Good manufacturing practices- schedule

1. SCHEDULE m Jijo thomas m.Pharm Pharmaceutics College of pharmaceutical sciences Trivandrum

2. contents Introduction Schedule M Part I Part II Schedule M I Schedule M II Schedule M III

3. introduction 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. " 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

4. US FDA GMP Regulation :  Section 21 of the  CFR  contains most regulations pertaining to food and drugs 21 Code of Federal Regulations Part 210 : Current Good Manufacturing Practice in Manufacturing Processing, packing, or Holding of Drugs. 21 Code of Federal Regulations Part 211:   Current Good Manufacturing Practice for Finished Pharmaceuticals. ICH GMP Regulation: Q7 /Q&As Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

5. Gmp regulations IN INDIA GMP regulations were introduced in the form of amended schedule M in 1988. Again amended by Drug & Cosmetics Rules 2001 and embraces rules 71,74,76&78 under the D&C rules 1945 Each licensee shall evolve appropriate methodology systems and procedures, which shall be documented and maintained for inspection and reference. The manufacturing premises shall be used exclusively for production of drugs and not for any other manufacturing.

6. SCHEDULE M

7. PART -1 GMP for premises & materials

8. 1. General Requirements 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

9. 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

10. 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

11. 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

12. 2 . 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

13. 3. 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

14. 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.

15. 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.

16. 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

17. 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

18. 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

19. 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

20. 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.

21. 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

22. The status of the contents (e.g. Quarantine, under test, released, approved, rejected) The manufacturing date, expiry date and re-test date.

23. 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

24. 12. Documentation and Records 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

25. 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

26. 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.

27. 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

28. 15. Self inspection and Quality Audit It is for the assessment of all or part of a system with the specific purpose of improving it 15.1 The program is designed to detect shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections shall be performed routinely and on specific occasions The team responsible for self-inspection shall consist of independent, experienced, qualified persons from within or outside the company who can evaluate the implementation of GMP objectively; all recommendations for corrective action shall be implemented.

29. 16. Quality Control System Quality control shall be concerned with sampling, specifications, testing, documentation, release procedures Materials are not released for use, nor products released for sale or supply until their quality has been judged to be satisfactory 15.2 The procedure for self-inspection shall be documented indicating self-inspection results; evaluation, conclusions and recommended corrective actions with effective follow up program.

30. 16.1 QC lab should have qualified and experience staff 16.2 QC lab may be divided into Chemical, Instrumentation, Microbiological and Biological testing 16.3 The QC department shall conduct stability studies of the products to ensure and assign their shelf life. All records of such studies shall be maintained 16.4 All instruments shall be calibrated and validated before adopted for routine testing 16.5 Pharmacopoeia, reference standards, working standards, references spectra, other reference materials and technical books, as required, shall be available in the QC Laboratory

31. 17. Specification 17.1 For raw materials and packaging materials They shall include: The designated name and internal code reference Reference, if any, to a pharmacopoeial monograph Qualitative and quantitative requirements with acceptance limits Name and address of manufacturer or supplier and original manufacturer of the material Specimen of printed material Directions for sampling and testing or reference to procedures Storage conditions and Maximum period of storage before re-testing

32. 17.2 For finished products. Appropriate specifications for finished products shall include : The designated name of the product and the code reference The formula or a reference to the formula and the pharmacopoeial reference Directions for sampling and testing or a reference to procedures A description of the dosage form and package details The storage conditions and precautions, where applicable The shelf-life

33. 18. Master Formula Records There shall be Master Formula records relating to all manufacturing procedures for each product and batch size These shall be prepared and endorsed by head of production and quality control The master Formula shall include: the name of the product together with product reference code relating to its specifications the patent or proprietary name of the product along with the generic name, a description of the dosage form, strength, composition of the product and batch size name , quantity, and reference number of all the starting materials to be used

34. A statement of the processing location and the principal equipment to be used detailed stepwise processing instructions and the time taken for each step the instructions for in-process control with their limits the requirements for storage conditions of the products, including the container, labeling and special storage conditions where applicable any special precautions to be observed and packing details and specimen labels

35. 19. Packing Records There shall be authorised packaging instructions for each product, pack size and type These shall include or have a reference to the following : Name of the product Description of the dosage form, strength and composition The pack size expressed in terms of the number of doses, weight or volume of the product in the final container Special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before the operations begin.

36. 20. Batch Packaging Records A batch packaging record shall be kept for each batch or part batch processed It shall be based on the relevant parts of the packaging instructions, and the method of preparation of such records shall be designed to avoid transcription errors 21. BATCH PROCESSING R ECORDS There shall be Batch Processing Record for each product It shall be based on the relevant parts of the currently approved Master Formula The method of preparation of such records included in the Master Formula shall be designed to avoid transcription errors

37. 22. Standard Operating Procedures ( SOP s ) There shall be written SOP and records for the : Receipt of each delivery of raw, primary and printed material Internal labeling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate For each instrument and equipment Sampling which include the person(s) authorized to take the samples Describing the details of the batch numbering which ensure that each batch of intermediate, bulk or finished product is identified with a specific batch number Testing materials and products at different stages of manufacture, describing the methods and equipment to be used

38. 23. Reference Samples 23.1 Each lot of every active ingredient, in a quality sufficient to carryout all the tests, except sterility and pyrogens / Bacterial Endotoxin Test, shall be retained for a period of 3 months after the date of expiry of the last batch produced from that active ingredient 23.2 . Samples of finished formulations shall be stored in the same or simulated containers in which the drug has been actually marketed

39. 24. REPROCESSING AND RECOVERIES: Where reprocessing is necessary, written procedures shall be established & approved by quality assurance department Recovery of product residue may be carried out , if permitted, in the master production 25.DISTRIBUTION RECORDS: Records of distribution shall be maintained in a manner such that finished batch of a drug can be traced to the retain level to facilitate prompt and complete recall of the batch, if and when necessary

40. 26. VALIDATION AND PROCESS VALIDATION: The process employed has been optimized , so that data generated may be considered credible & evaluated for consistency as well as relevance Validation studies shall conducted as per the pre-defined protocols These shall include validation of processing, testing and cleaning procedures 27. PRODUCT RECALLS: A prompt and effective product recall system of defective products shall be devised for timely information of all concerned stockiest, wholesalers, suppliers, up to the retail level within the shortest period The licensee may make use of both print and electronic media in this regard

41. 28. COMPLAINTS AND ADVERSE REACTIONS: All complaints thereof concerning product quality shall be carefully reviewed and recorded according to written procedures Reports of serious adverse drug reactions resulting from the use of a drug along with comments and documents shall be reported to the concerned licensing authority

42. 29. SITE MASTER FILE: It contains specific and factual GMP about the production and/or control of pharmaceutical manufacturing preparations carried out in the licensed premises It shall contain the following :- General Information Personnel Premises Equipment Sanitation Documentation Production Quality Control Loan license manufacture and License Distribution , Complaints and Product recall Self Inspection & Export of Drugs

43. General : Sterile products being very critical & sensitive in nature , a high degree of precautions, prevention & preparations are needed Prescribed standards for supply of water, air, active materials, maintenance of hygienic conditions Buildings and civil works: Built of standardized material to avoid cracks in critical areas Manufacturing area clearly separated into support areas, preparation areas, change areas and aseptic areas PART 1A: sterile products

44. Aseptic area: Walls, floors and ceilings should be impervious, non-shedding & non-cracking Walls shall be flat & ledges and recesses can be avoided Ceilings shall be solid & joints shall be sealed No sinks & drains in grade A & grade B areas Doors made of aluminum or steel material & shall open towards high pressure area Separate exit space from the aseptic areas is advisable Change rooms to aseptic areas shall be clearly demarcated into black, grey & white rooms

45. Air handling system: Critical areas conforming to grade B,C & D have separate air handling units Grade Class Operations Grade A Class 100 Aseptic preparation& filling Grade B Class 1000 Background room conditions for activities requiring grade A Grade C Class 10000 Preparation of solution to be filtered Grade D Class 100000 Handling of components after washing

46. Environment monitoring: Recommended periodic monitoring include: Particulate monitoring in air - 6 monthly HEPA filter integrity testing – yearly Air change rates – 6 monthly Air pressure differentials – daily Temperature & humidity – daily Microbiological monitoring – daily Garments: Made of non-shedding & tight weave material Outdoor clothing shall not be brought into sterile areas Sanitation: Employees carrying out sanitation shall be trained Different sanitizing agents used in rotation Records of rotational use these agents to be maintained

47. General requirements: Enclosed dust control manufacturing system shall be employed Suitable environmental conditions maintained by installation of air- conditioning Effective air-extraction system shall be provided with discharge Filters to retain dust to protect the local environment Sifting, mixing & granulation: All equipments shall be fitted with dust extractors Critical operating parameters like time &temperature shall be specified in master formula PART 1B: oral solid dosage forms

48. Monitored during processing & recorded in batch records Granulation & coating solution- made, stored & used in a manner to minimize contamination Tablet compression: Compressing machine – effective dust control facilities Suitable labelling to prevent mix up of granules & tablets on compression machinery Tablets examined for appearance, wt. variation, disintegration, hardness, friability & thickness Tablet coating: Air provided with suitable exhaust system & environmental control Air supplied to coating pans shall be filtered & of suitable quantity

49. Layout & design of manufacturing area – minimize risk of contamination & mix-up Manufacturing area – entry through double door air-lock facility Parts of equipment – made of stainless steel Quality of purified water used shall be specified & monitored routinely Manufacturing personnel shall wear non- shedding clothing Primary packaging area – air supply filtered through 5 micron filters & temperature not exceed 30 º C PART 1C : oral liquid dosage forms

50. Suitable air-lock shall be provided at the entrance Manufacturing area – air shall be filtered & air conditioned These areas to be fitted with exhaust systems Equipments designed to prevent product contamination For cleaning or drying no rags or clusters to be used Water used in compounding – Purified Water IP Powders used must be properly sieved Separate packaging section – for primary packaging PART 1D : topical preparations

51. General: Manufacture of MDI - minimum microbial & particulate contamination Building & civil works: Located on a solid foundation to reduce risk of cracking walls & floors Environmental condition: Where products or clean components are exposed, the area shall be supplied with filtered air of grade C Equipment: Manufacturing equipment – closed system where vessels & supply lines are stainless steel PART 1E : MDIs

52. Manufacture: Approved master formula records are required for manufacture of MDI Primary packaging material – cleaned by compressed air filtered through 0.2 micron filter Filled containers shall be quarantined for a suitable period to detect leaking containers Documentation : Temperature & humidity in the manufacturing area Periodic filled weights of formulation Records of rejections

53. PART 1F : APIs Buildings & civil works: Manufacture of antibiotics, steroids & cytotoxic substances – carried out in confined areas to prevent contamination of other manufactured drugs Air filtration system – includes pre-filters & particulate matter retention air filters Sterile products: Filling of such products must be done aseptically Manufacture of sterile API must include- filtration, crystallization & lyophilization

54. Utilities / Services: Equipments used – serviced, cleaned & maintained at appropriate intervals So as to prevent mal- function or contamination of drug product Equipment design, size & location: Equipment used in manufacture, processing, packaging or holding of API shall be adequate size, appropriate design & Suitably located to facilitate operations for its intended use & for its cleaning & maintenance Equipments - cleaned between successive batches

55. In- process control: For chemical reactions include: Reaction time Reaction mass appearance Reaction temperature Concentration of reactant Assay or purity of the product For physical operations include: Appearance & color Uniformity of blend Temperature of a process Concentration of solution Processing rate or time

56. Product containers & closures: Should comply with pharmacopoeial specification Containers & closures shall be non-reactive, additive, adsorptive or leachable To an extent that affects quality or purity of the drug

57. External preparation: Basic installation area : 30sq.m Ancillary area : 10sq.m Equipments include: Mixing & storage tank(stainless steel) Jacketed kettle(stainless container) Mixer A colloidal mill or suitable emulsifier A triple roller mill Liquid filling equipment Tube filling equipment PART II

58. Oral liquid preparation: Basic installation area :30sq.m Ancillary area:10sq.m Equipments include: Mixing & storage tanks Jacketed kettle Portable stirrer A colloidal mill Filtration equipment Semi automatic filling machine Pilfer proof cap sealing machine Water distillation unit deionizer Clarity testing inspection unit

59. Tablets: Basic installation area :60sq.m(uncoated) 30sq.m(coated) Ancillary area :20sq.m(uncoated) 10sq.m(coated) Tablet production department classified into four sections:

60. Mixing, granulation & drying section: Disintegrator & sifter Powder mixer Granulator wherever required Thermostatically controlled hot air oven Weighing machines C ompression section: Tablet compression machine Punch & die storage cabinets Tablet de-duster Tablet inspection unit Dissolution test apparatus In-process testing apparatus Air conditioning & dehumidifier

61. Packaging section: Strip /blister packaging machine Leak test apparatus Tablet counters Air-conditioner & dehumidifier Coating section: Jacketed kettle Coating pan Polishing pan Exhaust system Air conditioner & dehumidifier Weighing balance

62. Powders: Basic installation area : 30sq.m Equipments include: Disintegrator Mixer (electrically operated) Sifter Stainless steel vessels Filling equipment Capsules: Basic installation area : 25sq.m Ancillary area :10sq.m Equipments include: Mixing & blending equipment Capsule filling unit Capsule counters & Polishing equipment

63. Surgical dressing: Basic installation area :30sq.m Equipments include: Rolling & trimming machine Cutting equipment Folding & pressing machine for gauze Mixing tanks for processing medicated dressing Hot air dry oven Steam or dry heat sterilizer Ophthalmic preparations : Basic installation area : 25sq.m Equipments include: Hot air oven Kettle Colloidal mill Tube filling equipment

64. Mixing & storage tanks Seitz filter or sintered glass filters Liquid filling equipment Autoclaves Pessaries & suppositories: Basic installation area :20sq.m Equipments include: Mixing & pouring equipment Molding equipment Weighing devices Inhalers : Basic installation area : 20sq.m Equipments include: Mixing equipment Graduated delivery equipment Sealing equipment of medicament during filling

65. Repacking of drugs & pharmaceutical chemicals: Basic installation area: 30sq.m Equipments include: Sifter Stainless steel vessels Weighing & measuring equipment Filling equipment Electrical sealing machine

66. Parenteral preparation: Basic installation area : 60sq.m(partitioned into suitable sized cubicles with air lock arrangement) Process of manufacture divided into: Preparation of containers & closures Preparation of solution Filling & sealing Sterilization & testing Equipments include : Manufacturing area : Storage equipment Washing & drying equipment

67. Dust proof storage cabinet Water still Preparation & mixing tanks and equipments Filtering equipment Hot air sterilizer Aseptic filling & sealing room : Benches for filling & sealing Bacteriological filters Filling & sealing unit under laminar flow General room: Inspection table Leak testing equipment Labelling & packaging unit Storage equipment including cold storage & refrigeration

68. SCHEDULE M-I Requirements of factory premises of homoeopathic preparations General Requirements: Location and Surroundings; Buildings; Water supply Health, Clothing and Sanitation of Workers; Medical Services, container management etc. comes under this. Requirements of Plant and Equipment: Mother tinctures and Mother solution Section- An area of 55 sq. meters is recommended for basic installations Potentisation Section- Method of potentisation will be adopted as specified in Homoeopathic Pharmacopoeia of India Vol.I

69. SCHEDULE M-II : Requirement of premises for manufacture of cosmetics General Requirements: Location and Surroundings; Buildings; Water supply; Health, Clothing and Sanitation of Workers; Medical Services etc Requirements of Plant and Equipment: Specifications are given for only certain cosmetic preparations like Powers Creams, lotions, emulsions, pastes, cleansing milks, shampoos, pomade, brilliantine, shaving creams, and hair-oils etc Nail Polishes and Nail lacquers Lipsticks and lip-gloss Depilatories Preparations used for Eyes Aerosol Alcoholic Fragrance Solutions Hair Dyes Toilet Soaps Tooth po wders and toothpastes

70. SCHEDULE M-III Requirements of factory premises for manufacture of medical devices General Requirements: Location and Surroundings; Buildings; Water supply; Health, Clothing and Sanitation of Workers; Medical Services etc comes under this Requirements for Manufacture Of Medical Devices: Shall be conducted bat the licensed premises, and the process of manufacture is divided into following separate operations/Sections- Moulding Assembling Raw Materials Storage Area Washing , drying and sealing area Sterilization Testing facilities

71. c GMP What is cGMP ? : Usually see “ cGMP ” – where c = current, to emphasize that the expectations are dynamic  In India it is established in 2000 & amended from July 2004 It is periodically reversed and updated

72. conclusion GMP is an important tool in quality control of drug products Legal regulation of GMP is important to control the quality of drugs manufactured with in the country

73. REFERENCES Manual on Drugs and Cosmetics; sixth edition; 2009 Schedule M: Good Manufacturing Practices And Requirements Of Premises, Plant And Equipment For Pharmaceutical Products. Gazette Of India Extraordinary, Part II -section 3, Sub-section (I) Ministry Of Health And Family Welfare (Department Of Health) Ansel’s Pharmaceutical Dosage forms and Drug Delivery system ;L . V. Allen et al. ; eight edition; Current good manufacturing practices and current good compounding practices;67-91 Quality Assurance of Pharmaceuticals; Good manufacturing practices and inspection; Volume – 2; WHO Encyclopedia of pharmaceutical technology; third edition; volume – 1;Good Manufacturing Practices(GMPs): An overview;1941-1994

74. THANK YOU