Revised Schedule M, Drugs Rules, 1945

This document outlines significant revisions to Schedule M of the Drugs Rules, 1945, updating the Good Manufacturing Practices (GMP) and requirements for pharmaceutical manufacturing facilities in India. The revised schedule M aims to enhance product quality, safety, and efficacy by standardising manufacturing processes and infrastructure.

Main Themes and Important Points to consider:

• Emphasis on a Robust Product Quality System: The revised schedule places a strong emphasis on establishing and maintaining a comprehensive product quality system throughout the entire product lifecycle. This system should ensure “consistent delivery of products with appropriate quality attributes” (1.5(a)). Key elements include managing product and process knowledge, integrating GMP with other GXPs (GLP, GCP), and continuous improvement (1.5(b), 1.5(c)).
• Documentation and Control: Rigorous documentation is a cornerstone of the new regulations. Licensees are required to “evolve appropriate methodology, systems and procedures which shall be documented and maintained for inspection and reference” (Note under Schedule M). This includes detailed records for all stages of manufacturing, quality control, complaints, and self-inspections (Section 17). Documents must be unambiguous, approved, signed, and dated (17.2.2, 17.2.3).
• Qualification and Validation: A key requirement is the comprehensive qualification and validation of critical aspects of operations. Companies must define and document their qualification and validation programme in a master plan (5.1, 5.2). This includes establishing and providing documentary evidence that processes and equipment consistently perform as intended (5.3).
• Complaint Handling and Product Recall: Clear procedures for managing product complaints and initiating recalls are mandated. Investigations into product defects are required, and consideration must be given to checking other batches that might be affected (6.6). Decisions and actions taken in response to complaints must be recorded (6.8). Regular review of complaint records for recurring problems is essential (6.9). Licensing authorities must be informed of serious quality problems (6.10).
• Pharmacovigilance System: Licensees are required to have a pharmacovigilance system to collect, process, and forward reports of adverse drug reactions to the licensing authorities (6.11).
• Contract Manufacturing and Analysis: When activities are outsourced, a technical agreement must be in place defining responsibilities (2.3.3, 9.2.3). The contract giver is responsible for assessing the suitability and competence of the contract acceptor and ensuring GMP compliance (9.3.1). Auditing of contract facilities is permitted (9.2.2).
• Self-Inspection and Quality Audits: Regular self-inspection or quality audits are mandatory to appraise the effectiveness of the product quality system (1.5(l), 10.3). The self-inspection team must consist of experts familiar with GMP, who can be internal or external (10.3).
• Quality Unit Responsibilities: The quality unit (QA/QC) plays a central role, independent of production (API section, 2.1.4). Responsibilities include releasing/rejecting materials and products, reviewing batch records, investigating deviations, approving specifications and instructions, and overseeing stability monitoring and quality reviews (API section, 2.4(i-v), 2.5.1).
• Material Management: Detailed procedures for the receipt, identification, quarantine, storage, handling, sampling, testing, and approval/rejection of materials are required (API section, 7.1.1). Materials must be stored under appropriate conditions (14.5, API section 10.1.2). Re-evaluation of materials is necessary after prolonged storage or exposure to adverse conditions (API section, 7.5).
• Production and In-Process Controls: Weighing and measuring devices must be accurate and used under appropriate conditions (API section, 8.1.1). In-process controls are essential to ensure products remain within specification, with regular testing and recording of results (19.7.5, Tablet section, 3.8). Time limits specified in master production instructions must be met (API section, 8.2.1).
• Laboratory Controls and Analytical Methods: Adequate laboratory facilities must be available (API section, 11.1.1). Documented procedures for sampling, testing, and data storage are required (API section, 11.1.2). Specifications and test procedures must be scientifically sound and consistent with registration/filing documents (API section, 11.1.3). Analytical methods must be validated, especially if not from recognised pharmacopoeias (API section, 12.8.1). Stability monitoring programs are mandatory (API section, 11.4.1).
• Sterile Products Specific Requirements: Part II outlines stringent requirements for sterile product manufacturing. This includes specific air classification grades for different areas (“at rest” and “in operation” states) (Part II, 4.6.1, 4.6.2, 4.7.2), validated sterilisation processes (Part II, 6.4), media fills for aseptic processing (Part II, 5.6), endotoxin monitoring for injectable products (Part II, 2.4), and validated water systems (Part II, 9.6). Terminal sterilisation by heat in the final container is preferred where possible (Part II, 6.1). Detailed monitoring and recording of sterilisation cycles are required (Part II, 6.11.1.1).
• Hazardous Substances Specific Requirements: Part III addresses the manufacture of products containing hazardous substances. This often requires separate, dedicated facilities to protect personnel and the environment (Part III, 1.2). Specific air handling systems with appropriate filters are necessary (Part III, 9.5, 9.6, 9.7, 9.8).
• Radiopharmaceuticals Specific Requirements: Part V outlines specific requirements for radiopharmaceuticals, including training in safe handling of radioactive materials (Part V, 2.6), specific air pressure requirements (negative pressure for radioactivity handling, positive pressure for sterile processing) (Part V, 3.8), and distinct labelling requirements (Part V, 5.3).
• Phytopharmaceuticals Specific Requirements: Part VI provides specific GMP for phytopharmaceuticals. This includes appropriate storage conditions for plant materials (Part VI, 15.1), validated cleaning methods for equipment used for different products (Part VI, 8.1), and personnel training in the specific characteristics of phytopharmaceuticals (Part VI, 10.1, 10.2). Reference standards may include botanical samples or marker substances (Part VI, 16). Specific tests for quality control are listed, including identity tests and quantification of relevant substances (Part VI, 19.5, 19.6, 19.10). Stability studies for finished phytopharmaceutical drugs are required (Part VI, 23.4.8).
• Premises, Plant, and Equipment Details (Appendix II): Appendix II provides detailed requirements for the layout, area, and recommended equipment for the manufacture of various dosage forms, including Ointments, Oral Liquids, Tablets, Powders, Capsules, Surgical Dressings, Ophthalmic Preparations, Pessaries and Suppositories, Topical Preparations, External Preparations, and Parenteral Preparations. This includes specific recommendations for air conditioning, dust control, and equipment for different stages of production.

Note:-The guidelines published by the World Health Organization (WHO) on following aspects relating to GMP through their Technical Report Series from time to time may be considered for general guidance purposes:-

(1) Guidelines on the principles of airflow directions, air filtration standards, temperature, humidity and related parameters.

(2) GMP guidelines regarding the design, installation and operation of pharmaceutical water systems including guidance about which quality of water to use for specific applications, such as the manufacture of APIs and dosage forms.

(3) Guidelines on design, installation, qualification and maintenance of the HVAC systems of the manufacturing plant.

(4) GMP guidelines for validation.

(5) Guidelines on packaging of pharmaceutical products.

Quotes from the Revised Schedule M, Drugs Rules, 1945:

• “To achieve the objectives listed below, each licensee shall evolve appropriate methodology, systems and procedures which shall be documented and maintained for inspection and reference; and the manufacturing premises shall be used exclusively for production of drugs and no other manufacturing activity shall be undertaken therein.” (Note under Schedule M)
• “product quality system appropriate to the manufacture of pharmaceutical products shall ensure that— (a) product realisation is achieved by designing, qualifying, planning, implementing, maintaining and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes;” (1.5)
• “Good manufacturing practices are aimed primarily at managing and minimising the risks inherent in pharmaceutical manufacture to ensure the quality, safety and efficacy of products.” (3.1)
• “In accordance with GMP, each pharmaceutical company shall identify what qualification and validation work is required to prove that the critical aspects of their particular operation is controlled.” (5.1)
• “The licensing authorities shall be informed if a manufacturer is considering action following the faulty manufacture, product deterioration, a suspect product or any other serious quality problems with a product.” (6.10)
• “The licensee shall have a pharmacovigilance system in place for collecting, processing and forwarding the reports to the licensing authorities for information on the adverse drug reactions emerging from the use of drugs manufactured or marketed by the licensee.” (6.11)
• “Whenever possible products intended to be sterile shall be terminally sterilised by heat in their final container.” (Part II, 6.1)
• “The production of certain products containing hazardous substances shall generally be conducted in separate, dedicated, self-contained facilities.” (Part III, 1.2)
• “The production of sterile radioactive products shall therefore be carried out under negative pressure surrounded by a positive pressure zone ensuring that appropriate air quality requirements are met.” (Part V, 3.8)
• “Personnel dealing with the production and quality control of Phytopharmaceuticals shall have adequate qualifications and training in the specific issues relevant to Phytopharmaceuticals.” (Part VI, 10.2)
• “The integrity of individual packaging strips and blisters shall be subjected to vacuum test periodically to ensure leak proofness of each pocket strip and blister and records maintained.” (Tablet section, 7.4)

Conclusion:

The revised Schedule M represents a significant update to the regulatory framework for pharmaceutical manufacturing in India. It introduces more detailed and specific requirements for GMP, premises, plant, and equipment, with a strong emphasis on quality systems, documentation, validation, and risk management. The specific requirements for different categories of drugs (sterile, hazardous, radiopharmaceuticals, phytopharmaceuticals) demonstrate a tailored approach to ensuring product quality and safety. This revision aligns India’s pharmaceutical manufacturing standards more closely with international GMP guidelines.