GMP-Revised Schedule M- Indian regulation

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• REVISED SCHEDULE -MGOOD MANUFACTURING PRACTICES

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Overview

• Introduction
• Drugs and Cosmetics Act Rules
• Bill, Act, Rules regulations
• Schedules A-Y
• Schedule-M Revised Schedule-M
• Revised Schedule-M
• Part-1 Main principles- Major change
• Specific requirements
• GMP for APIs ICH Q7

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The Drugs and Cosmetics Act Rules

• The Drugs And Cosmetics Act, 1940
• The Drugs And Cosmetics Rules, 1945 .
• Rules established through the DrugsCosmetics Act
• Enforcement of D C Schedules started in 1947.
• An Act to regulate the import, manufacture,
  distribution and sale of drugs and cosmetics.

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Revised Schedule M

• The Rules have been amended time to time to meet
  the needs and to rectify any shortcomings in the
  process. (As amended up to 31.12.2016)
• Revised Schedule M
• General Statutory Rules (G.S.R) 999(E), Gazette
  made 5th Oct 2018 and was made available to the
  public on 9th Oct, 2018
• Notification for implementation- 28th Dec, 2023

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Bill, Act and Rule

• A Bill (Law) is the initial phase of an Act, ie
  a proposal for a new law.
• The Bills are introduced and passed by the Union
  and State Legislatures.
• Assent by President or Governor and then A bill
  becomes an Act
• Date of enforcement from the date of issue or
  Gazette notification
• An Act provides a comprehensive framework for the
  implementation of laws

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Act and Rule

• An Act defines, Why and how laws are enforced
  and laws tell us about what should and should
  not be done
• As an Act provides a broad legal framework, may
  not have every minute detail,
• Hence, enactment of Rules required the procedures
  for performing and implementing the Act.
• The Rules have been amended time to time to meet
  the needs and to rectify any shortcomings in the
  process.
• Acts make the law rules help to govern the law.

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Regulation

• Regulation should be used to describe the
  instrument by which the power to make substantive
  law is exercised.

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Drugs and Cosmetics Rule Schedules

• The Drugs And Cosmetics Rules, 1945
• Consists 25 Schedules - Schedule A to Y
• Schedules License requirement,
• Forms
• Classification of drugs
• Guidelines General specific etc

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Schedules. You Should Know .

• Schedule A Application for license for import,
  manufacture, and sale of the drug and cosmetic,
  the forms in which the license is granted and
  renewed, and forms.
• Schedule C List of biological and immunological
  products, antibiotics and ophthalmic lotions and
  ointments, and other products for parenteral use
  (injection)
• Schedule H List of drugs that are to be sold by
  retail against the prescription of a registered
  medical practitioner and which shall be labelled
  with Rx words schedule H drugs.

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Schedules. You Should Know ..

• Schedule L1 Good Laboratory Practices And
  Requirements Of Premises And Equipment
• Schedule M Good manufacturing practice (GMP) and
  the requirements of premises, plant, and
  equipment for the manufacture of drugs
• Schedule P Life period and conditions of storage
  of drugs.
• Schedule S Standards for cosmetics.

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Schedules. You Should Know ..

• Schedule U Particulars to be shown in the
  manufacturing record, a record of the raw
  materials, and in the analytical records of the
  drugs
• Schedule W Name of drugs that shall be marketed
  under generic names only.
• Schedule X Names of psychoactive drugs that
  special control measures are laid down. The
  distributor should keep a duplicate of the
  prescription for two years.
• Schedule Y Requirements and guidelines on
  clinical trials for the import and manufacture of
  new drugs

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Schedule M1 M3 (old)

• Schedule M Good manufacturing practice (GMP) and
  the requirements of premises, plant, and
  equipment for the Pharmaceutical Products.
• Schedule M-1 GMP and Requirements of Premises,
  Plant and Equipment for Homoeopathic Medicines.
• Schedule M-2 is titled Requirements of Factory
  Premises for Manufacture of Cosmetics.
• Schedule M-3 is titled Quality Management System
  For Notified Medical Devices And In-Vitro
  Diagnostics.

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Schedule M ( Rules 71, 74, 76 and 78)

• Schedule M is a section of the Drugs and
  Cosmetics Act of 1940 that outlines the Good
  Manufacturing Practices (GMP) for
  pharmaceuticals in India.
• Pharmaceutical manufacturers must adhere to
  ensure the quality, safety and efficacy of their
  products.
• GMP is mandatory for all drug manufacturers and
  that a separate schedule should be added to the
  Drugs and Cosmetics Act for this purpose.
• Schedule M was revised to align with WHO ICH
  Guidelines.

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What is Manufacturing (Schedule M)

• Manufacture in relation to any Drug or Cosmetic
  includes any process or part of a process
• for making, altering, ornamenting, finishing,
  packing, labelling, breaking up or otherwise
  treating or adopting any drug or cosmetic sale or
  distribution
• but does not include the compounding or
  dispensing of any drug, or the packing of any
  drug or cosmetic, in the ordinary course of
  retail business and to manufacture shall be
  construed accordingly

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Existing Schedule M

• Existing Schedule M is divided in Two Parts
• Part I General Manufacturing Practices for
  Premises and Materials. In this each section is
  explained with certain requirements but not in
  specific details.
• Subparts are Part IA to Part IF -GMP for Specific
  product Types.
• Part II Requirements of Plant and Equipment

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Existing Schedule M Sub-Parts of Part-I.

• Existing Schedule M Sub Part under PART-I.
• Subparts are Part IA to Part IF GMP for
  Specific product Types.
• Parts 1A Sterile products, parenteral
  preparations and sterile ophthalmic
  preparations.
• Part 1 B Oral solid dosage forms. (Tablets And
  Capsules).
• Part 1 C Oral liquids. (Syrup, Elixirs,
  Emulsions And Suspensions).
• Part 1 D Topical products, i.e. External
  preparations (creams, ointments, pastes,
  emulsions, lotions, solutions).
• Part 1 E Metered-dose-inhalers.
• Part 1 F Active Pharmaceutical Ingredients
  (bulk drugs)

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Existing Schedule M Part-II

• Schedule M-Part II Requirements of Plant and
  Equipment
• External Preparations
• Oral Liquid Preparations
• Tablets
• Powders
• Capsules
• Surgical Dressing
• Ophthalmic Preparations
• Pressurizes and suppositories?
• Inhalers and vitrallae.
• Repacking of Drugs and Pharmaceutical Chemicals
• Parenteral Preparations

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Schedule M - Existing Vs Revised
Existing Schedule M Revised Schedule M
Existing Schedule M is divided in Two parts Revised Schedule M of 2023 is divided as Part- I to Part XIII
Part 1 Good Manufacturing Practices For Premises And Materials Each section is explained with certain requirements but not in specific details. Subparts are Part IA to 1F Part IF GMP for API -Specific product Types  Part 1 Good Manufacturing Practices For Pharmaceutical Products Main Principles. 20 SECTIONS PQS, QRM, GMP etc. It is mandatory to follow irrespective of product category. An Appendix I -Site Master File
29 Chapters General requirements Warehouse-SMF Part- II to Part XIII Specific to products (Part 1A-1F of old)

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Revised Schedule M for API
Existing Schedule M Revised Schedule M
Part 1 F Active Pharmaceutical Ingredients (bulk drugs) Part-XII Active Pharmaceutical Ingredients (Old Part -1F) Part- 1F 5 page, but Part XII is 28 pages GMP Guidance -ICH Q7 18 chapters are same
51 Pages (428-478) (pages -Indicative) 124 pages (GSR 999E) (pages -Indicative)
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Revised Schedule M for APIs Vs ICH Q7
GMP Guide for APIs -ICH Q7 Schedule M - Revised
ICH 19 Sections Glossary 18 Sections- all are similar to ICH Q7
Introduction 1.1 Objective .. should indicates recommendations or replaced by an alternative sterile APIs are not covered. Introduction 1.1 General All should in Q7 are changed as shall sterile -as per sterile product
1.2 This guide applies .. This part applies
Agents, Brokers, Traders, Distributors, Re-packers, and Re-labellers This section is removed. Other rules covered
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Schedule M - Existing Vs Revised
Existing Schedule M Revised Schedule M
Part II Requirements of Plant and Equipment External Preparations, Oral Liquid Preparations, Tablets, Powders, Capsules, Surgical Dressing, Ophthalmic Preparations, Pressurizes and suppositories Inhalers and vitrallae. Repacking of Drugs and Pharmaceutical Chemicals Parenteral Preparations  Part II to Part XII Specified requirements for manufacturing, as per product categories. E.g. Sterile products, Oral Solid dosage Forms etc. Additional 5 categories are added Part XIII Requirements of plant and equipment for manufacturing of 11 categories of Pharma products
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Revised Schedule M Other Parts

• Specific requirements for manufacture of
• Part-II Sterile Products, Small Large Volume
  Parentals, Ophthalmic Preparations. Pg.
  33-46 (Old Part -1A)
• Part-III Hazardous substances such as Sex
  Hormones,
• Steroids or Cytotoxic substances
  Pg. 46-52 (Addition)
• Part-IV Biological Products Pg. 52-63 (Addition)
• Part V Radiopharmaceutical Products Pg. 63-68
  (Addition)
• Part VI Phytopharmaceutical Products Pg. 68-77
  (Addition)

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Revised Schedule M Other Parts

• Part VII Investigational Pharmaceutical Products
  for Clinical Trials in Human. Pg.
  77-82 (Addition)
• Part VIII Oral Solid Dosage Forms. Pg.82-87 (Old
  Part -1B)
• Part-IX Oral Liquids. Pg 87-88 (Old Part -1C)
• Part-X External Preparations. Pg 88-89 (Old
  Part -1D)
• Part-XI Metered Dose-Inhalers. Pg 89-91 (Old
  Part -1E)
• Part-XII Active Pharmaceutical Ingredients (Old
  Part -1F)
• Part- 1F 5 page, but Part XII is 28 pages
• GMP Guidance -ICH Q7 18 chapters are same

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Revised Schedule M Part-1

• Part I GMP For Pharmaceutical Products Main
  Principles
• Pharmaceutical Quality System
• Quality Risk Management
• Good Manufacturing Practices for Pharmaceutical
  Products
• Sanitation and Hygiene
• Qualification and Validation
• Complaints
• Product Recalls
• Change Control Required
• Production under loan licence or contract and
  contract analysis and other activities
• Self Inspection, Quality Audit, Supplier Audit
  and approval

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Revised Schedule M Part-1

• Personnel training personal Hygiene
• Premises
• Equipment
• Materials
• Reference Standards
• Waste Materials
• Documentation-Documents
• Good practices in Production
• Good practices in Quality Control
• Computerized Systems Appendix- SMF

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1.0 Pharmaceutical Quality System (PQS)

• Establish Quality manual /document to describe
  the Organisation Quality Management system all
  elements like roles of production , quality
  management responsibility, MRM etc.
• Senior management shall involve to effective
  implementation of PQS.
• GMP / GXP should be applied to all stages of
  product life cycle.
• Product and process knowledge is managed
  throughout all lifecycle stages.
• production and quality control operations shall
  be clearly specified in a written form
• BPR Review batch release, in the investigation
  of deviations

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1.0 Pharmaceutical Quality System (PQS)

• Product realisation is achieved by designing,
  qualifying, planning, implementing, maintaining
  and continuously improving a system
• There is a procedure for self-inspection or
  quality audit that regularly appraises the
  effectiveness and applicability of the product
  quality system.
• Deviations, shall be reported, investigated and
  recorded appropriate level of root cause CAPA
  shall be applied followed by effectiveness of
  CAPA shall be monitored
• Periodic management reviews shall be conducted to
  identify opportunities for continual improvement
  of products, processes and PQS.

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2.0 Quality Risk Management-ICH Q9

• Evaluation of the risk to quality is based on
  scientific knowledge, experience with the process
  considering risk to the patients.
• The level of effort, formality and documentation
  of the Quality Risk Management process is
  commensurate with the level of risk
• Regular, periodic quality reviews of all
  pharmaceutical products, shall be conducted with
  the objective of verifying the consistency of the
  existing process to identify product and process
  improvements

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2.0 QRM-Product Quality Review PQR

• 2.3 Product Quality Review shall include
• Review of critical in-process controls.
• Review of QMS elements, OOS, Deviation,
  complaints, returns, recalls, changes etc
• Review of the results of the stability monitoring
  programme and any adverse trends.
• Review of qualification status of relevant
  equipment and utilities, e.g., heating,
  ventilation and air conditioning, water or
  compressed gases and a review of the results of
  monitoring the output of such equipment and
  utilities

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3.0 Good Manufacturing Practices

• All manufacturing processes are clearly defined,
  systematically reviewed for associated risks in
  the light of scientific knowledge and experience,
  and shown to be capable of consistently
  manufacturing pharmaceutical products of the
  required quality that comply with their
  specifications.
• Qualification and validation are performed.
• Procedures are carried out correctly and
  personnel are should be trained.
• The proper storage and distribution of the
  products which minimises any risk to their
  quality.
• System is available to recall any batch of
  product from sale or supply

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4.0 Sanitation and hygiene

• Sanitation covers personnel, premises, equipment
  apparatus, production materials and containers
• A high level of sanitation and hygiene shall be
  practiced in every aspect of the manufacture of
  drugs.
• The scope of sanitation and hygiene covers
  personnel, premises, equipment and apparatus,
  production materials and containers, and
  disinfection to prevent contamination .
• Potential sources of contamination shall be
  eliminated through an integrated comprehensive
  programme of sanitation and hygiene

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5.0 Qualification and Validation

• Revised Schedule-M Elaborated as below
• Detailed discussion about Design qualification
  (DQ) / installation qualification (IQ)/
  operational qualification (OQ) Performance
  qualification (PQ).
• Any aspect of operation, including significant
  changes to the premises, facilities, equipment or
  processes, which may affect the quality of the
  product, directly or indirectly, shall be
  qualified and validated.
• The commitment to maintain continued validation
  status shall be stated -Quality manual or
  validation master plan

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6.0 Complaints and Adverse Reaction

• Revised Schedule-M Elaborated from existing
• There shall be written procedures describing the
  action to be taken, including the need to
  consider a recall, in the case of a complaint
  concerning a possible product defect.
• 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.
• 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

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7.0 Product Recalls

• 7.0 Product recalls
• The licensing authorities shall be promptly
  informed of any intention to recall the product
  because it is, or is suspected of being
  defective.
• Traceability- Distribution
• Communication Coordination
• API manufacturer to formulator -
• Regulatory authorities
• Recall committee action plan
• Mock recall

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8.0 Change Control 9.0 Contract production
Testing

• 8.0 Change Control
• Changes in raw materials, specifications,
  analytical methods, facilities, support systems,
  equipment (including computer hardware),
  processing steps, labelling and packaging
  materials and computer software
• 9.0 Production under loan licence or contract
  and contract analysis and other activities
• GMP is Applicable, ..Describes Contract
  production Contract analysis
• Role and Responsibilities of Contract giver,
  Contract Acceptor
• Agreement, Batch release,T echnology Transfer,
  SCM, Distribution etc

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10. Self-inspection Quality audit

• 10 Self-inspection, quality audits and
  suppliers audits and approval
• Detect any shortcomings and implementation of
  CAPA
• Self-inspection team
• Frequency of Audit-performed routinely and in
  specific occasions I.e. recall or inspection by
  licensing authorities. At least once in a year
• Self-inspection report Follow-up action
• Suppliers audit and approval RM/PM

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11.0 Personnel

• The establish system of Quality Assurance (QA)
• Necessary qualifications and practical
  experience.
• Training, including hygiene instruction, relevant
  to their needs
• Organization chart, Role and responsibilities of
  QA, QC, Production,
• Key personnel for supervising the production and
  QAQC shall possess the qualifications and
  experience as specified under the rules
• Define authorised person for approving a batch
  for release

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Section 12.0 to 15.0

• 12. Premises General, storage area, Ancillary
  area, weighing area, production, and QC
• 13. Equipment
• 14. Materials
• 15. Reference Standards
• As described in WHO GMP / ICH Q7

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16. Waste materials

• Proper and safe storage of waste materials
  waiting disposal. Toxic substances and flammable
  materials shall be stored in suitably
• Collect in suitable receptacles for removal to
  collection points outside the buildings and
  disposed of safely and in a sanitary manner at
  regular and frequent intervals.
• The disposal of sewage and effluents (solid,
  liquid and gas) shall be in conform the
  requirements / Pollution Control Board.
• All bio-medical waste shall be destroyed as per
  Bio-Medical Waste Rules, 2016.
• Rodenticides, insecticides, fumigating agents and
  sanitising materials shall be ensured tp prevent
  contamination

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17. Documentation

• 17. Documentation
• Documents shall be approved, signed and dated by
  the responsible persons.
• SOPs
• Recording entry of data shall be clear, Spacious,
  legible and indelible.
• Specifications and testing procedure Raw
  Material, Starting and packaging materials,
  Intermediate finished products
• Master formula records Batch processing
  records
• Packaging instructions and Labels
• GDP

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18 Good Practices in Production

• Good Practices in Production
• Detailed requirements about Good practices in
  production, Deviation control,
• Processing Packaing Operations
• Measures for Prevention of cross contamination
• Timeline for storage of equipment after cleaning,
  
• Any significant deviation from the expected yield
  shall be recorded and Investigated,
• Line clearance for packaging operations

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19.0 Good Practices in Quality Control

• Establish the requirements for Good practices in
  QC
• Qualification and validation
• Control of starting materials, intermediate, and
  Finshed products
• Part testing, in case CoA from the reliable
  manufacturer,
• Batch record review
• Out-of-specification results shall be
  investigated in accordance with an approved
  procedure and record shall be maintained.
• Retention sample AS/SM FP, Retest/ expiry
  1year.
• Other materials Minimum of two years

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19.0 Good Practices in Quality Control

• GMP-related computerized systems shall be
  validated.
• Program for stability studies of finished
  products to establishing shelf life
• When requiredstarting materials and intermediate
  products,
• Stability shall be determined prior to marketing
  and following any significant changes e.g.
  changes in in-process, equipment's or packaging
  materials.

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20.0 Computerised System

• Ensure the adequate qualification for the
  suitability of computer hardware and software
• Sufficient controls to prevent unauthorised
  access or changes to data.
• Shall have controls to prevent omissions in data
  and audit trail
• Where critical data are being entered manually,
  there shall be an additional check by second
  person on the accuracy of the data
• Changes to the computerised system shall be
  through change control
• A back-up system shall be ensured to prevent loss
  of records

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Schedule M for APIs- ICH Q7

• I INTRODUCTION- SCOPE(1)
• II QUALITY MANAGEMENT (2)
• A. Principles (2.1)
• B. Responsibilities of the Quality Unit(s)
  (2.2)
• C. Responsibility for Production Activities
  (2.3)
• D. Internal Audits (Self Inspection) (2.4)
• E. Product Quality Review (2.5)
• III. PERSONNEL (3)
• A. Personnel Qualifications (3.1)
• B. Personnel Hygiene (3.2)
• C. Consultants (3.3)

IV. BUILDINGS AND FACILITIES (4)
A. Design and Construction (4.1)
B. Utilities (4.2) C. Water (4.3) D.
Containment (4.4) E. Lighting (4.5) V. PROCESS
EQUIPMENT (5) A. Design and Construction
(5.1) B. Equipment Maintenance and Cleaning
(5.2) C. Calibration (5.3) D. Computerized
Systems (5.4) Contd..
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Schedule M for APIs- ICH Q7

• VI. DOCUMENTATION AND RECORDS (6)
• Documentation System and Specifications 6.1)
• Equipment Cleaning and Use Record (6.2)
• Records of Raw Materials, Intermediates, API
  Labeling and Packaging Materials (6.3)
• Master Production Instructions (Master
  Production and Control Records) (6.4)
• VI. DOCUMENTATION AND RECORDS (6)
• Batch Production Records (Batch Production and
  Control Records) (6.5)
• Laboratory Control Records (6.6)
• Batch Production Record Review (6.7)

• VII. MATERIALS MANAGEMENT (7)
• General Controls (7.1)
• Receipt and Quarantine (7.2)
• Sampling and Testing of Incoming Production
  Materials (7.3)
• Storage (7.4)
• VIII. PRODUCTION AND IN-PROCESS CONTROLS (8)
• A. Production Operations (8.1)
• B. Time Limits (8.2)
• C. In-process Sampling and Controls (8.3)
• D. Blending Batches of APIs (8.4)
• E. Contamination Control (8.5)

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Schedule M for APIs- ICH Q7

• IX. PACKAGING AND IDENTIFICATION LABELING OF APIs
  AND INTERMEDIATES (9)
• General (9.1)
• Packaging Materials (9.2)
• Label Issuance and Control (9.3)
• Packaging and Labeling Operations (9.4)
• X. STORAGE AND DISTRIBUTION (10)
• A. Warehousing Procedures (10.1)
• B. Distribution Procedures (10.2)

XI. LABORATORY CONTROLS (11) A. General
Controls (11.1) B. Testing of Intermediates and
APIs(11.2) C. Validation of Analytical
Procedures See Section 12. (11.3) D.
Certificates of Analysis (11.4) E. Stability
Monitoring of APIs (11.5) F. Expiry and Retest
Dating (11.6) G. Reserve/Retention Samples(11.7)
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Schedule M for APIs - ICH Q7

• XIV. REJECTION AND RE-USE OF MATERIALS (14)
• Rejection (14.1)
• Reprocessing (14.2)
• Reworking (14.3)
• Recovery of Materials and Solvents (14.4)
• Returns (14.5
• XV. COMPLAINTS AND RECALLS (15)
• XVI. CONTRACT MANUFACTURERS (INCLUDING
  LABORATORIES) (16)
• XVII SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY
  CELL CULTURE OR FERMENTATION (17)
• XVIII. APIS FOR USE IN CLINICAL TRIALS (18)

• XII. VALIDATION (12)
• Validation Policy (12.1)
• Validation Documentation (12.2)
• Qualification (12.3)
• Approaches to Process Validation (12.4)
• Process Validation Program (12.5)
• Periodic Review of Validated Systems (12.6)
• Cleaning Validation (12.7)
• Validation of Analytical Methods (12.8)
• XIII. CHANGE CONTROL (13)

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• Thank You
• Dr. A. Amsavel