GMP-Revised Schedule M for API- Dr. A. Amsavel.pdf

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

1. REVISED SCHEDULE -M
GOOD MANUFACTURING PRACTICES
Dr. A. Amsavel M.Sc., B.Ed., Ph.D.
1

2. 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
2

3. The Drugs and Cosmetics Act & Rules
The Drugs And Cosmetics Act, 1940
The Drugs And Cosmetics Rules, 1945 .
Rules established through the Drugs&CosmeticsAct
Enforcement of D & C Schedules started in 1947.
An Act to regulate the import, manufacture,
distribution and sale of drugs and cosmetics.
3

4. 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 5
th
Oct
2018 and was made available to the public on 9
th
Oct, 2018;
Notification for implementation-28
th
Dec, 2023
4

5. Bill, Act and Rule
A‘Bill’(Law) is theinitial phase of an Act,iea 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 acomprehensive frameworkfor the
implementation of laws
5

6. 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 anAct provides a broad legal framework, may not have
every minute detail,

Hence, enactment of Rulesrequiredthe 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.
6

7. Regulation
Regulation” should be used to describe the
instrument by which thepower to make
substantive law is exercised.
7

8. 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
8

9. 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.
9

10. 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.
10

11. 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
11

12. 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”.
12

13. 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.
13

14. 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
14

15. 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
15

16. ExistingSchedule 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)
16

17. ExistingSchedule M : Part-II
Schedule M-Part II Requirements of Plant and Equipment
1.External Preparations
2.Oral Liquid Preparations
3.Tablets
4.Powders
5.Capsules
6.Surgical Dressing
7.Ophthalmic Preparations
8.Pressurizes and suppositories
9.Inhalers and vitrallae.
10.Repacking of Drugs and Pharmaceutical Chemicals
11.Parenteral Preparations
17

18. 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)
18

19. Revised Schedule M –for API
ExistingSchedule M RevisedSchedule 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)
19

20. Revised Schedule M for APIs Vs ICH Q7
GMP Guide for APIs - ICH–Q7Schedule 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 guideapplies ….. Thispartapplies
17.Agents, Brokers, Traders,
Distributors, Re-packers, and Re-
labellers
Thissection is removed.
Other rules covered
20

21. Schedule M -Existing Vs Revised
ExistingSchedule M RevisedSchedule 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
21

22. 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 PhytopharmaceuticalProducts
Pg. 68-77 (Addition)
22

23. 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. Pg87-88 (Old Part -1C)
Part-X :External Preparations. Pg88-89 (Old Part -1D)
Part-XI :Metered Dose- Inhalers. Pg89-91 (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
23

24. Revised Schedule M: Part- 1
Part I: GMP For Pharmaceutical Products: Main Principles
1.Pharmaceutical Quality System
2.Quality Risk Management
3.Good Manufacturing Practices for Pharmaceutical Products
4.Sanitation and Hygiene
5.Qualification and Validation
6.Complaints
7.Product Recalls
8.Change Control Required
9.Production under loan licence or contract and contract analysis and
other activities
10.Self Inspection, Quality Audit, Supplier Audit and approval
24

25. Revised Schedule M: Part- 1
11.Personnel –training & personal Hygiene
12.Premises
13.Equipment
14.Materials
15.Reference Standards
16.Waste Materials
17.Documentation- Documents
18.Good practices in Production
19.Good practices in Quality Control
20.Computerized Systems &Appendix-SMF
25

26. 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
26

27. 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
.
27

28. 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
28

29. 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;
29

30. 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
30

31. 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 programmeof sanitation and
hygiene
31

32. 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
32

33. 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 pharmacovigilancesystem 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
33

34. 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
34

35. 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 Contractproduction & Contract analysis
Role and Responsibilities of Contract giver, Contract Acceptor
Agreement, Batch release,TechnologyTransfer, SCM, Distribution etc
35

36. 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
36

37. 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 QA&QC
shall possess the qualifications and experience as specified
under the rules
Define authorisedperson for approving a batch for release
37

38. 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
38

39. 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
39

40. 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, Intermediatefinished products
Master formula records & Batch processing records
Packaging instructions and Labels
GDP
40

41. 18: Good Practices in Production
Good Practices in Production
Detailed requirements about Good practices in
production, Deviation control,
Processing & PackaingOperations
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
41

42. 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
42

43. 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 requiredstartingmaterials 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.
43

44. 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
44

45. 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……..
Schedule M for APIs-ICH Q7

46. VI. DOCUMENTATION AND RECORDS (6)
A.Documentation System and Specifications
6.1)
B.Equipment Cleaning and Use Record (6.2)
C.Records of Raw Materials, Intermediates,
API Labeling and Packaging Materials (6.3)
D.Master Production Instructions (Master
Production and Control Records) (6.4)
VI. DOCUMENTATION AND RECORDS (6)
A.Batch Production Records (Batch
Production and Control Records) (6.5)
B.Laboratory Control Records (6.6)
C.Batch Production Record Review (6.7)
VII. MATERIALS MANAGEMENT (7)
A.General Controls (7.1)
B.Receipt and Quarantine (7.2)
C.Sampling and Testing of Incoming Production Materials (7.3)
D.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)
Schedule M for APIs-ICH Q7

47. IX. PACKAGING AND IDENTIFICATION LABELING
OF APIs AND INTERMEDIATES (9)
A.General (9.1)
B.Packaging Materials (9.2)
C.Label Issuance and Control (9.3)
D.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)
Schedule M for APIs-ICH Q7

48. XIV. REJECTION AND RE- USE OF MATERIALS (14)
A.Rejection (14.1)
B.Reprocessing (14.2)
C.Reworking (14.3)
D.Recovery of Materials and Solvents (14.4)
E.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)
A.Validation Policy (12.1)
B.Validation Documentation (12.2)
C.Qualification (12.3)
D.Approaches to Process Validation (12.4)
E.Process Validation Program (12.5)
F.Periodic Review of Validated Systems
(12.6)
G.Cleaning Validation (12.7)
H.Validation of Analytical Methods (12.8)
XIII. CHANGE CONTROL (13)
Schedule M for APIs -ICH Q7

49. Thank You
Dr. A. Amsavel
49