This is the last article of Schedule – M Part- 1.


Note: – External preparations (Creams, Ointments, Pastes, Emulsions, Lotions, Solutions, Dusting powders and identical products used for external applications). In addition to these requirements, following Specific Requirements shall also be followed;

  1. 1. The entrance to the area where topical products are manufactured should be through a suitable airlock. Outside the airlock, insectocutors shall be installed.
  2. The air to this manufacturing area shall be filtered through at least 20µ air filters and shall be air-conditioned. The area shall be ventilated.
  3. The area shall be fitted with an exhaust system of suitable capacity to effectively remove vapours, fumes, smoke, floating dust particles.
  4. The equipment used shall be designed and maintained to prevent the product from being accidentally contaminated with any foreign matter or lubricant.
  5. No rags or dusters shall be used in the process of cleaning or drying the process equipment or accessories used.
  6. Water used in compounding shall be Purified Water IP.
  7. Powders, wherever used, shall be suitably sieved before use.
  8. Heating vehicles and a base like petroleum jelly shall be done in separate mixing area in suitable stainless steel vessels, using steam, gas, electricity, solar energy, etc.
  9. A separate packing section may be provided for primary packaging of the products.

                                                                                [PART I-E]


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. Where medicaments are in suspended state, uniformity of suspension shall be established.

  1. Building and Civil Works:
  2. 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.
  3. All building surfaces shall be impervious, smooth and non-shedding. Flooring shall be continuous and provided with a cove between the floor and the wall as well as the wall to the ceiling. Ceiling shall be solid, continuous and covered to walls. Light fittings and air-grills shall be flush with the ceiling. All service lines requiring maintenance shall be erected in such a manner that these accessible from outside the production area.
  4. The manufacturing area shall be segregated into change rooms for personnel, container preparation area, bulk preparation and filling area, quarantine area and spray testing and packing areas.
  5. Secondary change rooms shall be provided for operators to change from factory clothing to special departmental clothing before entering the manufacturing and filling area.
  6. Separate area shall be provided for de-cartoning of components before they are air washed.
  7. The propellants used for manufacture shall be delivered to the manufacturing area distribution system by filtering them through 2µ filters. The bulk containers of propellants shall be stored, suitably identified, away from the manufacturing facilities.
  8. Environmental Conditions:
  9. Where products or clean components are exposed, the area shall be supplied with filtered air of Grade C.
  10. The requirements of temperature and humidity in the manufacturing area shall be decided depending on the type of product and propellants handled in the facility. Other support area shall have comfort levels of temperature and humidity.
  11. There shall be a difference in room pressure between the manufacturing area and the support areas and the differential pressure shall be not less than 15 Pascals (0.06 inches or 1.5mm water gauge).
  12. There shall be a written schedule for the monitoring of environmental conditions. Temperature and humidity shall be monitored daily.
  13. Garments:
  14. Personnel in the manufacturing and filling section shall wear suitable single-piece-garment made out of non-shedding, tight weave material. Personnel in support areas shall wear clean factory uniforms.
  15. Gloves made of suitable material having no interaction with the propellants shall be used by the operators in the manufacturing and filling areas. Preferably, disposable gloves shall be used.
  16. Suitable department-specific personnel protective equipment like footwear and safety glasses shall be used wherever hazard exists.
  17. Sanitation:
  18. There shall be written procedures for the sanitation of the MDI manufacturing facility. Special care should be taken to handle residues and rinses of propellants.
  19. Use of water for cleaning shall be restricted and controlled. Routinely used disinfectants are suitable for sanitizing the different areas. Records of sanitation shall be maintained.
  20. Equipment:
  21. Manufacturing equipment shall be of closed system. The vessels and supply lines shall be of stainless steel.
  22. Suitable check weights, spray testing machines and labeling machines shall be provided in the department.
  23. All the equipment shall be suitably calibrated and their performance validated on receipt and thereafter periodically.
  24. Manufacture:
  25. There shall be approved Master Formula Records for the manufacture of metered close inhalers. All propellants, liquids and gases shall be filtered through 2µ filters to remove particles.
  26. The primary packing material shall be appropriately cleaned by compressed air suitably filtered through 0.2µ filter. The humidity of compressed air shall be controlled as applicable.
  27. The valves shall be carefully handled and after de-cartoning, there shall be kept in clean, closed containers in the filling room.
  28. For suspensions, the bulk shall be kept stirred continuously.
  29. In-process controls shall include periodical checking of weight of bulk formulation filled in the containers. In a two-shot-filling process (liquid filling followed by gaseous filling), it shall be ensured that 100% check on weight is carried out.
  30. Filled containers shall be quarantined for a suitable period established by the manufacturer to detect leaking containers prior to testing, labeling and packing.
  31. Documentation:
  32. In addition to the routine good manufacturing practices documentation, manufacturing records shall show the following additional information:-

(a) Temperature and humidity in the manufacturing area;

(b) Periodic filled weights of the formulation;

(c) Records of rejections during on line check weighing;

(d) Records of rejection during spray testing.



  1. Building and Civil Works:
  2. Apart from the building requirements contained Part-I, General note, the active pharmaceutical ingredients facilities for manufacture of hazardous reactions, Beta- Lactum antibiotics. Steroids and Steroidal Hormones / Cytotoxic substances shall be provided in confined areas to prevent contamination of the other drugs manufactured.
  3. The final stage of preparation of a drug, like isolation / filtration / drying / milling / sieving and packing operations shall be provided with air filtration systems including pre-filters and finally with a 5 micron filter. Air handling systems with adequate number of air changes per hour or any other suitable system to control the air borne contamination shall be provided. Humidity / Temperature shall also be controlled for all the operations wherever required.
  4. Air filtration systems including pre-filters and particulate matter retention air filters shall be used, where appropriate, for air supplies to production areas. If air is re-circulated to production areas, measures shall be taken to control re-circulation of floating dust particles from production. In areas where air contamination occurs during production, there shall be adequate exhaust system to control contaminants.
  5. Ancillary area shall be provided for Boiler-house. Utility areas like heat exchangers, chilling workshop, store and supply of gases shall also be provided.
  6. For specified preparation like manufacture of sterile products and for certain antibiotics, sex hormones, Cytotoxic and Oncology products, separate enclosed areas shall be designed. The requirements for the sterile active pharmaceutical ingredient shall be in line with the facilities required for formulation to be filled aseptically.
  7. Sterile Products: Sterile active pharmaceutical ingredient filled aseptically shall be treated as formulation from the stage wherever the process demands like- crystallization, lyophilisation, filtration etc.
  8. Utilities / Services: Equipment like chilling plant, boiler, heat exchangers, vacuum and gas storage vessels shall be serviced, cleaned, sanitized and maintained at appropriate intervals to prevent mal-functions or contamination that may interfere with safety, identity, strength, quality or purity of the drug product.
  9. Equipment Design, Size and Location:
  10. Equipment used in the manufacture, processing, packing or holding of an active pharmaceutical ingredient shall be of appropriate design, adequate size and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
  11. If the equipment is used for different intermediates and active pharmaceutical ingredients, proper cleaning before switching from one product to another becomes particularly important. If cleaning of a specific type of equipment is difficult, the equipment may need to be dedicated to a particular intermediate or active pharmaceutical ingredient.
  12. The choice of cleaning methods, detergents and levels of cleaning shall be defined and justified. Selection of cleaning agents (e.g. solvents) should depend on : (a) the suitability of the cleaning agent to remove residues of raw materials, intermediates, precursors, degradation products and isomers, as appropriate; (b) whether the cleaning agent leaves a residue itself; (c) compatibility with equipment construction materials like centrifuge / filtration, dryer / fluid bed dryer, rotocone proton dryer, vacuum dryer, frit mill, multi-mill / jet mills / sewetters cut sizing; (d) test for absence of intermediate or active pharmaceutical ingredient in the final rinse.
  13. Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils used in the manufacture, processing, packing or holding of active pharmaceutical ingredients. These procedures shall include but should not be limited to the following : (a) assignment of responsibility for cleaning and maintaining equipment; (b) maintenance and cleaning program schedules, including where appropriate, sanitizing schedules; (c) a complete description of the methods and materials used to clean and maintain equipment, including instructions for de-assembling and reassembling each article of equipment to ensure proper cleaning and maintenance.; (d) removal or obliteration of previous batch identification; (e) protection of clean equipment from contamination prior to use; (f) inspection of equipment for cleanliness immediately before use; (g) establishing the maximum time that may elapse between completion of processing and equipment cleaning as well as between cleaning and equipment reuse.
  14. Equipment shall be cleaned between successive batches to prevent contamination and carry-over of degraded material or contaminants unless otherwise established by validation.
  15. As processing approaches the final purified active pharmaceutical ingredient, it is important to ensure that incidental carry over between batches does not have adverse impact on the established impurity profile. However, this does not generally hold good for any biological, active pharmaceutical ingredient where many of the processing steps are accomplished aseptically and where it is necessary to clean and sterilize equipment between batches.
  16. In-Process Controls:-
  17. In-process control for chemical reactions may include the following: (a) reaction time or reaction completion; (b) reaction mass appearance, clarity, completeness or pH solutions; (c) reaction temperature (d) concentration of a reactant; (e) assay or purity of the product (f) process completion check by TLC / any other means.
  18. In-process control for physical operations may include the following: (a) appearance and colour; (b) uniformity of the blend; (c) temperature of a process; (d) concentration of a solution; (e) processing rate or time; (f) particle size analysis; (g) bulk/tap density; (h) pH determination (i) moisture content.
  19. Product Containers and Closures:-
  20. All containers and closures shall comply with the Pharmacopoeial or any other requirement, suitable sampling methods, sample sizes, specifications, test methods, cleaning procedures and sterilization procedures, when indicated, shall be used to assure that containers, closures and other component parts of drug packages are suitable and are not reactive, additive, adsorptive or leachable to an extent that significantly affects the quality or purity of the drug.
  21. The drug product container shall be tested or re-examined as appropriate and approved or rejected and shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which these are unsuitable.
  22. Container closure system shall provide adequate protection against foreseeable external factors in storage / transportation and use that may cause deterioration or contamination of the active pharmaceutical ingredient.
  23. Bulk containers and closures shall be cleaned and, where indicated by the nature of the active pharmaceutical ingredient, sterilized to ensure that they are suitable for their intended use.
  24. The container shall be conspicuously marked with the name of the product and the following additional information concerning: (a) quality and standards, if specified; (b) manufacturing license number/drug master file number (whichever applicable), batch number; (c) date of manufacture and date of expiry; (d) method for container disposal (label shall give the methodology, if required); (e) storage conditions, if specified and name and address of the manufacturer, if available.
  25. Areas for different operation of active pharmaceutical ingredients (bulk drugs) section shall have appropriate area which may be suitably partitioned for different operations.

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