Schedule m

Schedule M is good manufacturing practices and requirements of premises, plants and equipment for pharmaceutical products.
Schedule M is a part of drugs and cosmetics act, 1940.

Schedule M- І:Requirements of factory premises for manufacture of homoeopathic preparations.
Schedule M- ІІ: :Requirements of factory premises for manufacture of cosmetics.
Schedule M- ІІІ: :Requirements of factory premises for manufacture of medical devices.

1. Schedule M S . Maria Priyadarshini M.Pharmacy 1 st Year (Pharmaceutical analysis and Quality Assurance) Schedule M SRI VENKATESHWARA COLLEGE OF PHARMACY

2. Contents Schedule M

3. SCHEDULE M Schedule M is good manufacturing practices and requirements of premises, plants and equipment for pharmaceutical products. Schedule M is a part of drugs and cosmetics act, 1940. Schedule M- І :Requirements of factory premises for manufacture of homoeopathic preparations. Schedule M- ІІ : :Requirements of factory premises for manufacture of cosmetics. Schedule M- ІІІ : :Requirements of factory premises for manufacture of medical devices. Schedule M

4. Contents: PART І : Good manufacturing practices for premises and materials. PART І A: specific requirements for manufacture of sterile products, parenteral preparations and sterile ophthalmic preparations. PART І B: specific requirements for manufacture of solid dosage forms. PART І C: specific requirements for manufacture of oral liquids. PART І D: specific requirements for manufacture of topical products. PART І E: specific requirements for manufacture of metered dose inhalers(MDI). PART І F: specific requirements for manufacture of active pharmaceutical ingredients (Bulk drugs). PART ІІ : requirements for plants and equipment. SCHEDULE M Schedule M

5. PART 1: GOOD MANUFACTURING PRACTICES FOR PREMISES AND MATERIALS General Requirements Warehousing Area Production area . Ancillary Areas . Quality Control Area . Personnel. Health, clothing and sanitation of workers . Manufacturing Operations and Controls Sanitation in the Manufacturing Premises. Raw Materials . Equipment Documentation and Records Labels and other Printed Materials. SCHEDULE M Schedule M

6. SCHEDULE M 14 . Quality Assurance . 15 . Self Inspection and Quality audit 16. Quality Control System 17. Specification 18. Master Formula Records 19. Packing Records 20. Batch Packaging Records 21. Batch Processing Records 22. Standard Operating Procedures (SOPs) and Records, regarding 23. Reference Samples . 24. Reprocessing and Recoveries 25. Distribution records 26. Validation and process validation 27. Product Recalls 28. Complaints and Adverse Reactions 29. Site Master File Schedule M

7.   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. Wate r – 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. SCHEDULE M Schedule M

8. SCHEDULE M Warehousing Area: 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. 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. Schedule M

9. SCHEDULE M Manufacturing/ Production area : Logical flow of materials. Dedicated areas for sensitive, biological, potent substances . Adequate facilities, should not be interrupted by maintenance . 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. Schedule M

10. SCHEDULE M 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 : 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. Schedule M

11. SCHEDULE M   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 . 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. Schedule M

12. SCHEDULE M 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. 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.  Schedule M

13. SCHEDULE M   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. Schedule M

14. SCHEDULE M 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. Schedule M

15. 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 . 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. SCHEDULE M Schedule M

16. SCHEDULE M 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. 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. Schedule M

17. SCHEDULE M Batch packaging record: Record of clean and free from previous product should be documented Ensure the equipment if clean, ready, suitable for use . 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., Schedule M

18. SCHEDULE M 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.  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 . 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. Schedule M

19. SCHEDULE M 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 . Reference material : – Reference materials should be stored till 3 months after the expiry of the product, in same conditions, final packed form. Schedule M

20.   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 . Complaints and adverse reactions : Complaints should be seriously reviewed and remedies shall be taken and recorded. Serious complaints should be reported to authorities.  SCHEDULE M Schedule M

21. SCHEDULE M 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  Schedule M

22. SCHEDULE M PART I-A Specific Requirements For Manufacture Of Sterile Products, Parenteral Preparations And Sterile Ophthalmic Preparations. General Building and Civil Works. Air Handling System (Central Air-Conditioning). Environmental Monitoring Garments . Sanitation Equipment. Water and Steam Systems Manufacturing Process Form-Fill-Seal Technology or Blow, Fill-Seal Technology . Product Containers and Closures. Documentation Schedule M

23. SCHEDULE M   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 monitored. Schedule M

24. SCHEDULE M Schedule M Air handling systems : Air Handling Units for sterile product manufacturing areas shall be different from those for other areas. Differential pressure between areas of different environmental standards shall be at least 15 Pascal Temperature and humidity in the aseptic areas shall not exceed 27 degree centigrade and relative humidity 55%, respectively. Environmental Monitoring: The recommended frequencies of periodic monitoring shall be as follows Particulate monitoring in air - 6 Monthly. ( b) HEPA filter integrity testing (smoke testing) - Yearly ( c) Air change rates - 6 Monthly . ( d) Air pressure differentials-Daily ( e) Temperature and humidity–Daily ( f) Microbiological monitoring by settle plates and/or swabs in aseptic areas - daily, and at decreased frequency in other areas

25. SCHEDULE M 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.  Schedule M

26. SCHEDULE M Water and Steam systems : Should be checked for Bio-burden , ≯500 in potable , ≯100CFU/ml. Water for injection 10CFU/ml, and should be at 70˚C temperature , continuous rotation . Manufacturing process : Bio-burden of bulk materials should be checked , ≯ 100CFU/ml, gases and liquids should filtered through membrane filters . Each lot should be prepared at one time ,one lot prepared at different times shall be evaluated differently for sterility . 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. Schedule M

27. SCHEDULE M  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. Schedule M

28. PART I-B Specific Requirements For Manufacture Of Oral Solid Dosage Forms (Tablets And Capsules) General Sifting, Mixing and Granulation . Compressions (Tablets ) Coating (Tablets ) Filling of Hard Gelatin Capsule Printing (Tablets and Capsules ) Packaging (Strip and Blister) SCHEDULE M Schedule M

29. SCHEDULE M   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: Machines are separated into cubicles , equipped with dust extractors or own extraction system. Labels should be provided to prevent mix up. In process quality control it should be performed ≯30 minutes . Schedule M

30. SCHEDULE M   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: 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. Packaging : Care to avoid previous batch products when using automated machines. Checked for defects, misprint, cuts, missing doses, improper sealing. Schedule M

31. References 1. Dr.B.S.Kuchekar, Mr.M.Khadatare, Mr.Sachin C.Itkar et.al; Forensic Pharmacy : Textbook : ISBN NO. 85790 – 01 – 9, Fourth Edition , Page No: 149 – 185. Schedule M

32. Any Queries ? ? ? Schedule M

33. Schedule M