Schedule M - GMP (Good Manufacturing Practices) and Requirements of Premises, Plant and Equipment

Schedule M

GMP (Good Manufacturing Practices) and Requirements of Premises, Plant and Equipment

In order to ensure production of quality drug formulation, it is necessary on the part of the manufacturer to follow well established and ethical approach involving different operations of manufacture. It was on several occasions discussed in professional meetings and conferences that there is a need for well set mandatary guidelines required to be followed by manufactures of different dosage formulations. It was with this background, Good Manufacturing Practices under Schedule M were made m~ndatory conditions for manufacturing operations of pharmaceutical formulations.

The quality of drug formulations is the sole responsibility of the manufacturer. He has to ensure the production of desired quality formulations and their stability until, the formulation reaches the consumer across the retailing counter. The Schedule M is covered under Rules 71, 74, 76 and 78 and is in two parts.

Part I deals with GMP relating to factory premises and materials.

Part II deals with requirement of plant and equipment.

PART I

Factory Premises and Materials (Salient Features)

General Requirements

Good location; free from contamination due to sewage, drain, fumes, dust, smoke, etc.; hygienic conditions; prevention of entry of insect/ rodents; interior surface of premises should be smooth; adequate lighting; proper ventilation; humidity control; underground drainage; concealed electrical and sanitary fittings in the premises; supply of pure water; regular cleaning and disinfection of premises; proper treatment of waste water; pollution control and disposal of pollutants.

Warehousing Area

Adequate area for orderly warehousing of various categories of materials; adapted to ensure good storage condition; protection from adverse weather conditions; separate earmarked areas in same warehouse for quarantine status; separate sampling area; segregation for storage of rejected, recalled or returned materials; safe and secure areas for NDPS and hazardous substances; safe storage of printed packaging material; separate dispensing areas for Beta lactum, sex hormones, cytotoxic substances and other special categories; regular checks and rodent control.

Sterile Products

Separate enclosed area with air locks; air supply through HEPA filters; routine microbial counts; laminar flow cabinets availability and access restricted only to authorized persons.

Working Space

Adequate space for orderly placement of equipment and material; and separate storage area for raw material "under test", "approved" and "rejected". The pipe-work, electrical fittings and ventilation openings should be properly designed.

Health, Clothing and Sanitation of Workers

The workers should be free from contagious diseases. It covers regular medical check-up facilities; proper toi let facility at a distance; personal cupboards and change room for workers.

Medical Services

First-aid facility; medical examination of workers and all other staff at the time of recruitment; periodic medical check-up of all staff members once in a year; services of physicians available at short notice, proper facilities for vaccinations, etc.

Sanitation in Manufacturing Premises

No accumulated waste; no dust particles as far as possible; proper disinfection and cleaning of premises and no stagnant water. The manufacturing premises should be used for specific purpose for which it is designed.

Equipment

Properly installed to achieve operational efficiency; good quality equipment to be used. The equipment used should be such to facilitate through cleaning; prevent physical and chemical change through contact and minimize contamination. The written instructions for utilization of equipment be provided and accuracy, precision should be maintained.

Raw Materials

Properly identified; analysed; containers of raw materials inspected for any damage; stored at optimum temperature; labeled properly; systematically sampled by quality control personnel; tested for compliance of required standards; released from quarantine by quality control personnel through written instructions; and rejected materials destroyed or returned back to the supplier.

Personnel

Manufacture under direct supervision of competent technical staff; separate Head for Q.C. laboratory; qualified and experienced personnel for Quality Assurance and Quality Control Operations; written duties assigned; adequate number of personnel; good laboratory practices and proper training of technical staff members.

Master Formula Records (MFR)

Licensee should maintain records relating to alI manufacturing procedures for each product and batch size to be manufactured. It also includes patent or proprietary status; name offormulation alongwith generic name if any; name, quantity, and reference number of starting materials; strength; dosage form; description; identification; composition; statement of processing location; step-wise processing instructions; in-process control; requirements for storage conditions; packaging details, etc.

Batch Packaging Records

It is based on relevant parts of packaging instructions. Transcription errors to be avoided; packaging equipment clean; planned packaging operations and proper maintenance of packaging records.

Batch Processing Records (BPR)

BPR for each product; clean equipment; name of product; number and batch being manufactured; dates and time of commencement of operation; significant intermediate stages; initials of operator of different steps of production; batch number; analytical control number; in-process control records; amount of product obtained; note on any deviation from master formula; addition of any recovered or reprocessed material.

Standard Operating Procedures (SOPs) and Records

SOP and records for receipts of each delivery of raw, primary and printed packing material; sampling; instrument and equipment; internal labeling; quarantine and storage; batch numbering; testing, records of analysis; equipment assembly and calibration; maintenance; cleaning and sanitation; personnel; pest control; complaints, and recalls made and returns received.

Manufacturing Operations and Controls

Competant technical staff supervision for weighing, measuring and other operations; nonsterile products free from E. coli and Salmonella microbes; conspicuously labelled with name, batch number, and other details; cross contamination avoided; and all process controls checked under master formula.

Reprocessing and Recovery

The reason for reprocessing should be specified, corrective measures for recovery should be spelt out only if permitted in Master Formula.

Product Containers

Compliance with pharmacopoeial requirements; cleaning procedures and sterilization procedure should be properly followed. There should be written schedule for programs for cleaning of container. When 1;lottles are not dried after washing, deionised water or de-ionised water be used for rinsing.

Labels and Other Printed Materials

Stored properly and separately; used as and when required and should not be inter-mixed.

Distribution Records

Records properly maintained; records of complaints, adverse reactions and other reactions from consumers are also maintained.

Quality Control System

Detailed instructions for quality control of raw materials and finished product; quality control for packaging and labeling; adequacy of storage, quality control procedure revised as and when possible and qualitative examination of returned products.

PART II

Plant and Equipment (Salient Features)

The Part II of Schedule M gives the details of the plant and equipment required for manufacture, quality control and quality assurance ofdifferent dosage forms. The specifications of equipl!1ents are also indicated. The details of requirements are categorized into 11 groups.

1. External Preparations

It covers ointments, emulsions, lo~ns, solutions, pastes, creams, dusting powders and other identical preparations.

(a) Minimum area: 30 square meters for basic installation and 10 square meters for anci llary area.

(b) Requirements: mixing and storage tanks, jacketed kettles of different types, electric mixer, planetary mixer, colloid mill, triple roller mill, liquid and tube filling equipments, etc.

2. Oral Liquid Preparations

It covers syrups, elixirs, emulsions and suspensions.

(a) Minimum area: 30 square meters for basic install .on -and 10 square meters for ancillary area;

(b) Requirements: SS mixing and storage tanks, jacketed kettles of different types, electric stirrer, electric colloidal mill, emulsifier, filtration equipment, bottle filling machine, cap sealing machine, de-ioniser or water distillation unit, clarity testing unit, etc.

3. Tablets

For effective production, tablet production department is divided into four sections

(i) Mixing, granulation and drying section

(ii) Tablet compression section

(iii) Packaging section (strip/blister)

(iv) Coating section

(a) Minimum area: A minimum of 60 square meters for basic installation and 20 square meters for ancillary area for un-coated tablets. For coated tablet, additional area of 30 square meters for coating section and 10 square meters for ancillary area.

(b) Requirements: Disintegrator, sifter, powder mixer, mass mixer, planetary mixer, rapid mixer granulator, granulator, hot air oven, weighing machines, compression machine (single, multi-punch, rotary), punches and dies storage cabinets, table de-duster, table insp~ction unit/belt, dissolution test apparatus, single pan balance, hardness tester, friability and disintegration test apparatus, strip/blister packaging machine, leak test apparatus, tablet counter, jacketed kettles of different types, SS coating pan, polishing pan, weighing balance, exhaust system and vacuum dust collector, air-conditioning system (wherever applicable), etc.

4. Powders

Area: Minimum 30 square meters; additional room for actual blending

Requirements: Disintegrator, electric mixer, sifter, SS vessels and scoops of suitable sizes, filling equipment, weighing balance, etc.

5. Capsules

Area: A separate enclosed area, suitably air-conditioned and dehumidified. A minimum area of 25 square meters for basic installation and 10 square meters for ancillary area each for penicillin and non-penicillin section.

Requirements (for hard gelatin capsules): Electrical mixing and blending equipment, capsule filling units (semi-automatic and automatic), capsules counters, weighing balance, disintegration test apparatus, capsule polishing equipment, etc.

6. Surgical Dressings

Area: Minimum 30 square meters for basic installation; for medicated dressing additional room required.

Requirements: Rolling, staining, cutting, folding and pressing machines; mixing tanks, hot air oven, steam sterilizer, work tables, etc.

7. Opthalmic Preparations

It includes eye-ointment, eye lotions and other preparations for external use. Separate enclosed areas with air-lock arrangements required.

Area: Minimum 25 square meters for basic installation and 10 square meters for ancillary area;

Requirements: Hot air ovens, jacketed kettles of different types, colloid mill, ointment mill, SS-mixing and storage tanks; tube washing, drying, cleaning and filling machines; automatic vial washing machine, vial drying machines, sintered glass funnels, autoclave, liquid filling equipment, laminar flow units, air conditioning and dehumidification arrangement. rubber bung washing machine, etc.

8. Pessaries and Suppositories :

Area: Minimum 25 square meters for basic installation

Requirements: Mixing, pouring and moulding equipments; weighing devices. For pessaries manufactured by granulation and compression, requirements shall be as given under "tablet".

9. Inhalers and Vitrallae

Area: Minimum 25 square meters for basic installation

Requirements: Mixing, graduated delivery and sealing equipments

10. Repacking of Drugs and Pharmaceuticals

Area: Minimum 30 square meters for basic installation. Exhaust system be provided in case of operations involving floating particles.

Requirements: Weighing, measuring and fillingequipments; powder disintegrator, electrically operated powder sifter, electric sealing machine, SS scoops and vessels, etc.

11. Parenteral Preparations

The whole operation of manufacture (small volume injectables and large volume parenterals) in glass and plastic preparations are divided in separate areas/rooms.

Parenteral Preparations in glass containers :

It includes areas for water management, containers, closures preparation, solution preparation, filling, capping, sealing, sterilization, quarantine, visual inspection and packaging.

Area: Minimum 150 square meters for basic installation and 100 square meters for ancillary area for small volume injectables.

Requirements: Distillation unit, de-ionised water unit, thermostatically controlled water storage tank, transfer pumps, SS service lines for carrying water, automatic rotary ampoule/ vial/bottle washing machine, automatic closures, washing machine, dryer, double ended sterilizer; storage equipment for ampoules, vials, bottles and closures, SS benches/stools, dust proof storage cabinets, mixing SS tanks, portable stirrer, filtration equipment, transfer pumps, automatic ampoule/vial/bottle filling, capping, sealing machines under laminar air flow work station; gas lines for nitrogen, oxygen and carbon dioxide; steam sterilizer, hot air sterilizer, storage cabinets, visual inspection units, batch coding, machine labeling unit, pressure leak test apparatus, etc.

For large volume parenterals the mll1lmUm area required is 150 square meters each for basic installation and ancillary area.

Parenteral Preparations in Plastic Containers by Form - Fill- Seal/Blow, Fill- Seal technology

The operational activjties are in separate areas for water management, solution preparation, container-moulding-cum-filling, sealing, sterijization, quarantine, visual inspection and packaging.

Area: Minimum 250 square meters for basic installation and 150 square meters for ancillary area. Areas for formulations meant for external and internal uses shall be separately provided. A minimum of 100 squares meters be provided for packaging materials for large volume parenterals.

Requirements: De-ionised water treatment unit, distillation unit (multi-column with heat exchangers), thermostatically controlled water storage tank, transfer pumps, SS service lines for car'tying water, storage tanks, solution preparation tanks, transfer pumps, cartridge and membrane filters, steril form-fill-seal machine, plastic granules feeding device, super-heated steam sterilizer, adequate number of platforms, racks for storage, visual inspection unit, pressure leak test apparatus, batch coding machine, labelling unit, etc.