1. “Good Manufacturing Practices”
SCHEDULE M
“Good Manufacturing Practices”
contents
Introduction
Schedule M
Part I- GMP for Premises and material
Part II- Specific requirements of plant and equipment.
Schedule M I
Schedule M II
Schedule M III .

2. INTRODUCTION GMP regulations IN INDIA
GMP regulations were introduced in the form of amended schedule M in
Again amended by Drug & Cosmetics Rules 2001 and embraces rules 71,74,76&78 under the D&C rules 1945
"GMP" - A set of principles and procedures which, when followed by manufacturers for therapeutic goods, helps ensure that the products manufactured will have the required quality

3. What is “GMP”???
GMP is that part of Quality assurance which ensures that the products are consistently manufactured and controlled to the Quality standards appropriate to their intended use.
Schedule “M” Requirement of factory premises, plant and equipments for pharmaceutical products,
M-1 Requirement of factory premises for manufacturing of homeopathic preparations,
M-2 Requirement of factory premises for manufacturing of cosmetics,
M-3 Requirement of factory premises for manufacturing of medical devices.

4. Schedule M PART -1: GMP for premises & materials
Specific requirements for manufacture of sterile products, parenteral preparations, & sterile ophthalmic preparation
Part 1A
Specific requirements for manufacture of oral solid dosage forms
Part 1B
Specific requirements for manufacture of oral liquids
Part 1C
Specific requirements for manufacture of topical preparations
Part 1D
Specific requirements for manufacture of metered dose inhalers (MDI)
Part 1E
Specific requirements for manufacture of active pharmaceutical ingredients (bulk drugs)
Part 1F

5. Specifications should be made for…
For raw materials and packaging materials.
For product containers and closures.
For in-process and bulk products.
For finished products.
For preparation of containers and closures.

6. Part I: GMP for Premises and Materials1.
General requirement 2.
Warehousing area 3.
Production area 4.
Ancillary area 5
QC area 6
Personnel 7
Health ,clothing sanitation of workers 8
Mfg operations and controls 9
Sanitation in Mfg premises 10
Raw materials 11
Equipments 12
Documentation and records 13
Labels and printed materials 14 QA 15
Self inspection and Quality Audit 16
QC system 17
Specification 18
Master formula Record 19
Packaging Records 20
Batch Packaging Records 21
Batch Processing Records 22
SOP and records 23
Reference sample 24
Reprocessing and Recoveries 25
Distribution Records 26
Validation & process Validation 27
Product Recalls 28
Complaints & adverse Reactions 29
Site master Files

7. Part II: Specific requirements of plant and equipment1.
External preparation 2.
Oral liquid preparation 3.
Tablets 4.
Powders 5
Capsules 6
Surgical dressing 7
Opthalmic preperations 8
Pessaries and suppositories 9
Inhelars and vitrallae 10
Repakageing g drugs and pharmaceutical chemicals 11
Parentral preperations

8. Schedule M Part I General requirement Location and surrounding
1.1 . Location and surroundings: The factory building(s) for manufacture of drugs shall be so situated that it avoid risk of contamination from external environmental including open sewage, drain, public lavatory 1.2. Building and premises : Buildings shall be designed, constructed, adapted and maintained to permit production of drugs under hygienic conditions They shall conform to the conditions laid down in the Factories Act, 1948 The premises used for manufacturing, processing, warehousing, packaging, labeling and testing purposes shall be compatible with other drug manufacturing operations adequate working space to avoid the risk of mix-up between different materials & avoid the possibilities of contamination and cross contamination designed / constructed / maintained to prevent entry of insects, pests, birds, and rodents Well illuminated, effectively ventilated, with proper Air Handling Units
General requirement
Location and surrounding
Building and premises
Water system
Disposal of Waste

9. Schedule M Part I General requirement Location and surrounding
1.3 Water System: There shall be validated system for treatment of water in accordance with standards specified by the Bureau of Indian Standards or Local Municipality or Pharmacopoeial specification Water shall be stored in tanks, which do not adversely affect quality of water and ensure freedom from microbiological growth The tank shall be cleaned periodically and records maintained by the licensee in this behalf 1.4. Disposal of waste The disposal of sewage and effluents (solid, liquid and gas) be in conformity with the requirements of Environment Pollution Control Board All bio-medical waste shall be destroyed as per the provisions of the Bio-Medical Waste (Management and Handling) Rules, 1996 Records shall be maintained for all disposal of waste Provisions shall be made for the proper and safe storage of waste materials awaiting disposal
General requirement
Location and surrounding
Building and premises
Water system
Disposal of Waste

10. Schedule M Part I Warehousing Area Production area
Warehousing Area 2.1 Adequate areas to allow orderly warehousing of various categories of materials. 2.2 Good storage conditions 2.3 There shall be a separate sampling for active raw materials and excipients 2.4. Segregation shall be provided for the storage of rejected, recalled or returned materials or products 2.5 Highly hazardous, poisonous and explosive materials shall be stored in safe and secure areas Production area 3.1. Separate dedicated and self-contained facilities shall be made available for the production of sensitive pharmaceutical products 3.2. Orderly and logical positioning of equipment and materials and movement of personnel to minimize risk of omission or wrong application of any manufacturing and control measures 3.3. Services lines shall preferably be identified by colours and the nature of the supply and direction of the flow shall be marked/indicated
Warehousing Area
 Production area

11. Schedule M Part I 4. Ancillary Areas 5. Quality Control Area.
4. Ancillary Areas 4.1 Rest and refreshment rooms shall be separate from other areas. Facilities for changing, storing clothes and for washing and toilet purposes shall be adequate for the number of users. 4.2 Animal houses shall be those as prescribed in Rule 150-C(3) of the Drugs and Cosmetics Rules, 1945 which shall be adopted for production purposes. 5. Quality Control Area 5.1. QC Lab shall be independent of the production areas. Separate areas each for physico-chemical, biological, microbiological or radio-isotope analysis 5.2 Adequate space shall be provided to avoid mix-ups and proper storage for test samples, retained samples, reference standards, reagents and records.
4. Ancillary Areas
5. Quality Control Area.

12. Schedule M Part I 6. Personnel
6. Personnel 6.1. Qualifications and practical experience in the relevant field 6.2. Written duties of technical and Quality Control personnel shall be laid and follow strictly 6.3. Number of personnel employed shall be adequate and in direct proportion to the workload 7. Health, clothing and sanitation of workers 7.1 Prior to employment, all personnel, shall undergo medical examination and a periodically examination is carried out, records are also maintained 7.2 Proper training shall be given to all employees to maintain personnel hygiene and adequate facilities for personal cleanliness 7.3 Smoking, eating, drinking, chewing , food, drink and personal medicines not permitted in production, laboratory, storage area
6. Personnel
7. Health, clothing and sanitation of workers

13. Schedule M Part I 8. Manufacturing Operations and Controls
8.1 All manufacturing operations shall be carried out under the supervision of technical staff approved by the Licensing Authority
8.2. Precautions against mix-up and cross contamination-
By proper air handling system, pressure differential, segregation, status labelling and cleaning. Proper records and SOP there of shall be maintained.
Processing of sensitive drugs and cytotoxic substances in segregated areas
Proper labeling of materials and equipments
Packaging lines shall be independent and adequately segregated
All printing and overprinting shall be authorized in writing
The manufacturing environment maintained at the required levels of temperature, humidity and cleanliness
Schedule M Part I
8. Manufacturing Operations and Controls

14. Schedule M Part I 9. Sanitation in the Manufacturing Premises
9.1 The manufacturing premises shall be cleaned and in an orderly manner
9.2 The manufacturing areas shall not be used for other operations
9.3 A routine sanitation program shall be drawn up which shall be properly recorded and which indicate–
specific areas to be cleaned and cleaning intervals
cleaning procedure to be followed
personnel assigned to and responsible for the cleaning operation.
10. Raw Materials
10.1 Keeping an inventory of all raw materials to be used and maintain records as per Schedule U
10.2 Authorized staff who examine each consignment for its integrity
10.3 Labeling with the following information:
Name of the product and the internal code reference and analytical reference number
Manufacturer’s name, address and batch number
The status of the contents (e.g. Quarantine, under test, released, approved, rejected)
The manufacturing date, expiry date and re-test date.
9. Sanitation in the Manufacturing Premises
10. Raw Materials

16. Schedule M Part I 11. Equipment 12. Documentation and Records
11. Equipment 11.1 Equipment shall be located, designed, constructed, adapted to suit the operations and log book is maintained 11.2 Equipment shall be calibrated and checked on a scheduled basis in accordance to SOP and maintain records 11.3 Equipment shall be inert and defective are removed and labeled 12. Documentation is an essential part of the Quality assurance system and Its aim is to define the specifications for all materials, method of manufacture and control to release a batch of drug for sale 12.1 Documents shall be approved, signed and dated by authorized persons 12.2 Documents shall specify : the title, nature and purpose laid out in an orderly fashion & kept up to date 12.3 SOP shall be retained for at least one year after the expiry date of the finished product 12.3 Data may be recorded by electronic data processing systems but Master Formulae and detailed operating procedures relating to the system in use shall also be available in a hard copy to facilitate checking of the accuracy of the records
11. Equipment
12. Documentation and Records

17. Schedule M Part I 13. Labels and other Printed Materials
13. Labels and other Printed Materials Labels are necessary for identification of the drugs and their use. The Printing shall be done in bright colours and in a legible manner The label shall carry all the prescribed details about the product 13.1 All containers and equipment shall bear appropriate labels 13.2 Prior to release, all labels for containers shall be examined by the QC Department 13.3 Records of receipt of all labeling and packaging materials shall be maintained and unused coded, damaged labels and packaging materials shall be destroyed and recorded. 14. Quality Assurance It is a wide-ranging concept concerning all matters that individually or collectively influence the quality of a product It shall ensure that: - The pharmaceutical products are designed and developed in a way that takes account of the requirement of GMP ,GLP and GCP Adequate controls on starting materials, intermediate products, and other in-process controls, calibrations, and validations are carried out Products are released after authorized persons have certified
13. Labels and other Printed Materials
14. Quality Assurance

20. 1. GENERAL
Sterile products, being very critical and sensitive in nature, a very high degree of precautions, prevention and preparations are needed to ensure aseptic conditions in all areas.
2. BUILDING AND CIVIL WORKS
Proper foundation is maintained to avoid any cracks. The manufacturing area is separated into different areas like
Washing area.
Component preparation area.
Storage area.
Preparation area – Blending Manufacturing Area. Non aseptic Area etc.

21. 3. AIR HANDLING SYSTEM (CENTRAL AIR-CONDITIONING)
Air Handling Units for sterile product manufacturing areas shall be different from those for other areas.
Critical areas, such as the aseptic filling area, sterilized components unloading area and change room conforming to Grades B, C and D respectively shall have separate air handling units.
The filling, manufacture, filter configuration, and terminal sterilization in the air handling system shall be suitably designed to achieve the Grade of air.
Unless there are product specific requirements, temperature and humidity in the aseptic areas shall not exceed 27°C and relative humidity 55%, respectively.

22. Airborne Particulate Classification For Manufacture
Of Sterile Products.
Types Of Operations To Be Carried Out In The Various
Grades For Aseptic Preparations

23. Types Of Operations To Be Carried Out In The Various
Grades For Terminally Sterilized Products

24. 4. ENVIRONMENTAL MONITORING
All environmental parameters shall be verified and established at the time of installation and thereafter monitored at periodic intervals and recorded.
The recommended frequencies of periodic monitoring shall be as follows :-
Particulate monitoring in air
6 Monthly
HEPA filter integrity testing (smoke testing)
Yearly
Air change rates.
Air pressure differentials.
Daily.
Temperature and humidity
Daily
Microbiological monitoring by settle plates and/or swabs in aseptic areas

25. 5) GARMENTS
Only clean, sterilized and protective garments shall be used at each work session where aseptic filtration and filling operations are undertaken.
The garments shall be made of non-shedding and tight weave material.
Cotton garments shall not be used.
Garments shall be single piece with fastenings at cuffs, neck and at legs to ensure close fit.
Footwear should be suitably plastic or rubber material and cleaned with bactericide.
Safety goggles and numbered glass should be sanitized.

26. 6) SANITATION
This includes written procedures for sanitation which is performed by trained employee.
Distilled water acquired from plant at 70°C or alcohol or isopropyl alcohol may be used in dilution of disinfectant.
Diluted disinfectants shall bear the label “use before”, based on microbiological establishment of the germicidal properties.
The solutions shall be adequately labeled and documents maintained
Formaldehyde may be used normally for fumigation of aseptic area.
Cleaning of sterile processing facilities shall be undertaken with air suction devices or with non-linting sponges or clothes.

27. 7) EQUIPMENT
The special equipment required for manufacturing sterile products includes component washing machines, steam sterilizers, dry heat sterilizers, membrane filter assemblies, manufacturing vessels, blenders, liquid filling machines, powder filling machines, sealing and labeling machines, vacuum testing chambers, inspection machines, lyophilisers, pressure vessels etc. may be provided with SOP, depending upon the type and volume of activity.
The construction material used - stainless steel 316 or Boro-silicate glass (if glass containers) and the tubing shall be capable of being washed and autoclaved.
Installation qualification should be performed.

28. 8) MANUFACTURING PROCESS
Manufacture of sterile products shall be carried out only in areas under defined conditions.
Gases coming in contact with the sterile product shall be filtered through two 0.22 µ hydrophobic filters connected in-series.
Each lot of finished product shall be filled in one continuous operation. In each case, where one batch is filled in using more than one operation, each lot shall be tested separately for sterility and held separately till sterility test results are known.
Special care shall be exercised while filling products in powder form so as not to contaminate the environment during transfer of powder to filling machine-hopper.

29. Terminally sterilized products.
Preparation of primary packaging material such as glass bottles, ampoules and rubber stoppers shall be done in at least Grade D environment.
All the process used for component preparation shall be validated.
Filling of products requiring terminal sterilization shall be done under
Grade A environment with a Grade C background.
Preparation of solutions, which are to be sterilized by filtration, shall be done in Grade C environment, and
The preparation of materials and products shall be in a Grade A environment with Grade B in background.

30. NOTE:
Glass bottles-Glass bottles made of USP Type-I and USP Type-II glass shall only be used
Plastic containers
Rubber closures
Care should be taken that above materials should comply with standard specifications

31. 9) Documentation
The manufacturing records relating to manufacture of sterile products shall indicate the following details:-
(1) Serial number of the Batch Manufacturing Record.
(2) Name of the product
(3) Reference to Master Formula Record.
(4) Batch/Lot number
(5) Batch/Lot size.
(6) Date of commencement of manufacture and date of completion of
manufacture.
(7) Date of manufacture and assigned date of expiry.
(8) Date of each step in manufacturing.
(9) Names of all ingredients with the grade given by the quality control department.
(10) Quality of all ingredients.

32. (11) Control reference numbers for all ingredients
(11) Control reference numbers for all ingredients. (12) Time and duration of blending, mixing, etc. whenever applicable. (13) pH of solution whenever applicable. (14) Filter integrity testing records (15) Temperature and humidity records whenever applicable (16) Records of plate-counts whenever applicable. (17) Results of pyrogen and/or bacterial endotoxin & toxicity. (18) Results of weight or volume of drug filled in containers. (19) Bulk sterility in case of aseptically filled products. (20) Leak test records. (21) Sterilization records including autoclave leakage test records, load details,date, duration, temperature, pressure, etc.

33. (22) Total number of containers filled
(22) Total number of containers filled. (23) Total numbers of containers rejected at each stage (24) Environmental monitoring records. (25) Specimens of printed packaging materials. (26) Records of destruction of rejected containers printed packaging and testing. (27) Signature of competent technical staff responsible for manufacture and testing.

34. Master Formula Records
There shall be master formula records relating to all manufacturing procedures formula shall include: -
The name of the product together with product reference code.
The patent or proprietary name of the product along with the generic name, size.
Name, quantity, and reference number of all the starting materials to be used.

35. REFERENCES
Gazette Of India Extraordinary, Part II-section 3, Sub- setion [(I)] Ministry Of Health And Family Welfare(department Of Health) New Delhi, The 11 December, 2001

36. THANK YOU -PHARMA STREET