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Last Updated on June 21, 2025 by The Health Master
Revised Schedule M
The revised Schedule M, notified in January 2024, introduces stricter standards aimed at improving the quality and safety of pharmaceutical products.
The government has further issued a final notification vide GSR 127(E) dated 11-02-2025 regarding the extension of the deadline for revised schedule M, and now the timeline has been extended till 31-12-2025.
The manufacturers have to submit the application, including a detailed plan outlining a roadmap for gap analysis and to upgrading their facilities to meet the requirements of revised Schedule M. We have provided key points on gap analysis.
WHO-TRS Implementation:
Previous Schedule M:
No requirement to follow Technical report series which were published, time to time, by WHO. No co-relation or mandate to implement TRS.
Revised Schedule M:
The guidelines published by the World Health Organization (WHO) on following aspects relating to GMP through their Technical Report Series from time to time shall 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.
Water system:
Previous Schedule M:
For core manufacturing area of tablet, capsules, sachets, oral liquid and external manufacturing area, Water having purified water IP specification was mandatory.
But, the purified water generation system, storage, and circulation were not address in depth.
Revised Schedule M:
While in revised schedule M, no special instructions for water specification.
But, special note of TRS-WHO implementation, constraint the manufacturers to made mandatory, water generation system, storage tanks, re-circulation, pumping, treatment of water, etc as par with current TRS of WHO.
Environment control:
Previous Schedule M:
For core manufacturing area of tablet, capsules, sachets, oral liquid and external manufacturing area, AHU was mandatory.
But, Final filter to blow air in the core room, was having 5-micron filters. 5-micron filters, installed at terminal or plenum, were adequate. No classification was mandatory.
Revised Schedule M:
For core manufacturing area of tablet, capsules, sachets, oral liquid and external manufacturing area, AHU is mandatory.
CLASS-D classification is made mandatory.
Final filter to blow air in the core room, should be having 0.3-micron HEPA filters. 0.3-micron HEPA filters, should be installed at terminal side only, not at plenum side.
Cross-contamination-1:
Previous Schedule M:
Airlocks were not mandatory at each entry of the core manufacturing rooms.
The room pressure differentials were to be provided at negative side for TABLET, CAPSULE, SACHETS, or POWDER GENERATING FORMULATIONS, as compare to adjacent lobby, which was without any classification.
Same way, the room pressure differentials were to be provided at positive side for ORAL LIQUID formulations, as compare to adjacent lobby, which was without any classification.
Revised Schedule M:
Airlocks are made mandatory at each entry of the core manufacturing rooms.
The room pressure differentials should be provided at positive side for ORAL LIQUID formulation, as compare to adjacent airlock.
Airlock should be provided with 0.3-micron HEPA filters having CLASS-D classification.
Cross-contamination-2:
Previous Schedule M:
For core manufacturing area of tablet, capsules, sachets, oral liquid and external manufacturing area, Separate MATERIAL TRANSFER AIRLOCKS and MEN ENTRY AIRLOCKS were not mandatory.
Pass-box provided were not made mandatory with classification. No classification was mandatory.
Revised Schedule M:
For core manufacturing area of tablet, capsules, sachets, oral liquid and external manufacturing area, Separate MATERIAL TRANSFER AIRLOCKS and MEN ENTRY AIRLOCKS are made mandatory.
Both MAL and PAL are made mandatory with classification having CLASS-D.
If pass-box are provided, they are made mandatory with classification.
Passbox between two rooms having same CLASS-D qualification, may be static pass-box.
But, pass-box between two rooms having different classification (i.e. between Classified area and Non-Classified area), should be with dynamic system (Having 0.3-MICRON HEPA filter).
Cross-contamination-3:
Previous Schedule M:
For core manufacturing area of SEX HORMONE, STEROIDS and CYTOTOXIC Substances (API as well as Formulation), Separate Manufacturing facility was mandatory.
But, cross-contamination, personal safety and environment safety systems were not addressed, in details.
Revised Schedule M:
For core manufacturing area of SEX HORMONE, STEROIDS and CYTOTOXIC Substances (API as well as Formulation), Separate SELF-CONTAINED Manufacturing facility is made mandatory.
Separate entry, separate staff, separate Air handling systems are made mandatory.
All manufacturing critical equipment and processes are made mandatorily in CLOSED SYSTEM or Barrier technology.
For personals working in above category of API or Formulation, Self-contained breathing apparatus (SCBA) with HEPA -N95 filter, with Central breathing air supply system having controlled temperature, humidity, Carbon dioxide, carbon monoxide, and Sulphur dioxide, with ISO standard, are made mandatory.
No direct air venting to outside environment.
Air shall be exhausted to outside through HEPA filters only.
No re-circulation of Air TO CRITICAL MANUFACTURING AREA OF ABOVE PRODUCTS.
Single pass air handling systems with NO RECIRCULATION are made mandatory.
Exhaust of return air should be performed by bag to bag system having HEPA filets.
For personals, who are exiting from critical manufacturing area, should be passed through AIR SHOWER, MIST SHOWER or WATER SHOWER, are made mandatory.
The self-contained air shower system should be with HEPA filter supply and inter-lock doors.
The gowning should be thrown for de-contamination during exit of the critical manufacturing area of above products.
Contract and agreements
Previous Schedule M:
Production under loan license or contract manufacturing or contrct analysis and other activities were not addressed in previous schedule M.
Revised Schedule M:
Loan license contract with complete understandings of products, work, testing, quality issues, responsibilities, liabilities, monitoring and review.
The contract system is addressed in depth, in revised schedule M para 9 of general chapter.
Other contracts like Outside testing of product, technology transfer, stability testing study before manufacturing license, or validation / calibration contracts, Waste disposal contracts, and other relevant contracts, are made mandatory, in revised schedule M para 9 of general chapter.
Other activities in manufacturing area
Previous Schedule M:
For manufacturing area of API as well as Formulation, Separate Manufacturing facility was not mandatory for other activities.
Revised Schedule M:
For manufacturing area of API as well as Formulation, the facility should be exclusively for production of DRUGS.
No other manufacturing activity shall be undertaken therein.
Computerized Systems
Previous Schedule M:
limited aspects were covered
Revised Schedule M:
Newly added as separate principle with specific requirements complying global standards.
Very significant section regarding the regulatory agencies’ present strategy.
The qualification, validation, review, and data management related to computerized systems are covered in detail in this section.
Validation needs to be grounded in the system’s complexity, diversity, and criticality.
Any modifications to the electronic system must follow a change procedure with upholding and approving each and every record.
These documents will show that the system is kept up to date and validated.
There must be a backup system in place to ensure that documents are never permanently lost because of failure or collapse of the system.
Computerized systems must be equipped with sufficient safeguards against unwanted access or modifications to the data.
Pharmaceutical Quality System (PQS), Quality Risk Management, Product Quality Review
Previous Schedule M:
No section in existing Schedule M or nor mentioned in sub chapters of quality system.
Revised Schedule M:
Newly added. Separate specific requirements mentioned.
Qualification and Validation Product process validation
Previous Schedule M:
These requirements are specified with minimum emphasis. six product specific manufacture requirements are specified.
Revised Schedule M:
Newly Added. Detailed requirements of equipment qualification along with process validation are specified.
In revised Schedule M, another 5 categories are added. Total 11 product specific manufacture requirements are specified.
Self-inspection, quality audits and suppliers’ audits and approval
Previous Schedule M:
The activity is limited up to internal inspection
Revised Schedule M:
This activity is more clarified and extended beyond self-inspection towards supplier approval through quality audits of his premises and processes.
Documentation
Previous Schedule M:
General principles of good documentation practices and electronic documents were mentioned.
Revised Schedule M:
Specific requirements are mentioned as per ALCOA principles from global standards. ALCOA: – Attributable, Legible, Contemporaneous, Original and Accurate.
Gist of 31 Chapters on Schedule M
Revised Schedule M Guidelines: Drug Recall and Ensuring Pharma Quality
Pharmaceutical Quality: Key Amendments in Revised Schedule M
Revised Schedule M: The Role of Pharmaceutical Waste Management
Gap analysis for Revised Schedule M
Important short notes for Industry and Regulators
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