PART 1A: sterile products 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

Walls shall be flat & ledges and recesses can be avoided 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

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

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

Manufacturing process Include component washing machines, steam sterilizers, membrane filters, liquid & powder filling machine , sealing & labelling machines etc Equipment Potable water – microbiological specification(<500cfu/ml) & Absence of individual pathogens per 100ml used for preparation of purified water Steam coming in contact with products primary containers shall be sterile & pyrogen free Water and steam system Bulk raw materials monitored for bio-burden periodically A limit of not more than 100cfu/ml is recommended Finished products shall be filled in continuous operation with great care Manufacturing process

Sterilization Documentation Terminal sterilization(filling of products) - grade A Preparation of solution(sterilized by filtration) - grade C Sterilization process should be validated Biological/ chemical indicators – to monitor sterilization Documentation Records related to manufacture of products should be maintained

PART 1B: oral solid dosage forms 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

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

Filling of hard gelatin capsules Stored in conditions which ensure safety from effects of excessive heat & moisture Filling of hard gelatin capsules Special care must be taken to avoid product mix-up during printing Done using edible colors & suitable printing ink Printing(tablets & Capsules) Before packaging operation all ‘rogue’ tablets & capsules are removed Strips - inspected for defects such as misprint, cut on foil, missing tablets & improper sealing Packaging

PART 1C : oral liquid dosage forms 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 30ºC

PART 1D : topical preparations 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

Building & civil works: PART 1E : MDIs 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

Manufacture: Documentation : 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

Buildings & civil works: 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

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

For chemical reactions include: 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

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

External preparation: Basic installation area: 30sq.m PART II 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

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

Basic installation area :60sq.m(uncoated) 30sq.m(coated) 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: Mixing, granulation & drying section Tablet compression section Packaging section Coating section (wherever required)

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

Packaging section: Coating 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

Basic installation area: 30sq.m Equipments include: 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 Mixing & blending equipment Capsule filling unit Capsule counters & Polishing equipment

Basic installation area:30sq.m Equipments include: 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 Hot air oven Kettle Colloidal mill Tube filling equipment

Pessaries & suppositories: Basic installation area:20sq.m 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 Mixing equipment Graduated delivery equipment Sealing equipment of medicament during filling

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

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

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

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

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 powders and toothpastes

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

cGMP 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

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

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

Thank you -pharma street