The General Requirements as given in SCHEDULE M – GMP – PART 1 of this Schedule relating to requirements of Good Manufacturing Practices for Premises and materials for pharmaceutical products shall be complied for the manufacture of Active Pharmaceutial Ingredients (Bulk Drugs). In addition to these requirements, the following Specific Requirement shall also be followed.


Building and Civil Works

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.

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.

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 recirculated 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.

Ancillary area shall be provided for Boiler-house. Utility areas like heat exchangers, chilling workshop, store and supply of gases shall also be provided.

For specified preparation like manufacture of sterile products and for certain antibiotics, sexhormones, 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.

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. all conditions applicable to formulations that are required to be filled aseptically shall apply mutates mutandis for the manufacture of sterile active pharmaceutical ingredients involving stages like filtration crystallization and lyophilisation.

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.

Equipment Design, Size and Location

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.

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.

  • 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.
  • 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.

Equipment shall be cleaned between successive batches to prevent contamination and carry-over of degraded material or contaminants unless otherwise established by validation.

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.

In-Process Controls

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.

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

Product Containers and Closures

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.

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.

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.

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.

  • 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 licence 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.

Areas for different operation of active pharmaceutical ingredients (bulk drugs) section shall have appropriate area which may be suitably partitioned for different operations.

Reference : Drugs and Cosmetics act 1940