, Clothing and Sanitation of workers 8 Dept. of Pharmaceutics

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Ancillary area – Adequate, separate space for rest room, refreshment room, wash rooms. Separate for males and females. Separate animal houses away from manufacturing area. Change rooms with written instructions for disinfection. Separate areas for workshop, maintenance department, storage of spares. Manufacturing/ Production area Logical flow of materials. Dedicated areas for sensitive, biological, potent substances. Adequate facilities, should not be interrupted by maintenance. Equipment – Properly designed, place according to layout, minimum risk of errors. Qualified, validated equipment. Do not add contaminants, should be cleaned thoroughly. Defectives are separated and labeled. 10

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Manufacturing operations and controls – All operation should be performed by qualified staff under supervision. Labeled with batch number, stage of process. Cross contamination should be prevented. Independent AHU for different products. Left over’s are completely removed after production or closing hours. Packaging materials should be properly checked. Standard operating procedures – Receipt of Raw materials – Product name, receipt details, quantity. Sampling – Sampling methods, plans, quantity, containers used, precautions taken to prevent contamination of sensitive products. Batch numbering – issue a number, should be able to track at any stage. Testing – written procedures to proceed on different equipments. Record of analysis – all details required to fill forms during analysis like product details, validation records, calibration records etc., Thursday, September 12, 2013 11 Dept. of Pharmaceutics

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Validation and Process Validation– It is essential part of GMP, records and reports for validation should be maintained. Any small changes which reflect the quality of the product should be validated. Sanitation in manufacturing premises Cleaning and maintenance should be done regularly. No fare through, no storage of products other than manufactured in the premises Should be well lit. Specifications – Raw materials – name, code reference, Pharmacopoeial requirements Containers and closures – cleaning, compliance. In process – authenticated specifications for bulk, finished products. Finished products – name, formula, qualitative, quantitative requirements, shelf life, storage etc., Thursday, September 12, 2013 12 Dept. of Pharmaceutics

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Quality control area – To perform tests for controlling quality, adequate area for preventing cross contamination. Air locks and laminar air flow facilities for microbiology labs. Separate areas for specific products, storage of reference, test samples, adequate instruments. Quality control system – Duties are to perform sampling, testing, documenting, validating instruments, implementing control procedures. Should have adequate area, equipment, qualified and experienced personnel, Sop’s beside the equipment, for sampling, testing, packaging etc., Access to all the areas of the premises. Availability of Pharmacopoeial reference standards, reference spectra, relevant reference standards. Thursday, September 12, 2013 13 Dept. of Pharmaceutics

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Quality assurance – It influences the quality of the product. It should ensure practice of GMP, GLP, GCP. Should have control on raw materials, intermediates, finished products, validation, calibration. No product should be distributed unless assured by the department. Self inspection and quality audits – Separate experienced team for inspection of quality, evaluate practice of GMP. Procedure of inspection, results, recommendations, actions should be documented. Performed routinely or specifically when product recall or repeated reprocessing. Premises, building, raw materials, storage area, equipment, IPQC, sanitation, hygiene, validation, recall procedures, complaint management, results, corrective actions implemented should be documented. 14 Dept. of Pharmaceutics

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Master formula record – Manufactured products should be documented. It should include name of product, reference, patent number, proprietary or generic name, dosage form, strength, materials used, equipment, step wise processes, intermediates, finished product, expected yield, acceptable limits, IPQC limits, storage requirements, containers, labels, special precautions. Batch processing record Before the process beginning work station should be clean of previous product. During the process every minute detail should be recorded like name of product, material batch number, date of commencement, equipment, major steps, intermediate stages, IPQC results, operator’s signature, etc., Thursday, September 12, 2013 15 Dept. of Pharmaceutics

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Packaging record – Detailed instruction of packaging should be written It should have name of the product, dosage form, codes or reference number, packaging description, in process control, sampling, acceptance criteria, After completion reconcile issued, packed, returned, missing labels and careful investigation should be done Batch packaging record Record of clean and free from previous product should be documented Ensure the equipment if clean, ready, suitable for use. Reprocessing and Recovery - Quality assurance personnel are concerned with the reprocessing. They should establish and give limitations for reprocessing. The problem should be investigated and rectified in reprocessing. Residual solvents can be recovered according to master formula. 17

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Labels and printed matter – Labels should be given to indicate the status of process, avoid mix up’s Labels should be legibly printed, dark colored, Before dispatch quality control dept. should ensure of proper labeling and Checked for inserts, leaflets placed. Adequate number of samples should be collected. Records of received labels should be maintained, unused codes should be documented. Documentation – It is essential part of quality assurance, required for audits, inspections. It should contain all the details, any alteration at time of operation should be noted and signed by authorities responsible. Electronic documentation should be easily available, password protected. Distribution records – Pretests should be done before dispatch for assuring quality, QC should certify the product. Records of distribution should be maintained for efficient recall of products. 18 Dept. of Pharmaceutics

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Product recall – Products should be distributed only after approval of quality control and quality assurance departments. If any problem is discovered the product should be recalled from the market form all levels of distribution Written procedures should be available for recall. Electronic and print media can be used for recalls. Quantities recovered should be compared with distribution and stored separately till final report is issued. Reference material – Reference materials should be stored till 3 months after the expiry of the product, in same conditions, final packed form. Complaints and adverse reactions – Complaints should be seriously reviewed and remedies shall be taken and recorded. Serious complaints should be reported to authorities. Thursday, September 12, 2013 19 Dept. of Pharmaceutics

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Site master file – Licensee shall maintain sufficient information in the site master file. General information – premises, licensed products, no. of employees, activities, quality control, storage, distribution, etc Premises – layout, materials used for construction, ventilation, special area, sanitation, preventive maintenance programs etc., Personnel – records of employees, health, hygienic, responsibilities. Equipment – list, description, validation, calibration of equipment. Sanitation – written procedures and specifications. Documentation – preparation and revision of documents, documents related to product quality, Production Quality control activity Distribution, complaint management – recording of distribution, arrangements for handling complaints, product recalls. Self inspection Export Thursday, September 12, 2013 20 Dept. of Pharmaceutics

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Part I A Requirements for Parenteral products Thursday, September 12, 2013 21 Dept. of Pharmaceutics

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General requirements These being sterile products should not be manufactured in damp, dark, dirt, water supply, air, materials should meet requirements Building and facilities - Quality material should be used in construction, there should not be any cracks, facilities maintenance & repair should not interfere with integrity. Separate areas like supporting area, change rooms, preparation area, aseptic area. Materials suspected for contamination are not allowed. In aseptic area, flooring should be unbroken, joints should be coved, light fittings, air vent/grills, windows should flush with the walls. No sinks in grade A, B rooms Pressure gradient should be maintained, furniture should not impart contaminants. Air locks should be provided to change rooms, visual or audio warning system should be installed. Color coded change rooms for different grade areas Intercom and pass box for communication and passage of materials. Drains should be periodically monitered. 22

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Air handling unit - Individualized air handling units should be provided for different products. Number of exchanges should be > 20 at a flow rate of 0.3 (vertical), 0.4 (horizontal) m/sec, 27 ± 2° C, 55 ± 5 RH, 15 pa differential pressure. Environmental Monitoring - Periodic tests should be carried out 23

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Garments - No out door garments, no cotton garments which shed fibers. Clean and protective garments, gloves, masks, plastic or rubber footwear (cleaned daily with bacteriocide). Trained in changing garments. Sanitation - Procedures should be written and made available, personnel specific should be trained. Agents should be used in rotation, combination, concentrations. Equipment - Washing machines, blenders, manufacturing vessels, stem sterilizers, filter assemblies, filling machines, vacuum chambers, lyophilizer, sealing, labeling machines, integrated machines. Effectiveness of sterilizers , temperature mapping of sterilizers, fill volume of filling machines should be validated and done once a year. Thursday, September 12, 2013 24 Dept. of Pharmaceutics

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Water and Steam systems - Manufacturing process – Form fill seal, Blow fill seal technology - Thermoplastic granules are used for forming, filled and sealed in the same line. Blowing or formation of container is done in a separate area and then filled and sealed. Terminally sterilized products should be filled in class A environment. 25

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Autoclaves, Sterilizers (Dry heat, Moist heat) Before employing in to process they should be validated for efficiency, reaching temperatures. Product containers and closures – Pharmacopoeial grade containers should only be used. Type I, II glass should only be used for parenterals, type III for sterile non- parenterals. Containers should not leak, leach, add, adsorb, stable, non reactive. Designed for easy cleaning and handling. Documentation - All the process employed should be documented. Documentation of environmental monitoring, separate lines for small and large volume preparations, glass and plastic containers, automation. Notes - Thursday, September 12, 2013 26 Dept. of Pharmaceutics

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Part I B Oral solid dosage forms Thursday, September 12, 2013 27 Dept. of Pharmaceutics

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General - Dry substances produces lot of dust and hence building is constructed to minimize cross contamination. Air conditioners, dust extractors should be provided. Pressure differences maintained. Sifting, mixing and granulation - All operations should be performed by equipping with dust extractors. Times for mixing, blending, granulating should be mentioned in master formula files. Filter bags if used should not be used for another production unless washed properly. Compression - 28

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Care to prevent mix up while performing with different batches, different products. Edible grade colors, suitable printing ink should be used. Quality control department should assure its quality before dispatch. Coating - Coating solutions should be immediately prepared to minimize microbial contamination. Air used for drying should be filtered, exhaust should be provided to prevent environmental contamination. Filling of hard gelatin capsules - Considered as drug components. Temperature, humidity should be properly maintained. Printing tablets and capsules - Packaging – Care to avoid previous batch products when using automated machines. Checked for defects, misprint, cuts, missing doses, improper sealing. Thursday, September 12, 2013 29 Dept. of Pharmaceutics

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Part I C Requirements for oral liquids Thursday, September 12, 2013 30 Dept. of Pharmaceutics

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Building – Premises should suit manufacturing oral liquids. Airlocks should be provided. Tanks, mixers, pipes should be designed for easy cleaning, preventing microbial growth. Washing machinery for containers, closures with high pressure air, water, steam jets. Purified water – Microbial count should not exceed 100 CFU/ml, recirculation, UV treatment, chemical sanitization should be done. Written procedures should be established. Manufacturing - No fiber shedding materials should be used (gunny bags, wooden pallets) Mixing and filling should be monitored. If the product is not immediately stored time for storing should be included in master formula record and validated. Thursday, September 12, 2013 31 Dept. of Pharmaceutics

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Part I D Requirements for External preparations Should be provided with airlocks Insectocuters should be provided. Air should be filtered through 20µ filter. Exhaust to remove fumes Suitable cleaning equipment Purified water should be used. Powders should be properly sieved. Preparation, packaging in separate areas. Thursday, September 12, 2013 32 Dept. of Pharmaceutics

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Part I E Requirements for metered dose inhibitors. Thursday, September 12, 2013 33 Dept. of Pharmaceutics

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General - Done in microbial free, particulate free areas. Building - Smoothly finished, windows and fitting flushed with walls. Separate areas for change room, production, ancillary area, quarantine, spray testing, packaging. Propellant gas filtered through 2µ filter, color labeled for identification, direction of flow. Environmental control - Grade c environment, temperature and humidity as per propellant requirement. Garments - Non-shedding, tight wear, single piece garment, gloves of suitable material Thursday, September 12, 2013 34 Dept. of Pharmaceutics

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Equipment – Closed systems, vessels, supply lines made of stainless steel. Sanitation - Written procedures should be available, special care with residues, propellant treatment Water for cleaning should be restricted, routine disinfectants should be used. Manufacturing - Approved master formula should be available in hand. Gases and liquids should be filtered through 2 µ filters. Gases used for cleaning 1° packaging should also be filtered. Suspensions should be stirred continuously. Periodic weight checks of filled containers. Quarantined for checking leakage. Documentation - In addition to routine documentation fill weight, spray testing, temperature and humidity conditions, rejections should be recorded. 35

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Part I F Requirements for Active Pharmaceutical Ingredients Thursday, September 12, 2013 36 Dept. of Pharmaceutics

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Buildings and facilities - Isolated and confined areas for hazardous substances, Beta-lactum antibiotics, carcinogenics, hormones. Adequate number of air exchanges if filtered air is reused. Sterile products - Aseptic conditions for products intended to be sterile. Utilities and services - Chilling units, boilers, heat exchangers, vacuum, vessels and tanks maintained and serviced at appropriate intervals. Equipment design, size - Appropriate design, size, location to facilitate production, cleaning, sanitation, maintenance . Should be properly cleaned or else dedicated to particular product. Selection of cleaning solvent based on raw materials, intermediate, finished products, suitability with instrument material. No traces of previous product should be found in final rinse. 37

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In process control - Reaction time, appearance, clarity, pH, assay, Purity checked by thin layer chromatography. Physical properties like color, appearance, uniformity of blend, temperature , temperature, processing time, moisture, bulk density, pH should be checked. Product container and closure - Should comply with pharmaceutical requirements. Non reactive, non additive, adsorptive, un leachable. Adequate protection from foreseeable factors. Labeling with name, quality, quantity, date of manufacture, expiry, license number, storage conditions. Thursday, September 12, 2013 38 Dept. of Pharmaceutics

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Part II Requirements for Plant and Equipment External preparations – Ointment, Lotion, Cream, Paste, Solution, Emulsions Storage tanks, mixing tanks, heat jacketed kettles, electrically operated mixers, planetary mixer, colloidal mill, ointment mill, triple roller mill, liquid and tube filling machines. Oral liquid preparations – Elixer, Syrups, Solutions, Suspensions, Emulsions Mixing and storage tanks, jacketed kettles, portable stirrer, filtration machines, filling machines, pilfer proof sealing machines, water distillation, deionizers Thursday, September 12, 2013 39 Dept. of Pharmaceutics

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Tablets - Manufacturing is done in closed separate cubicles. Includes 4 stages. Mixing , granulation and drying – weighing machines, sifters, disintegrators, mixers, planetary mixer, rapid mixer granulator, hot air ovens. Compression – compression machine, dies, punches, de duster, inspection belt, dissolution, IPQC equipment, air conditioning, humidity control arrangement. Packaging – strip or blister packing apparatus, leak test apparatus, tablet counter Coating – jacketed kettle, coating pans, exhaust for dust and fumes, air conditioning, dehumidification, Thursday, September 12, 2013 40 Dept. of Pharmaceutics

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Powders - Weighing machines, disintegrators, electrically operated mixers, sifters, vessels, scoops, filling equipment, exhaust for floating particles. Capsules - Balances, mixing, blending, filling, polishing, counting machines. Exhaust for dust particles in air. Area of 25 sq.mts, ancillary area of 10 sq.mts. Surgical dressing - Rolling, trimming machines, cutting equipment, folding and pressing machine, mixing tanks for processing medicated dressings, ovens, sterilizers. Thursday, September 12, 2013 41 Dept. of Pharmaceutics

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Opthalmic preparations - Mixing tanks, jacketed kettle, planetary mixer, colloidal mill, ointment mill, tube , rubber bung washing machine, dryers, filling, crimping machines, membrane filters, hot air ovens, autoclaves, air-conditioning, dehumidifiers. Area of 25 sq.mts, area should be maintained aseptically. Pessaries and suppositories - Weighing, mixing, pouring, moulding equipment. Area of 25 sq.mts. Inhalers and vitrallae - Weighing, graduated delivery unit, sealing equipments. Area of 25 sq.mts. Repacking of drugs and pharmaceuticals – Weighing, disintegrators, sifters, scoops, vessels, filling and electrically sealing machines, suitable exhaust . Area of 30 sq.mts. 42

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Parenterals – separate for large volume, small volume, glass, plastic containers. Glass containers – Water management area – deionization, distillation, storage, pumps, service lines Containers and closures – washing machines, dryers, sterilizers, storage. Solution preparation area – mixing table, portable stirrer, filling equipment, transfer pumps. Filling capping and sealing – automatic filling and sealing, aseptic conditions, leak test apparatus, sterilizers. Quarantine area – storage cabinet, work platform, benches Visual inspection area – inspection unit, conveyor belt with black and white background, illumination. Packaging area – coding machines, labeling machines, benches and stools. Area of 150 sq.mts, ancillary 100 sq.mts. Air locks, aseptic conditions. Thursday, September 12, 2013 43 Dept. of Pharmaceutics

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Plastic containers – Water management area – deionization, distillation, storage, pumps, service lines Containers and closures – washing machines, dryers, sterilizers, storage. Solution preparation area – mixing table, portable stirrer, filling equipment, transfer pumps. Filling capping and sealing – automatic filling and sealing, aseptic conditions, leak test apparatus, sterilizers. Sterilization – dry heat, moist heat sterilizers, autoclaves. Quarantine area – storage cabinet, work platform, benches Visual inspection area – inspection unit, conveyor belt with black and white background, illumination. Packaging area – coding machines, labeling machines, benches and stools. Area of 200 sq.mts, ancillary 150 sq.mts, air locks, aseptic conditions. Thursday, September 12, 2013 44 Dept. of Pharmaceutics

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M – I Special requirements for Homeopathic medications. Requirement of Premises Requirement of Plant and Equipment Tinctures and solutions area of 55 sq.mts, separate storage areas, bonded areas for alcohol. Tablets, pellets and granules Ointments and lotions Syrups and tonics Ophthalmic preparations 45 Dept. of Pharmaceutics

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M –II Special requirements for Cosmetics General requirements Plant and equipment Powders Creams, Lotions, Shampoos, Shaving creams Nail polish, Nail lacquers Lipstick, Lip-gloss Eye preparations Eyebrow, Eyelashes, Eye liners Kajal, Surma Aerosols Alcoholic fragrance solutions Hair dyes Toothpastes (15 sq.mts) Toilet soap (area of 100 sq.mts) Thursday, September 12, 2013 46 Dept. of Pharmaceutics

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M – III Special requirements for Medical devices. General requirements Manufacturing Moulding ( injection moulding, extruder, PVC compounder Assembling ( compression machine to fit drip chamber, PVC cutter, bag sealing machine, leak test apparatus) Storage area Drying area Testing area Aseptic environment should be maintained. Thursday, September 12, 2013 47 Dept. of Pharmaceutics

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References – Central drug standards control organization P.P. Sharma, How to practice GMPs, A Treatise on GMPs, 6 edition, 2010, Vandana Publications Pvt. Ltd. Thursday, September 12, 2013 48 Dept. of Pharmaceutics For detailed notes or .pptx format push a mail to Feel free…

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