Essentials of Good Manufacturing Practices (GMP) in Homoeopathy

Dr Juthika Gogoi 

Good Manufacturing Practice is a system for ensuring that the practices required in order to conform to the guidelines recommended by agencies that control the authorization and licensing for the production, pharmaceutical products which is controlled according to quality standards.

It helps to minimise the risks involved in any pharmaceutical production that cannot be eliminated through testing the final products.

It is included in the SCHEDULE M-1 of the Drugs and Cosmetics Rules, 1945 [Rule 85-E(2)].

Central government has notified the draft of rules for GMP.

The draft is notified in consultation with Drugs Technical Advisory Board and was notified on 2^nd August 2005.

Draft rules are divided into 11 parts:

1. General requirements.

1. Locations and surroundings:

• The premises shall be situated at a clean place which shall not be adjacent to open drains, public lavatory or any factory producing pollution of any kind, garbage dump, slaughter house or any other source likely to cause contamination from the external environment.
• The premises shall be located away railways lines so that the performance of sensitive electronic equipment is not affected by vibrations.
• The drains shall facilitate easy flow of the effluent and shall be cleared periodically.
• It shall be designed that the entry of the rodents is checked.

2. Building 

• The premises shall not be used for any purpose other than manufacture of homoeopathic drugs.
• Other facilities, if needed could be provided in separate buildings in the same campus.
• Crude raw materials, packing materials, etc shall be stored and handled in places earmarked for them and shall not taken inside areas.
• Heating, washing, drying, packing and labelling etc, wherever needed shall be done in dedicated ancillary areas adjacent to the manufacturing sections concerned.
• The walls and the flooring of the manufacturing areas shall be smooth, and free from chinks, cracks and crevices and shall be washable .
• The designs of the windows, window-panes and all fittings shall be such that they will not facilitate accumulation, lodging of dust and other contaminants.

1. Rooms:

• The rooms shall be airy, well ventilated and maintained at temperatures which are moderate and comfortable.
• All sections shall be free from birds, insects, rodents, worms etc. and suitable measures shall be taken for the same.

2. Water:

• The water used for manufacture of drugs shall be of the quality as prescribed in the rules or in the Homoeopathic Pharmacopoeia.
• The water shall be prepared from pure drinking water free from pathogenic organism.

3. Disposal of waste:

• The waste shall be disposed in such a manner that they are not hazardous to health of the public, cattle or plants.
• There should be adequate arrangement for disposal of waste water and other residues from the laboratory.

4. Factories act:

• The building used for the factory shall be constructed so as to permit production under hygiene conditions laid down in the Factories Act, 1948 (Act 63 of 1948).

5. Medical services:

• The manufacturer shall provide facilities for first aid, medical inspections each and every sections of the workers shall be medically examined for fitness at the time of employment and subsequently at periodic intervals.

6. Safety measures:

• First aid facilities should be provided and staff shall be imparted knowledge and training in first aid measures.
• Fire control equipment in suitable number shall be provided. 

7. Workbenches:

• Workbenches shall be provided in all the sections.
• The workbenches in general shall have smooth, washable.

8. Container management:

• Proper arrangements shall be made for receiving containers, closures and packing materials in secluded areas.
• The use of soaps and detergents are used to wash containers and closures for primary packing.
• Plastic containers which are likely to absorb active principles or likely to get contaminated may not be used.
• Glass containers that is made of neutral glass shall be used.

2. Plants and equipments

1. General:

• The entry to all manufacturing sections shall be regulated and persons not associated with the activities in the sections shall not have access to them.
• There shall be arrangement for personal cleanliness of workers and toilets.
• There shall be suitable arrangement separate for men and women to change for from their outside dress and footwear into the factory dress and footwear.
• Suitable head-covers and gloves shall be provided to the workers.
• There shall be separate area for foods or rest.
• Spitting, smoking, chewing, littering etc in the manufacturing or ancillary areas shall not be permitted.
• Standards operating practices (SOPs) for cleaning and sanitation, personal hygiene of the workers, general and specific upkeep of the plant, equipment and premises and every activity associated with manufacture of drugs including procurement, quarantine, testing, and warehousing of materials shall be written and adopted.  
• No person with any contagious disease shall be involved in any of the manufacturing activities.
• There shall be proper arrangements for maintenance of the equipment and systems.
• There shall be separate dedicated areas for each ancillary activity such as receipt, cleaning, warehousing and issue of raw materials, packing materials, containers and closures etc.
• Adequate measures shall be taken for entry or presence of insects, rodents, birds, lizards and other animals into the raw material handling areas.
• Every material shall have proper identification and control numbers and inventory tags and labels displaying status of the quality being used.
• Materials with odour shall be kept in tightly closed containers and shall be well protected from other materials.
• A well-equipped laboratory for quality control or quality assurance of raw materials and finished products and for carrying out in process controls shall be provided.

2. Personnel: 

• Manufacturing the drugs shall be under the control of approved technical staff that possess the qualifications prescribed in rule 85.

3. Requirements of equipments and facilities.

1. Mother tincture and mother solution.

 The following equipment and facilities shall be provided:

• Disintegrator
• Sieved separator
• Balances, weights and fluid measures, all in metric system.
• Chopping board and knife.
• Macerators with lids
• Percolators
• Moisture determinations apparatus etc.
• The areas and facilities for manufacture of mother tinctures and mother solutions shall be separate and shall be of 55 square metres for each for basic installations.

2. Potentisation section

                 The section shall have the following facilities;

• Workbenches with washable tops.
• Facilities for orderly storage of different potencies and back potencies of various drugs.
• Suitable devices for measuring and dispensing of potencies into the potentisation phials.
• Potentiser with counter.
• An area of 20 square meters shall be provided for basic installations.

3. Containers and closures section:

• Separate area for preparation of containers and closures shall be provided adjacent to the potentisation section.
• Washing tanks with suitable mechanical or hand operated brushes.
• Rinsing tanks, purified water shall be used for rinsing.
• Closures washing
• Drying chambers.

4. Trituration, Tableting, Pills and Globules making sections:

    The following basic equipment and facilities shall be provided

• Triturating machine
• Disintegrator.
• Mass mixer
• Granulator
• Tablet punching machine
• Sieved separator etc.

               An area of 55 square meters shall be provided for basic installations.

5. Syrups and other oral liquid section:

The following basic equipment and facilities shall be provided:

• Mixing and storage tanks.
• Portable stirrer.
• Filter press.
• Filling and sealing machine, pH meter.
• Adequate number of workbenches shall be provided.
• Visual inspection table shall be provided.

            An area of 20 square meters shall be provided for basic installations.

6. Ointment and lotion sections:

   The following basic equipment and facilities  shall be provided:

• Mixing tanks.
• Kettle
• Suitable powder mixer.
• Ointment mill
• Filling and sealing machine etc.
• An area of 20 square meters shall be provided for basic installations.
• An ancillary areas for washing and heating purposes shall be provided.

7. Ophthalmic preparation section:

          The following basic equipment and facilities shall be provided:

• Hot air oven
• Laminar air flow bench
• Air handling unit with HEPA filters to provide filtered air and positive pressure to the section and air locks.
• Ointments mills
• Filling machines for liquids ointments 
• Necessary workbenches, visual inspection bench etc.
• An area of 20 square meters shall be provided for basic installations.

4. Quality control division

1. Functions:

                 A separate quality control division shall be provided in the premises. The section shall be under the control of an approved technical officer. The section also carry out in-process quality checks of the products.

The functions of the division shall include:

• To test the identity, quality and purity of the raw materials.
• To test the identity, quality and purity of the finished products.
• To prepare and validate the methods of analysis, validate the equipment, monitor their use, take steps for proper maintenance, etc.
• To approve or reject containers, closures and packing materials.
• To exercise or carry out in-process control of products.
• To prescribe SOPs on all matters concerning quality of materials and products.
• To monitor the storage and handling of raw materials, finished products, containers, closures and packing materials.
• To investigate complaints on quality of products and take appropriate measures and to examine returned goods and recommend their proper disposal.

2. Personnel:

• The quality staff shall be full-time personnel.
• Analysis and tests for drugs, raw materials etc shall be done by qualified and approved technical staff.
• The technical staff shall have the minimum qualification of degree in homoeopathy pharmacy or science with botany or chemistry as the principle subjects and experience not less than 2 years. 

3. Equipment:

         The following equipment shall be provided:

• Dissecting microscope
• TLC apparatus
• U.V lamp viewer
• Distillation apparatus.
• Polarimeter 
• Refractometer
• U.V Spectrophotometer
• Rotary microtome
• Tablet Disintegration Machine etc.

5. Raw materials

1. Raw materials of plant origin-

1. The raw materials of plants origin used for manufacture of drugs shall be of the following specifications: 

• The materials shall be those recently collected and dried and shall be free from moisture so as to eliminate the risk deterioration and infestation with pests moulds etc.
• When dry materials are procured they shall be from healthy plants and shall in un-process form, free from all extraneous matters and should not be more than 6 months old.

2. To facilitate proper identification and purity of the material and to exercise proper quality control of the material the following conditions must be satisfied:

• A small twig of the plant with the leaves shall be available if the part used is bark of the plant.
• If the plants with flowers are to be used, a few dry flowers shall be also be available with the aerial twig.
• The materials shall be free from insecticides, fungicides etc.
• Each consignment of the material shall be accompanied by a statement of the supplier’s name; name of the plant with description of the part supplied; the pharmacopoial reference, place of collection, date and time of collection and packaging and weight.

2. Raw materials of chemical origin:

• They shall be of respective pharmacopoeial standard and statements of their specification shall accompany the materials.

3. Raw materials of animal origin:

• The materials shall be collected from healthy animals and of pharmacopoeial specifications.
• The materials shall be those collected, packed and transported under proper hygiene conditions and protected from all contamination.

4. Sarcodes:

• The materials shall be those collected from healthy animals and of pharmacopoeial specification.
• The materials shall collected, packed and transported under proper hygiene condition and protected from all contamination.

5. Nosodes:

• As these are derived from diseased animals or human beings they shall be autoclaved immediately after collection and preserved and transported under proper hygiene conditions and protected from all contamination as specified in homoeopathic pharmacopoeia.

6. Procedures

1. Manufacture of Mother Tincture:

• Every material shall be identified and checked for its purity. They shall be cleaned and processed by cutting, chopping etc. for use in macerators or percolators.
• Mother tinctures shall be preserved in tight closed neutral containers at temperatures preferably below 25℃, protected from light.

2. Manufacture of attenuations:

• It shall be prepared in a clean room environment with filtered air and positive pressure inside.
• The methods used shall be reproducible and shall be validated.
• It shall be preserved in proper labelled glass containers.
• Alcohol and other vehicles used shall be of Homoeopathic Pharmacopeia specification and shall be free from impurities etc.

3. Trituration:

• Trituration technique is used to manufacture drugs from insoluble strains.
• The procedure specified in the Homoeopathic pharmacopoeia shall be adopted.

4. Formulation: 

• Compound formulations shall preferably be in liquid and solid forms and the potency of the ingredients shall be detectable.
• Complete pharmacopoeial name of each ingredient shall be printed on the label along with composition.

5. Medicated Insert pellets:

• Pellets shall be manufactured in clean rooms free from particulate contaminants.
• The procedures shall be validated.

7. Laboratory

• Test as per the pharmacopoeia and requirements shall be carried out on products and materials.
• Sterility tests shall be carried out whenever applicable.
• Controls samples shall be preserved for not less than 3 years after the last sales.

8. Packing and labelling

• A minimum area of 50 square meters shall be provided for packing and labelling section.

9. Expiry Date

• Not exceeding 60 months from the date of manufacture.

10. 10.Standard Operating Practices

• It shall be development for various activities such as receipt, identification, cleaning, drying, sampling etc. of all materials.
• Labels and packing materials shall be examined foe correctness and compliance with rules.
• Records shall be maintained for their printing, use, destruction etc.

11. 11.Records and Registers

• It shall include records of production, of raw materials, testing, sales and other supplies, rejection, complaints and action taken, SOPs, log books of equipment, master formula record, medical examination etc.
• All records shall be maintained for a period of 1year after expiry of a batch or for 3 years whichever is later.

References

1. Garg.A.Ram. Manual drugs & cosmetics. 9^th ed. New Delhi: Commercial Law Publisers; 2016. p.493-502.
2. Mandal.M. A textbook of homoeopathic pharmacy. 3^rd ed. Kolkata: New central book agency(P)Ltd; 2012. p.111-118.  
3. https://en.wikipedia.org/wiki/Good_manufacturing_practice.
4. https://ispe.org/initiatives/regulatory-resources/gmp.
5. https://ispe.org/initiatives/regulatory-resources/gmp/what-is-gmp.

Dr Juthika Gogoi
PGT Pharmacy
Fr Muller Homoeopathy Medical College. Mangalore