Schedule "M"

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“SCHEDULE M” (Good Manufacturing Practices):

Alok Ranjan Gaur M-Pharm 1 st year Pharmacology Department of Pharmacy Pranveer singh Institute of Technology Kanpur “SCHEDULE M” (Good Manufacturing Practices) By

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. "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. 2 Department of Pharmacy (PSIT) What is "GMP"

History:

The good manufacturing practices (GMP) guidelines are a means to assure this very quality of drugs. GMP regulation were introduced in the form of amended Schedule M in 1988. T he Schedule M has again been amended in a major way by the drug and cosmetics (8 th amendment) rules,2001 and embraces rules 71,74,76 and 78 under the Drug &Cosmetics Rules,1995. 3 Department of Pharmacy (PSIT) History

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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 Department of Pharmacy (PSIT)

Contents:

PART I- GMP for Premises and material, PART I(A)- Specific Requirements for manufacturing sterile products, SVPs & LVPs and sterile ophthalmic Preparations. PART I (B)- Specific requirement for Manufacture of oral Solid Dosage Forms (Tablet and capsule). PART I (C)- special requirement for manufacture of oral liquids (syrup, elixir, emulsion and suspension. 5 Department of Pharmacy (PSIT) Contents

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PART I (D)- Manufacture of External Preparation (Creams, Ointment, Paste, Emulsion, Lotion, solution, Dusting Powder and dental Products). PART I (E)- Specific Requirements for manufacturing of Metered dose inhalers. PART I (F)- Specific requirement of Premises, Plant and Material For manufacture of Bulk drugs. PART II- Specific Requirements of plant and Equipment. 6 Department of Pharmacy (PSIT)

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General Requirement Location and Surroundings Buildings and premises , Water system Disposal of waste Warehousing area Production area Ancillary areas Quality control area Personnel 7 Department of Pharmacy (PSIT) PART-I GMP FOR PREMISES AND MATERIALS

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Health ,Clothing and sanitation of workers Manufacturing operation and Control (precaution against mix-up and cross- contamination) Sanitation in the manufacturing premises Raw material Equipment Documentation and Records Labels and other printed material Quality assurance Self inspection and quality audit Quality control system 8 Department of Pharmacy (PSIT)

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● Specifications i . For raw materials and packaging materials. ii. For product containers and closures. ii. For in-process and bulk products. iv. For finished products. v. For preparation of containers and closures. ● Master Formula Records There shall be Master Formula records relating to all manufacturing procedures Formula shall include: - (a) the name of the product together with product reference code (b) the patent or proprietary name of the product along with the generic name, size; (c) name, quantity, and reference number of all the starting materials to be used. 9 Department of Pharmacy (PSIT)

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(d) a statement of the processing location, (e) the methods, or reference to the methods, equipments including cleaning, assembling, calibrating, sterilizing, (f) detailed stepwise processing instructions, (g) the instructions for in-process control; (h) the requirements for storage conditions of the products, ( i ) packing details and specimen label, ● Packing Records These shall include (a) name of the product; (b) description of the dosage form; (c) the pack size; (d) complete list of all the packaging materials; (e) description of the packaging operations; (f) details of in-process controls; 10 Department of Pharmacy (PSIT)

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● Batch Packaging Records, ● Batch Processing Records , ● Standard Operating Procedures (SOPs) and Records, regarding - a) Receipt of materials b) Sampling c) Batch Numbering d) Testing e) Records of Analysis f) Reference Samples g) Reprocessing and Recoveries h) Distribution records i ) Validation and process validation j) Product Recalls k) Complaints and Adverse Reactions . 11 Department of Pharmacy (PSIT)

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Site Master File a) General information, b) Personnel c) Premises d) Equipments e) Sanitation . f) Documentation g) Production h) Quality Control. i ) Loan licence manufacture and licensee j) Distribution, complaints and product recall. k) Self inspection. l) Export of drugs. 12 Department of Pharmacy (PSIT)

PART I (A) Requirement for Manufacture of sterile products SVPs & LVPs and Ophthalmic Premises:

Aseptic Area Air handling System (Central Air- Conditioning) Environmental monitoring Garments Sanitation Equipment Manufacturing processes Sterilization Documentation 13 Department of Pharmacy (PSIT) PART I (A) Requirement for Manufacture of sterile products SVPs & LVPs and Ophthalmic Premises

TABLE -I AIRBORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE OF STERILE PRODUCTS.:

14 Department of Pharmacy (PSIT) TABLE -I AIRBORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE OF STERILE PRODUCTS.

TABLE- II TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR ASEPTIC PREPARATIONS:

15 Department of Pharmacy (PSIT) TABLE- II TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR ASEPTIC PREPARATIONS

TABLE- III TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR TERMINALLY STERILIZED PRODUCTS.:

16 Department of Pharmacy (PSIT) TABLE- III TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR TERMINALLY STERILIZED PRODUCTS.

Environmental Monitoring:

Particulate monitoring in air . 6 Monthly. HEPA filter integrity testing (smoke testing) . Yearly Air change rates . 6 Monthly. Air pressure differentials . Daily. Temperature and humidity . Daily Microbiological monitoring by settle plates and/or swabs in aseptic areas- daily, and at decreased frequency in other areas. Note: The above frequencies of monitoring shall be changed as per the requirements and load in individual cases. 17 Department of Pharmacy (PSIT) Environmental Monitoring

TABLE-IV RECOMMENDED LIMITS FOR MICROBIOLOGICAL MONITORING OF CLEAN AREAS IN OPERATION.:

18 Department of Pharmacy (PSIT) TABLE-IV RECOMMENDED LIMITS FOR MICROBIOLOGICAL MONITORING OF CLEAN AREAS IN OPERATION. NOTE : (a) These are average values. (b) Individual settle plates may be exposed for not less than two hours in Grade B, C and D areas and for not less than thirty minutes in Grade A area.

Garments:

19 Department of Pharmacy (PSIT) ● Outdoor clothing shall not be brought into the sterile areas. ● The garments shall be made of non-shedding and tight weave material. ● Cotton garments shall not be used. The garments shall shed virtually no fibres or particulate matter. Garments

Sanitation:

20 Department of Pharmacy (PSIT) ● Employees carrying out sanitation of aseptic areas shall be trained specifically for this purpose. ● Different sanitizing agent shall be used in rotation and the concentrations of the same shall be as per the recommendations of the manufacturer. Records of rotational use of sanitizing agents shall be maintained. Sanitation

Equipments:

Department of Pharmacy (PSIT) 21 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 labelling machines, vacuum testing chambers, inspection machines. suitable and fully integrated washing sterilizing filling lines may be provided, depending upon the type and volume of activity. Equipments

Water and Steam system:

Department of Pharmacy (PSIT) 22 Potable water meeting microbiological specification of not more than 500 cfu /ml. Indicating absence of individual pathogenic microorganisms, Escherichia coli, Salmonella, Staphylococcus aureus and Pseudomonas aereuginosa per 100 ml. sample shall be used for the preparation of purified water. Water and Steam system

Manufacturing Process:

Department of Pharmacy (PSIT) 23 Manufacturing Process Bulk raw materials shall be monitored for bio-burden periodically. Bioburden of bulk solution prior to membrane filtration shall be monitored periodically and a limit of not more than 100 cfu per ml is recommended. The time between the start of the preparation of the solution and its sterilization or filtration through a micro-organism retaining filter shall be minimized.

Sterilization:

All the sterilization process shall be appropriately validated. The validity of the process shall be verified at regular intervals, but at least annually. The sterilizer shall be double ended to prevent mix-ups. Periodic bio-burden monitoring of products before terminal sterilization shall be carried out and controlled to limits specified for the product in the Master Formula. 24 Department of Pharmacy (PSIT) Sterilization

Documentation:

Serial number of the Batch Manufacturing Record. Name of the product Reference to Master Formula Record. Batch/Lot number Batch/Lot size. Date of commencement of manufacture and date of completion of manufacture. Date of manufacture and assigned date of expiry. Date of each step in manufacturing. Names of all ingredients with the grade given by the quality control department. Quality of all ingredients. Control reference numbers for all ingredients. Time and duration of blending, mixing, etc. whenever applicable. pH of solution whenever applicable. Filter integrity testing records 25 Department of Pharmacy (PSIT) Documentation

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Temperature and humidity records whenever applicable Records of plate-counts whenever applicable. Results of pyrogen and/or bacterial endotoxin & toxicity. Results of weight or volume of drug filled in containers. Bulk sterility in case of aseptically filled products. Leak test records. Inspection records. Sterilization records including autoclave leakage test records, load details, date, duration , temperature , pressure, etc. Container washing records. Total number of containers filled. Total numbers of containers rejected at each stage Theoretical yield, permissible yield, actual yield and variation thereof. 26 Department of Pharmacy (PSIT)

PART I (B) Specific Requirements for manufacture of oral solid dosage form:

General Requirements Sifting, Mixing and granulation Tablet compression Tablet coating Filling of hard gelatin capsule Printing of tablet and capsule Packaging (strip or blister) 27 Department of Pharmacy (PSIT) PART I (B) S pecific Requirements for manufacture of oral solid dosage form

PART I (C) Specific Requirements for manufacture of oral liquid dosage form (Syrup, Elixir, Emulsion and Suspension):

Building and equipments Purified water Manufacturing 28 Department of Pharmacy (PSIT) PART I (C) S pecific Requirements for manufacture of oral liquid dosage form (Syrup, Elixir, Emulsion and Suspension)

PART I-D SPECIFIC REQUIREMENTS FOR MANUFACTURE OF TOPICAL PRODUCTS i.e. EXTERNAL PREPARATIONS (CREAMS, OINTMENTS, PASTES, EMULSIONS, LOTIONS, SOLUTIONS, DUSTING POWDERS AND DENTAL PRODUCTS) :

The entrance to the area where topical products are manufactured should be through a suitable airlock. Outside the airlock, insect ocutors shall be installed. The air to this manufacturing area shall be filtered through at least 20µ air filters and shall be air-conditioned. The area shall be ventilated. The area shall be fitted with an exhaust system of suitable capacity to effectively remove vapours, fumes, smoke, floating dust particles. The equipment used shall be designed and maintained to prevent the product from being accidentally contaminated with any foreign matter or lubricant. No rags or dusters shall be used in the process of cleaning or drying the process equipment or accessories used. 29 Department of Pharmacy (PSIT) PART I-D SPECIFIC REQUIREMENTS FOR MANUFACTURE OF TOPICAL PRODUCTS i.e. EXTERNAL PREPARATIONS (CREAMS, OINTMENTS, PASTES, EMULSIONS, LOTIONS, SOLUTIONS, DUSTING POWDERS AND DENTAL PRODUCTS)

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Water used in compounding shall be Purified Water IP. Powders, wherever used, shall be suitably sieved before use. Heating vehicles and a base like petroleum jelly shall be done in separate mixing area in suitable stainless steel vessels, using steam, gas, electricity, solar energy, etc. A separate packing section may be provided for primary packaging of the products. 30 Department of Pharmacy (PSIT)

PART I-E SPECIFIC REQUIREMENTS FOR MANUFACTURE OF METERED-DOSE-INHALERS (MDI):

General Manufacture of Metered-Dose-Inhalers shall be done under conditions which shall ensure minimum microbial and particulate contamination. Building and Civil Works The building shall be located on a solid foundation to reduce risk of cracking walls and floor due to the movement of equipment and machinery. Environmental Conditions Where products or clean components are exposed, the area shall be supplied with filtered air of Grade C. 31 Department of Pharmacy (PSIT) PART I-E SPECIFIC REQUIREMENTS FOR MANUFACTURE OF METERED-DOSE-INHALERS (MDI)

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Documentation- In addition to the routine good manufacturing practices documentation, manufacturing records shall show the following additional information:- Temperature and humidity in the manufacturing area. Periodic filled weights of the formulation. Records of rejections during on line check weighing. Records of rejection during spray testing. 32 Department of Pharmacy (PSIT)

PART I-F SPECIFIC REQUIREMENTS OF PREMISES, PLANT AND MATERIALS FOR MANUFACTURE OF ACTIVE PHARMACEUTIAL INGREDIENTS (BULK DRUGS).:

Building and Civil Works Apart from the building requirements contained Part-I, General note, the active pharmaceutical ingredients facilities for manufacture of hazardous reactions, Beta- Lactum antibiotics. Steroids and Steroidal Hormones / Cytotoxic substances shall be provided in confined areas to prevent contamination of the other drugs manufactured. 33 Department of Pharmacy (PSIT) PART I-F SPECIFIC REQUIREMENTS OF PREMISES, PLANT AND MATERIALS FOR MANUFACTURE OF ACTIVE PHARMACEUTIAL INGREDIENTS (BULK DRUGS).

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Sterile Products. Sterile active pharmaceutical ingredient filled aseptically shall be treated as formulation from the stage wherever the process demands like crystallization , lyophilisation, filtration etc. ● Utilities / Services. Equipment like chilling plant, boiler, heat exchangers, vacuum and gas storage vessels shall be serviced, cleaned, sanitized and maintained at appropriate intervals to prevent mal-functions or contamination that may interfere with safety, identity, strength, quality or purity of the drug product. 34 Department of Pharmacy (PSIT)

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Equipment Design, Size and Location Equipment used in the manufacture, processing, packing or holding of an active pharmaceutical ingredient shall be of appropriate design, adequate size and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. 35 Department of Pharmacy (PSIT)

PART- II REQUIREMENTS OF PLANT AND EQUIPMENT :

External Preparations Oral liquid Preparation Tablets Powders Capsules Surgical dressing Ophthalmic preparation Repacking of Drugs and Pharmaceutical Chemicals Parenteral preparations Inhalers and vitrallae Parenteral preparations in glass containers,- 36 Department of Pharmacy (PSIT) PART- II REQUIREMENTS OF PLANT AND EQUIPMENT

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(1).External Preparation Mixing and storage tanks (stainless steel), Jacketted Kettle (steam, gas or electrically heated), Mixer (electrically operated) Planetary mixer A colloid mill or a suitable emulsifier. A triple roller mill or an ointment mill. Liquid filling equipment (electrically operated). Jar or tube filling equipment (electrically operated) Area. - A minimum area of 30 sq. m. for basic installation of ten square meters for Ancillary area is recommended. 37 Department of Pharmacy (PSIT)

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(2).Oral liquid Preparation s The following equipments are commended for the manufacture of oral/internal use preparations namely: - 1. Mixing and storage tanks (stainless steel), 2. Jacketted Kettle / Stainless steel tank (steam, gas or electrically heated). 3. Portable stirrer (electrically operated) 4. A colloid mill or suitable emulsifier (electrically operated) 5. Suitable filtration equipment (electrically operated) 6. Semi-automatic/automatic bottle filling machine 77 7. Pilfer proof cap sealing machine. 8. Water distillation unit or deioniser 9. Clarity testing inspection units. 38 Department of Pharmacy (PSIT)

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( 3). Tablets The tabletting section shall be free from dust and floating particles and may be air-conditioned. connected to a vacuum dust collector or an exhaust system. For effective operations, tablet production department shall be divided into four distinct and separate sections as follows: - (a) Mixing, Granulation and Drying section. (b) Tablet compression section. (c) Packaging section (strip/blister machine wherever required). (d) Coating section (wherever required). 39 Department of Pharmacy (PSIT)

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● The following electrically operated equipments are recommended for the manufacture of compressed tablets and hypodermic tablets, in each of the above sections, namely: - (a) Granulation-cum-Drying section (1) Disintegrator and sifter (2) Powder mixer (3) Mass mixer/Planetary mixer/Rapid mixer granulator. (4) Granulator (5) Thermostatically controlled hot air oven with trays (preferably mounted on a trolley)/Fluid bed dryer. (6) Weighing machines. (b) Compression section. (1) Tablet compression machine, single/multi punch/ rotatory . (2) Punch and dies storage cabinets. (3) Tablet de-duster (4) Tablet Inspection unit/belt. (5) Dissolution test apparatus (6) In-process testing equipment like single pan electronic balance, hardness tester, friability and disintegration test apparatus. (7) Air-conditioning and dehumidification arrangement (wherever necessary) 40 Department of Pharmacy (PSIT)

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(c) Packaging section. (1) Strip/blister packaging machine. (2) Leak test apparatus (vacuum system) (3) Tablet counters (wherever applicable) (4) Air-conditioning and dehumidification arrangement (where ever applicable). Area. - A minimum area of sixty square meters for basic installation and twenty square meters for Ancillary area is recommended for un-coated tablets. (d) Coating section, (1) Jacketted kettle (steam, gas or electrically heated for preparing coating suspension). 2) Coating pan (stainless steel) 3) Polishing pan (where applicable) 4) Exhaust system (including vacuum dust collector) 5) Air-conditioning and dehumidification arrangement. 6) Weighing balance. Area. - A minimum additional area of thirty square meters for coating section for basic installation and ten square meters for Ancillary area is recommended. 41 Department of Pharmacy (PSIT)

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( 4) Powders The following equipment is recommended for the manufacture of powders, (1) Disintegrator (2) Mixer (electrically operated) (3) Sifter. (4) Stainless steel vessels and scoops of suitable sizes. (5) Filling equipment (electrically operated). (6) Weighing balance. Area. - A minimum area of thirty square meters is recommended . ( 5)Capsules separate enclosed area suitably air-conditioned and dehumidified with an airlock arrangement shall be provided. The following equipment is recommended for filling Hard Gelatin Capsules, namely: - (1) Mixing and blending equipment (electrically or power driven). (2) Capsules filling units (preferably semi automatic or automatic filling machines). (3) Capsules counters (4) Weighing balance. (5) Disintegration test apparatus. (6) Capsule polishing equipment. 42 Department of Pharmacy (PSIT)

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(6) Surgical Dressing The following equipment is recommended for the manufacture of Surgical Dressings other than Absorbent Cotton Wool, namely:- (1) Rolling machine (2) Trimming machine (3) Cutting equipment. (4) Folding and pressing machine for gauze. (5) Mixing tanks for processing medicated dressing. (6) Hot air dry oven. (7) Steam sterilizer or dry heat sterilizer or other suitable equipment. (8) Work tables/benches for different operations Area. - A minimum area of thirty square meters is recommended to allow for the basic installations. 43 Department of Pharmacy (PSIT)

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(7) Ophthalmic Preparations. separate enclosed areas with airlock arrangement shall be provided. The following equipment is recommended for the manufacture under aseptic conditions of Eye-Ointment, Eye-Lotions and other preparations for external use, namely (1) Thermostatically controlled hot air ovens (preferably double ended). (2) Jacketted kettle/stainless steel tanks (steam, gas or electrically heated). (3) Mixing and storage tanks of stainless steel/Planetary mixer. (4) Colloid mill or ointment mill. (5) Tube filling and crimping equipment (semi-automatic or automatic filling. (6) Tube cleaning equipment (air jet type), (7) Tube washing and drying equipment, if required (8) Automatic vial washing machine. (9) Vial drying oven. (10) Rubber bung washing machine. (11) Sintered glass funnel, Seitz filter and filter candle (12) Liquid filling equipment (semi-automatic or automatic filling machines). (13) Autoclave ( preferably ventilator autoclave). (14) Air conditioning and dehumidification arrangement (15) Laminar airflow units. Area. - A minimum area of twenty-five square meters for basic installation and ten square meters for Ancillary area is recommended. 44 Department of Pharmacy (PSIT)

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(8) Pessaries and Suppositories ( i ) The following equipment is recommended for manufacture of Pessaries and Suppositories, namely: - (1) Mixing and pouring equipment (2) Moulding equipment. (3) Weighing devices. Area. - A minimum area of twenty square meters is recommended to allow for the basic installation. (ii) In the case of Pessaries manufactured by granulation and compression, the requirements as indicated under Item 3 of Tablet, shall be provided. (9). Inhalers and Vitrallae The following equipment is recommended for manufacture of inhalers and vitrallae , namely: - (1) Mixing equipment. (2) Graduated delivery equipment for measurement of the medicament during filling. (3) Sealing equipment. Area. - An area of minimum 20 square meters is recommended for the basic installations. 45 Department of Pharmacy (PSIT)

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(10) . Repacking of Drugs and Pharmaceutical Chemicals. The following equipment is recommended for repacking of drugs and pharmaceuticals chemicals, namely:- (1) Powder disintegrator (2) Powder sifter (electrically operated) (3) Stainless steel scoops and vessels of suitable sizes (4) Weighing and measuring equipment. (5) Filling equipment (semi-automatic / automatic machines). (6) Electric sealing machine. Area- An area of minimum 30 square meters is recommended for the basic installation. In case of operations involving floating particles of fine powder, a suitable exhaust system shall be provided. 46 Department of Pharmacy (PSIT)

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(11). Parenteral Preparations The whole operation of manufacture of parenteral preparations (SVP and LVP) in glass and plastic containers may be divided. 11.1 Parenteral preparations in glass containers,- (1) Water management area (2) Containers and closures preparation area (3) Solution preparation area (4) Filling, capping and sealing area (5) Sterilization area (6) Quarantine area (7) Visual inspection area (8) Packaging area Area. - A minimum area of one 150 square meters for the basic installation and an Ancillary area of 100 square meters for SVP are recommended. For LVP an area of 150 square meters each for the basic installation and for Ancillary area is recommended. 47 Department of Pharmacy (PSIT)

REFRENCES:

http://www.pharmabiz.com/article/detnews.asp?articleid=54668&sectionid envfor.nic.in/divisions/ csurv / biosafety /.../12.%20 Schedule %20M.PDF cdsco.nic.in/html/GMP/ ScheduleM (GMP). pdf www.irs.gov/efile/article/0,,id=185683,00.html ahmedabad.quikr.com/Consultants-for-GMP- Schedule - M -ISO13485-CE-Marking-W0QQAdIdZ66533207 48 Department of Pharmacy (PSIT) REFRENCES

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THANK YOU 49 Department of Pharmacy (PSIT)