GOOD MANUFACTURING PRACTICE FOR PHARMACEUTICAL PRODUCTS
National College of Pharmacy, Manassery, Calicut
Good manufacturing practice (GMP) comprises that part of quality assurance aimed at ensuring that a product is consistently manufactured to a quality appropriated to its intended use. GMP requires that the manufacturing process is fully defined before it is initiated and that all necessary facilities are provided. In practice, this means that personnel must be adequately trained, suitable premises and equipment used, correct materials used, approved procedures adopted, suitable and transport facilities available and appropriate records made.
The quality of pharmaceutical products depends on the degree of care taken in its preparation. Final checks carried out on the finished products are useful in confirming that the correct ingredients have been used and that that materials have been correctly processed. It is however essential that proper in process control is exercised and that it is adequately documented to provide reliable evidence that the correct procedures have been followed. The need for GMP is recognized throughout the world. More than 20 countries have issued their own GMP guidelines. (The essential components of GMP are summarized in figure 1.)
Why it is required?
The Good Manufacturing Practices are prescribed to ensure that:
(i) Raw materials used in the manufacture of pharmaceuticals are authentic, of prescribed quality and are free from contamination.
(ii) The manufacturing process is as has been prescribed to maintain the standards.
(iii) Adequate quality control measures are adopted and
(iv) The manufactured drug which is released for sale has the prescribed quality.
(v) To achieve the objectives listed above, each licencee shall evolve methodology and procedures for following the prescribed process of manufacture of drugs which should be documented as a manual and kept for reference and inspection. However, teaching institutions and registered qualified Vaidyas, Siddhas and Hakeems who prepare medicines on their own to dispense to their patients and not selling such drugs in the market are exempted from the purview of G.M.P.
World Health Organization (WHO) GMP
WHO defines good manufacturing practice has "that part of quality assurance which assures that products are consistently produced and controlled to the quality standards appropriate to their indented use and as required by the marketing authorization"
GMP covers all aspects of the manufacturing process: defined manufacturing processes; critical manufacturing steps; suitable premises, storage, transport; qualified and trained production and quality control personnel; adequate laboratory facilities; approved written procedures and instructions; records to show all steps of defined procedures have been taken; full traceability of a product through batch rewards and distribution records and systems for recall and investigation of complaints.
GMP REQUIREMENTS FOR PREMISES AND MATERIALS FOR PHARMACEUTICAL PRODUCTS
1. GENERAL REQUIREMENTS
1.1. Location and surroundings.- The factory building(s) for manufacture of drugs shall be so situated and shall have such measures as to avoid risk of contamination from external environment including open sewage, drain, public lavatory or any factory which produces disagreeable or obnoxious, odour, fumes, excessive soot, dust, smoke, chemical or biological emissions.
1.2. Buildings and premises.– The building(s) used for the factory shall be designed, constructed, adapted and maintained to suit the manufacturing operations so as to permit production of drugs under hygienic conditions. They shall conform to the conditions laid down in the Factories Act, 1948 (63 of 1948).
The premises used for manufacturing, processing, warehousing, packaging, labeling and testing purposes shall be -
- compatible with other drug manufacturing operations that may be carried out in the same or adjacent area / section;
- adequately provided with working space to allow orderly and logical placement of equipment, materials and movement of personnel so as to :
- avoid the risk of mix-up between different categories of drugs or with raw materials, intermediates and in-process material;
- avoid the possibilities of contamination and cross-contamination by providing suitable mechanism;
(iii) designed / constructed / maintained to prevent entry of insects, pests, birds, vermins, and rodents. Interior surface (walls, floors, and ceilings) shall be smooth and free from cracks, and permit easy cleaning, painting and disinfection;
(iv) air conditioned, where prescribed for the operations and dosage forms under production. The production and dispensing areas shall be well lighted, effectively ventilated, with air control facilities and may have proper Air Handling Units (wherever applicable) to maintain conditions including temperature and,wherever necessary, humidity
as defined for the relevant product. These conditions shall be appropriate to the category of drugs and nature of the operation. These shall also be suitable to the comforts of the personnel working with protective clothing, products handled, operations undertaken within them in relation to the external environment. These areas shall be regularly monitored for compliance with required specifications;
(v) provided with drainage system, as specified for the various categories of products, which shall be of adequate size and so designed as to prevent back- flow and/or to prevent insects and rodents entering the premises. Open channels shall be avoided in manufacturing areas and, where provided, these shall be shallow to facilitate cleaning and disinfection;
(vi) The walls and floors of the areas where manufacture of drugs is carried out shall be free from cracks and open joints to avoid accumulation of dust. These shall be smooth, washable, coved and shall permit easy and effective cleaning and disinfection. The interior surfaces shall not shed particles. A periodical record of cleaning and painting of the premises shall be maintained.
1.3 Water system
There shall be validated system for treatment of water drawn from own or any other source to render it potable in accordance with standards specified by the Bureau of Indian Standards or Local Municipality, as the case may be, so as to produce Purified Water conforming to Pharmacopoeial specification. Purified Water so produced shall only be used for all the operations except washing and cleaning operations where potable water may be used. 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.
1.4 Disposal of waste
(i) The disposal of sewage and effluents (solid, liquid and gas) from the manufactory shall be in conformity with the requirements of Environment Pollution Control Board.
(ii) All bio-medical waste shall be destroyed as per the provisions of the Bio-Medical Waste (Management and Handling) Rules, 1996.
(iii) Additional precautions shall be taken for the storage and disposal of rejected drugs. Records shall be maintained for all disposal of waste.
(iv) Provisions shall be made for the proper and safe storage of waste materials awaiting disposal. Hazardous, toxic substances and flammable materials shall be stored in suitably designed and segregated enclosed areas in conformity with Central and State Legislations.
2. WAREHOUSING AREA
- Adequate areas shall be designed to allow sufficient and orderly warehousing of various categories of materials and products like starting and packaging materials, intermediates, bulk and finished products, products in quarantine, released, rejected, returned or recalled, machine and equipment spare parts and change items.
- Warehousing areas shall be designed and adapted to ensure good storage conditions. They shall be clean, dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g., temperature, humidity), these shall be provided, monitored and recorded. Storage areas shall have appropriate house-keeping and rodent, pests and vermin control procedures and records maintained. Proper racks, bins and platforms shall be provided for the storage of materials.
- Receiving and dispatch bays shall protect materials and products from adverse weather conditions.
- Where quarantine status is ensured by warehousing in separate earmarked areas in the same warehouse or store, these areas shall be clearly demarcated. Any system replacing the physical quarantine, shall give equivalent assurance of segregation. Access to these areas shall be restricted to authorized persons.
- There shall be a separate sampling area in the warehousing area for active raw materials and excipients. If sampling is performed in any other area, it shall be conducted in such a way as to prevent contamination, cross- contamination and mix- up.
- Segregation shall be provided for the storage of rejected, recalled or returned materials or products. Such areas, materials or products shall be suitably marked and secured. Access to these areas and materials shall be restricted.
- Highly hazardous, poisonous and explosive materials such as narcotics, psychotropic drugs and substances presenting potential risks of abuse, fire or explosion shall be stored in safe and secure areas. Adequate fire protection measures shall be provided in conformity with the rules of the concerned civic authority.
- Printed packaging materials shall be stored in safe, separate and secure areas.
- Separate dispensing areas for (Beta)
lactum, Sex Hormones and Cyto-toxic substances or any such special categories of products shall be provided with proper supply of filtered air and suitable measures for dust control to avoid contamination. Such areas shall be under differential pressure.
- Sampling and dispensing of sterile materials shall be conducted under aseptic conditions conforming to Grade A, which can also be performed in a dedicated area within the manufacturing facility.
- Regular checks shall be made to ensure adequate steps are taken against spillage, breakage and leakage of containers.
- Rodent treatments (pest control) should be done regularly and at least once in a year and record maintained.
3. PRODUCTION AREA
1.The production area shall be designed to allow the production preferably in uni-flow and with logical sequence of operations.
2.In order to avoid the risk of cross-contamination, separate dedicated and self-contained facilities shall be made available for the production of sensitive pharmaceutical products like penicillin or biological preparations with live micro-organisms. Separate dedicated facilities shall be provided for the manufacture of contamination causing and potent products such as Beta lactum, Sex Hormones and Cyto-toxic substances.
3.Working and in-process space shall be adequate to permit orderly and logical positioning of equipment and materials and movement of personnel to avoid cross-contamination and to minimize risk of omission or wrong application of any of manufacturing and control measures.
4.Pipe-work, electrical fittings, ventilation openings and similar service lines shall be designed, fixed and constructed to avoid creation of recesses. Service lines shall preferably be identified by colours and the
nature of the
supply and direction of the flow
shall be marked/indicated.
4. ANCILLARY AREAS
- Rest and refreshment rooms shall be separate from other areas. These areas shall not lead directly to the manufacturing and storage areas.
- Facilities for changing, storing clothes and for washing and toilet purposes shall be easily accessible and adequate for the number of users. Toilets, separate for males and females, shall not be directly connected with production or storage areas. There shall be written instructions for cleaning and disinfection for such areas.
- Maintenance workshops shall be separate and away from production areas. Whenever spares, changed parts and tools are stored in the production area, these shall be kept in dedicated rooms or lockers. Tools and spare parts for use in sterile areas shall be disinfected before these are carried inside the production areas.
- Areas housing animals shall be isolated from other areas. The other requirements regarding 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.
5. QUALITY CONTROL AREA
1.Quality Control Laboratories shall be independent of the production areas. Separate areas shall be provided each for physico-chemical, biological, microbiological or radio-isotope analysis. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis.
2.Quality Control Laboratories shall be designed appropriately for the operations to be carried out in them. Adequate space shall be provided to avoid mix-ups and cross-contamination. Sufficient and suitable storage space shall be provided for test samples, retained samples, reference standards, reagents and records.
3.The design of the laboratory shall take into account the suitability of construction materials and ventilation. Separate air handling units and other requirements shall be provided for biological, microbiological and radioisotopes testing areas. The laboratory shall be provided with regular supply of water of appropriate quality for cleaning and testing purposes.
.4.Quality Control Laboratory shall be divided into separate sections i.e. for chemical, microbiological and wherever required, biological Testing. These shall have adequate area for basic installation and for ancillary purposes. The microbiology section shall have arrangements such as airlocks and laminar air flow work station, wherever considered necessary.
1.The manufacture shall be conducted under the direct supervision of competent technical staff with prescribed qualifications and practical experience in the relevant dosage form and / or active pharmaceutical products.
2.The head of the Quality Control Laboratory shall be independent of the manufacturing unit. The testing shall be conducted under the direct supervision of competent technical staff who shall be whole time employees of the licensee.
3.Personnel for Quality Assurance and Quality Control operations shall be suitably qualified and experienced.
4.Written duties of technical and Quality Control personnel shall be laid and followed strictly.
5.Number of personnel employed shall be adequate and in direct proportion to the workload.
6.The licensee shall ensure in accordance with a written instruction that all personnel in production area or into Quality Control Laboratories shall receive training appropriate to the duties and responsibility assigned to them. They shall be provided with
regular in-service training.
7. HEALTH, CLOTHING AND SANITATION OF WORKERS
7.1.The personnel handling Beta-lactum antibiotics shall be tested for Penicillin sensitivity before employment and those handling sex hormones, cytotoxic substances and other potent drugs shall be periodically examined for adverse effects. These personnel should be moved out of these sections
(except in dedicated facilities), by rotation, as a health safeguard.
7.2. Prior to employment, all personnel, shall undergo medical examination including eye examination, and shall be free from Tuberculosis, skin and other communicable or contagious diseases. Thereafter, they should be medically examined periodically, at least once a year. Records shall be maintained thereof. The licensee shall provide the services of a qualified physician for assessing the health status of personnel involved in different activities.
7.3 All persons, prior to and during employment, shall be trained in practices which ensure personnel hygiene. A high level of personal hygiene shall be observed by all those engaged in the manufacturing processes. Instructions to this effect shall be displayed in change-rooms and other strategic locations.
7.4 No person showing, at any time, apparent illness or open lesions which may adversely affect the quality of products, shall be allowed to handle starting materials, packaging materials, In-process materials, and drug products until his condition is no longer judged to be a risk.
7.5 All employees shall be instructed to report about their illness or abnormal health condition to their immediate supervisor so that appropriate action can be taken.
7.6 Direct contact shall be avoided between the unprotected hands of personnel and raw materials, intermediate or finished, unpacked products.
7.7 All personnel shall wear clean body coverings appropriate to their duties. Before entry into the manufacturing area, there shall be change rooms separate for each sex with adequate facilities for personal cleanliness such as wash basin with running water,
clean towels, hand dryers, soaps, disinfectants etc. The change rooms shall be provided with cabinets for the storage of personal belongings of the personnel.
7.8 Smoking, eating, drinking, chewing or keeping plants, food, drink and personal medicines shall not be permitted in production, laboratory, storage and other areas where they might adversely influence the product quality.
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. Each critical step in the process relating to the selection, weighing and measuring of raw material addition during various stages shall be performed by trained personnel under the direct personal supervision of approved technical staff.
The contents of all vessels and containers used in manufacture and storage during the various manufacturing stages shall be conspicuously labeled with the name of the product, batch no., batch size and stage of manufacture. Each label should be initialed and dated by the authorized
Products not prepared under aseptic conditions are required to be free from pathogens like Salmonella, Escherichia coli, Pyocyanea etc.
8. 2. Precautions against mix–up and cross-contamination –
8. 2. 1. The licensee shall prevent mix-up and cross- contamination of drug material and drug product (from environmental dust) by proper air-handling system, pressure differential, segregation, status labeling and cleaning. Proper records and Standard Operating Procedures thereof shall be maintained.
8. 2. 2. The licensee shall ensure processing of sensitive drugs like Beta-Lactum antibiotics, sex hormones and cycotoxic substances in segregated areas or isolated production areas within the building with independent air-handling unit and proper pressure differentials. The effective segregation of these areas shall be demonstrated with adequate records of maintenance and services.
8. 2. 3. To prevent mix-ups during production stages, material under- process shall be conspicuously labeled to demonstrate their status. All equipment used for production shall be labeled with their current status.
8. 2. 4. Packaging lines shall be independent and adequately segregated. It shall be ensured that all left-overs of the previous packaging operations, including labels, cartons and caps are cleared before the
8. 2. 5. Before packaging operations are begun, steps shall be taken to ensure that the work area, packaging lines, printing machines, and other equipment are clean and free from any products, materials and spillages. The line clearance shall be performed according to an appropriate checklist and recorded.
8. 2. 6. The correct details of any printing (for example of batch numbers or expiry dates) done separately or in the course of the packaging shall be re-checked at regular intervals. All printing and over-printing shall be authorised in writing.
8. 2. 7. The manufacturing environment shall be maintained at the required levels of temperature, humidity and cleanliness.
8. 2. 8. Authorised persons shall ensure change-over into specific uniforms before undertaking any manufacturing operations including packaging.
8. 2. 9. There shall be segregated enclosed areas, secured for recalled or rejected material and for such material which are to be re-processed or recovered.
9. SANITATION IN THE MANUFACTURING PREMISES
9. 1. The manufacturing premises shall be cleaned and maintained in an orderly manner, so that it is free from accumulated waste, dust, debris and other similar material. A validated cleaning procedure
shall be maintained.
9. 2. The manufacturing areas shall not be used for storage of materials, except for the
material being processed. It shall not be used as a general thoroughfare.
9. 3. A routine sanitation program shall be drawn up and observed, which shall be properly recorded and which shall indicate –
- specific areas to be cleaned and cleaning intervals;
- cleaning procedure to be followed, including equipment and materials to be used for cleaning; and
- personnel assigned to and responsible for the cleaning operation.
9. 4. The adequacy of the working and in-process storage space shall permit the orderly and logical positioning of equipment and materials so as to minimise the risk of mix-up between different pharmaceutical products or their components to avoid cross-contamination, and to minimise the risk of omission or wrong application of any of the manufacturing or control steps.
9. 5. Production areas shall be well lit, particularly where visual on-line controls are carried out.
10. RAW MATERIALS
10. 1. The licensee shall keep an inventory of all raw-materials to be used at any stage of manufacture of drugs and maintain records as per Schedule U.
10. 2. All incoming materials shall be quarantined immediately after receipt or processing. All materials shall be stored under appropriate conditions and in an orderly fashion to permit batch segregation and stock rotation by a 'first in/first expiry' - 'first-out' principle. All incoming materials shall be checked to ensure that the consignment corresponds to the order placed.
10. 3. All incoming materials shall be purchased from approved sources under valid purchase vouchers. Wherever possible, raw materials should be purchased directly from the producers.
10. 4. Authorised staff appointed by the
licensee in this behalf, which may include personnel from the quality control department, shall examine each consignment on receipt and shall check each container for integrity of package and seal. Damaged containers shall be identified, recorded and segregated.
10. 5. If a single delivery of material is made up of different batches, each batch shall be considered as a separate batch for sampling, testing and release.
10. 6. Raw materials in the storage area shall be appropriately labeled. Labels shall be clearly marked with the following information :
- designated name of the product and the internal code reference, where applicable, and analytical reference number;
- manufacturer's name, address and batch number;
- the status of the contents (e.g. quarantine, under test, released, approved, rejected);
- the manufacturing date, expiry date and re-test date.
10. 7. There shall be adequate separate areas for materials "under test", "approved ", and "rejected" with arrangements and equipment to allow dry, clean and orderly placement of stored materials and products, wherever necessary, under controlled temperature and humidity.
10. 8. Containers from which samples have been drawn shall be identified.
10. 9. Only raw materials which have been released by the Quality Control Department and which are within their shelf-life shall be used. It shall be ensured that shelf-life of formulation product shall not exceed with that of active raw materials used.
10. 10. It shall be ensured that all the containers of raw materials are placed on the raised platforms/racks and not placed directly on the floor.
11. 1. Equipment shall be located, designed, constructed, adapted and maintained to suit the operations to be carried out. The layout and design of the equipment shall aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt and, in general, any adverse effect on the quality of products. Each equipment shall be provided with a log book, wherever necessary.
11. 2. Balances and other measuring equipment of an appropriate range, accuracy and precision shall be available in the raw-material stores, production and in-process control operations and these shall be calibrated and checked on a scheduled basis in accordance with Standard Operating Procedures and records maintained.
11. 3. The parts of the production equipment that come into contact with the product shall not be reactive, additive or adsorptive to an extent that would affect the quality of the product.
11. 4. To avoid accidental contamination, wherever possible, non-toxic/edible grade lubricants shall be used and the equipment shall be maintained in a way that lubricants do not contaminate the products being produced.
11. 5. Defective equipment shall be removed from production and Quality Control areas or appropriately labeled.
12. DOCUMENTATION AND RECORDS
Documentation is an essential part of the Quality assurance system and, as such, shall be related to all aspects of Good Manufacturing Practices (GMP). Its aim is to define the specifications for all materials, method of manufacture and control, to ensure that all personnel concerned with manufacture know the information necessary to decide whether or not to release a batch of a drug for sale and to provide an audit trail that shall permit investigation of the history of any suspected defective batch.
12.1. Documents designed, prepared, reviewed and controlled, wherever applicable, shall comply with these rules.
12. 2. Documents shall be approved, signed and dated by appropriate and authorized persons.
12. 3. Documents shall specify the title, nature and purpose. They shall be laid out in an orderly fashion and be easy to check. Reproduced documents shall be clear and legible. Documents shall be regularly reviewed and kept up to date. Any alteration made in the entry of a document shall be signed and dated.
12. 4. The records shall be made or completed at the time of each operation in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records and associated Standard Operating Procedures (SOP) shall be retained for at least one year after the expiry date of the finished product.
12. 5. Data may be recorded by electronic data processing systems or other reliable means, 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. Wherever documentation is handled by electronic data processing methods, authorized persons shall enter or modify data in the computer. There shall be record of changes and deletions. Access shall be restricted by 'passwords' or other means and the result of entry of critical data shall be independently checked. Batch records electronically stored shall be protected by a suitable back-up. During the period of retention, all relevant data shall be readily available.
13. LABELS AND OTHER PRINTED MATERIALS
Labels are absolutely 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. Different colour coded labels shall be used to indicate the status of a product (for example: under test, approved, passed, rejected).
13. 2. To avoid chance of mix-up in printed packaging materials, product leaflets, relating to different products, shall be stored separately.
13. 3. Prior to release, all labels for containers, cartons and boxes and all circulars, inserts and leaflets shall be examined by the Quality Control Department of the licensee.
13. 4. Prior to packaging and labeling of a given batch of a drug, it shall be ensured by the licensee that samples are drawn from the bulk and duly tested, approved and released by the quality control personnel.
13. 5. Records of receipt of all labelling and packaging materials shall be maintained for each shipment received indicating receipt, control reference numbers and whether accepted or rejected. Unused coded and damaged labels and packaging materials shall be destroyed and recorded.
13.6. The label or accompanying document of reference standards and reference culture shall indicate concentration, lot number, potency, date on which container was first opened and storage conditions, where appropriate.
14. QUALITY ASSURANCE
is a wide ranging concept concerning all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that products are of the quality required for their intended use.
14. 1. The system of quality assurance appropriate to the manufacture of pharmaceutical products shall ensure that:
- the pharmaceutical products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practices (hereinafter referred as GMP) and other associated codes such as those of Good Laboratory Practices (hereinafter referred as GLP) and Good Clinical Practices (herein after referred as GCP).
- adequate arrangements are made for manufacture, supply, and use of the correct starting and packaging materials.
- adequate controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations, and validations are carried out.
- the finished product is correctly processed and checked in accordance with established procedures.
- the pharmaceutical products are not released for sale or supplied before authorized persons have certified that each production batch has been produced and controlled in accordance with the requirements of the label claim and any other provisions relevant to production, control and release of pharmaceutical products.
15. SELF INSPECTION AND QUALITY AUDIT
It may be useful to constitute a self inspection team supplemented with a quality audit procedure for assessment of all or part of a system with the specific purpose of improving it.
15 1. To evaluate the manufacturer's compliance with GMP in all aspects of production and quality control, concept of self-inspection shall be followed. The manufacturer shall constitute a team of independent, experienced, qualified persons from within or outside the company, who can audit objectively the implementation of methodology and procedures evolved. The procedure for self-inspection shall be documented indicating self-inspection results, evaluation, conclusions and recommended corrective actions with effective follow up program. The recommendations for corrective action shall be adopted.
15. 2. The program shall be designed to detect shortcomings in the implementation of Good Manufacturing Practice and to recommend the necessary corrective actions. Self-inspections shall be performed routinely and on specific occasions, like when product recalls or repeated rejections
occur or when an inspection by the licensing authorities is announced. The team responsible for self-inspection shall consist of personnel who can evaluate the implementation of Good Manufacturing Practice objectively; all recommendations for corrective action shall be implemented.
15. 3. Written instructions for self-inspection shall be drawn up which shall include the following :
- Premises including personnel facilities.
- Maintenance of buildings and equipment.
- Storage of starting materials and finished products.
- Production and in-process controls.
- Quality control.
- Sanitation and hygiene.
- Validation and revalidation programmes.
- Calibration of instruments or measurement systems.
- Recall procedures.
- Complaints management.
- Labels control.
- Results of previous self-inspections and any corrective steps taken.
16. QUALITY CONTROL SYSTEM
Quality control shall be concerned with sampling, specifications, testing, documentation, release procedures which ensure that the necessary and relevant tests are actually carried and that the materials are not released for use, nor products released for sale or supply until their quality has been judged to be satisfactory. It is not confined to laboratory operations but shall be involved in all decisions concerning the quality of the product. It shall be ensured that all quality control arrangements are effectively and reliably carried out. The department as a whole shall have other duties such as to establish, evaluate, validate and implement all Quality Control Procedures and methods.
16. 1. Every manufacturing establishment shall establish its own quality control laboratory managed by qualified and experienced staff.
16. 2. The area of the quality control laboratory may be divided into Chemical, Instrumentation, Microbiological and Biological testing. Separate provision should be made for testing radio active material is used for manufacturing.
16. 3. Adequate area having the required storage conditions shall be provided for keeping reference samples. The quality control department shall evaluate, maintain and store reference samples.
16. 4. Standard operating procedures shall be available for sampling, inspecting, and testing of raw materials, intermediate, bulk finished products and packing materials and, wherever necessary, for monitoring environmental conditions.
16. 5. There shall be authorized and dated specifications for all materials, products, reagents and solvents including test of identity, content, purity and quality. These shall include specifications for water, solvents and reagents used in analysis.
16. 6. No batch of the product shall be released for sale or supply until it has been certified by the authorised person(s) that it is in accordance with the requirements of the standards laid down.
16. 7. Reference/retained samples from each batch of the products manufactured shall be maintained in a quantity which is at least twice the quantity of the drug required to conduct all the tests, except sterility and pyrogen/Bacterial Endotoxin Test performed on the active material and the product manufactured. The retained product shall be kept in its final pack or a simulated pack for a period of three months after the date of expiry.
16. 8. Assessment of records pertaining to finished products shall include all relevant factors, including the production conditions, the results of inprocess testing, the manufacturing (including packaging) documentation, compliance with the specification for the finished product, and an examination of the finished pack. Assessment records should be signed by the person incharged of production and countersigned by the authorised quality control personnel before a product is released for sale or distribution.
16. 9. Quality control personnel shall have access to production areas for sampling and investigation, as appropriate.
16. 10. The quality control department shall conduct stability studies of the products to ensure and assign their shelf life at the prescribed conditions of storage. All records of such studies shall be maintained.
16. 11. The in-charge of Quality Assurance shall investigate all product complaints and records thereof shall be maintained.
16. 12. All instruments shall be calibrated and testing procedures validated before these are adopted for routine testing. Periodical calibration of instrument and validation of procedures should be carried out.
16. 13. Each specifications for raw materials, intermediates, final products, and packing materials shall be approved and maintained by the Quality Control Department. Periodic revisions of the specifications shall be carried out whenever changes are necessary.
16. 14. Pharmacopoeiae, reference standards, working standards, reference spectra, other reference materials and technical books, as required, shall be made available in the Quality Control Laboratory of the licensee.
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.
17. 2. For Product Containers and Closures –
17. 2. 1. All containers and closures intended for use shall comply with the pharmacopoeial requirements. Suitable validated test methods, sample sizes, specifications, cleaning procedure and sterilization procedure, wherever indicated, shall be strictly followed to ensure that these are not reactive, additive, adsorptive, or leach to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used.
17. 2. 2. Whenever bottles are being used, the written schedule of cleaning shall be laid down and followed. Where bottles are not dried after washing, they should be rinsed with de-ionised water or distilled water, as the case may be.
17. 3. For in-process and bulk products.— Specifications for in-process material, intermediate and bulk products shall be available. The specifications should be authenticated.
17. 4. 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 qualitative and quantitative requirements, with the acceptance limits for release.
- the storage conditions and precautions, where applicable, and
- the shelf-life.
For preparation of containers and closures. – The requirements mentioned in the Schedule do not include requirements of machinery, equipments and premises required for preparation of containers and closures for different dosage forms and categories of drugs. The suitability and adequacy of the machinery, equipment and premises shall be examined taking into consideration the requirements of each licensee in this respect.
18 MASTER FORMULA RECORDS
There shall be Master Formula records relating to all manufacturing procedures for each product and batch size to be manufactured. These shall be prepared and endorsed by the competent technical staff i.e. 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. Mention any substance that may 'disappear' in the course of processing.
- a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.
- a statement of the processing location and the principal equipment to be used.
- the methods, or reference to the methods, to be used for preparing the critical equipment including cleaning, assembling, calibrating, sterilizing.
- detailed stepwise processing instructions and the time taken for each step.
- the instructions for in-process controls with their limits.
- the requirements for storage conditions of the products, including the container, labelling and special storage conditions where applicable.
- any special precautions to be observed.
- packing details and specimen labels.
19 PACKAGING 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 or doses, weight or volume of the product in the final container.
- complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material.
- reprocessing of the relevant printed packaging materials and specimens indicating where batch number and expiry date of the product have been applied.
- 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.
- description of the packaging operation, including any significant subsidiary operations and equipment to be used.
- details of in-process controls with instructions for sampling and acceptance.
- upon completion of the packing and labeling operation, a reconciliation shall be made between number of labeling and packaging units issued, number of units labeled, packed and excess returned or destroyed. Any significant or unusual discrepancy in the numbers shall be carefully investigated before releasing the final batch.
20. BATCH PACKAGING RECORDS
20. 1. 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.
20. 2. Before any packaging operations begins, checks shall be made and recorded that the equipment and the work stations are clear of the previous products, documents or materials not required for the planned packaging operations, and that the
equipment is clean and suitable for use.
21. BATCH PROCESSING RECORDS
21.1 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.
21.2. Before starting of any process inspect all the manufacturing area and ensure that the equipment and work station are clear of previous products. This should be documented and recorded.
21.3. During processing, the following information shall be recorded at the time each action is taken and the record shall be dated and signed by the person responsible for the processing operations:
( a ) the name of the product,
( b ) the number of the batch being manufactured,
( c ) dates and time of commencement, of significant intermediate stages and of completion of production,
( d ) initials of the operator of different significant steps of production and where appropriate, of the person who checked each of these operations,
( e ) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed,
( f ) any relevant processing operation or event and major equipment used,
( g ) a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained,
(h ) the amount of product obtained after different and critical stages of manufacture (yield),
( i ) comments or explanations for significant deviations from the expected yield limits shall be given,
( j ) notes on special problems including details, with signed authorization, for any deviation from the master formula,
(k) addition of any recovered or reprocessed material with reference to recovery or reprocessing stages.
22. STANDARD OPERATING PROCEDURES (SOPS) AND RECORDS, REGARDING
22. 1. Receipt of Materials;
22. 1. 1. There shall be written Standard Operating Procedures and records for the receipt of each delivery of raw, primary and printed packaging material.
22. 1. 2. The records of the receipts shall include
(a) container number
(b) the date of receipt
(c) the manufacturer's and / or supplier's name
(d) the manufacturer's batch or reference number
(e) the total quantity, and number of containers, quantity in each container received
(f) the control reference number assigned after receipt
(g) any other relevant comment or information.
22. 1. 3 There shall be written standard operating procedures for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.
22. 1. 4. There shall be Standard Operating Procedures available for each instrument and equipment and these shall be placed in close proximity to the related instrument and equipment.
22. 2. Sampling.-
22. 2. 1. There shall be written Standard Operating Procedures for sampling, which include the person(s) authorized to take the samples.
22. 2. 2. The sampling instructions shall include:
- the method of sampling and the sampling plan,
- the equipment to be used,
- any precautions to be observed to avoid contamination of the material or any deterioration in its quality,
- the quantity of samples to be taken,
- instructions for any required sub-division or pooling of the samples,
- the type of sample container to be used,
- any specific precautions to be observed, especially in regard to sampling of sterile or hazardous material.
22. 3. Batch Numbering.-
22. 3. 1. There shall be Standard Operating Procedures describing the details of the batch ( lot ) numbering set up with the objective of ensuring that each batch of intermediate, bulk or finished product is identified with a specific batch number.
22.3. 2. Batch numbering standard operating procedures applied to a processing stage and to the respective packaging stage shall be same or traceable to demonstrate that they belong to one homogenous mix.
22. 3. 3. Batch number allocation shall be immediately recorded in a logbook or by electronic data processing system. The record shall include date of allocation, product identity and size of batch.
22. 4. Testing
22. 4. 1. There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded.
22. 5. Records of analysis.-
22. 5. 1. The records shall include the following data.
- name of the material or product and the dosage form,
- batch number, details of manufacturer and / or supplier;
- references of relevant specifications and testing procedures,
- test results, including observations and calculations, and reference to any specifications ( limits ),
- dates of testing;
- initials of the persons who performed the testing;
- initials of the persons who verified the testing and the detailed calculations,
- a statement of release or rejection, and
- signature and date of the designated responsible person.
22. 5. 2. There shall be written standard operating procedures and the associated records of actions taken for:
- equipment assembly and validation;
- analytical apparatus and calibration;
- maintenance, cleaning and sanitation;
- personnel matters including qualification, training, clothing, hygiene;
- environmental monitoring;
- pest control;
- recalls made;
- returns received.
23. REFERENCE SAMPLES
23. 1. Each lot of every active ingredient, in a quantity sufficient to carry out 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.
24. REPROCESSING AND RECOVERIES
24. 1. Where reprocessing is necessary, written procedures shall be established and approved by the Quality Assurance Department that shall specify the conditions and limitations of repeating chemical reactions. Such re-processing shall be validated.
24. 2. If the product batch has to be reprocessed, the procedure shall be authorized and recorded. An investigation shall be carried out into the causes necessitating re -processing and appropriate corrective measures shall be taken for prevention of recurrence. Re-processed batch shall be subjected to stability evaluation.
24. 3. Recovery of product residue may be carried out, if permitted, in the master production and control records by incorporating it in subsequent batches of the product.
25. DISTRIBUTION RECORDS
25. 1. Prior to distribution or dispatch of given batch of a drug, it shall be ensured that the batch has been duly tested, approved and released by the quality control personnel. Pre-dispatch inspection shall be performed on each consignment on a random basis to ensure that only
the correct goods are dispatched. Detailed instructions for warehousing and stocking of Large Volume Parenterals, if stocked, shall be in existence and shall be complied with after the batch is released for distribution. Periodic audits of warehousing practices followed at distribution centers shall be carried out and records thereof shall be maintained. Standard Operating Procedures shall be developed for warehousing of products.
25. 2. Records for distribution shall be maintained in a manner
that finished batch of a drug can be traced to the retail level to facilitate prompt and complete recall of the batch, if and when necessary.
26 VALIDATION AND PROCESS VALIDATION
26. 1. Validation studies shall be an essential part of Good Manufacturing Practices and shall be conducted as per the pre-defined protocols. These shall include validation of processing, testing and cleaning procedures.
26. 2. A written report summarizing recorded results and conclusions shall be prepared, documented and maintained.
26. 3. Processes and procedures shall be established on the basis of validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Critical processes shall be validated, prospectively or retrospectively.
26. 4. When any new master formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified shall be demonstrated to yield a product consistently of the
26. 5. Significant changes to the manufacturing process, including any change in equipment or materials that may affect product quality and / or the reproducibility of the process, shall be validated.
26. PRODUCT RECALLS
27. 1. A prompt and effective product recall system of defective products shall be devised for timely information of all concerned stockists, 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.
27. 2. There shall be an established written procedure in the form of Standard Operating Procedure for effective recall of products distributed by the licensee. Recall operations shall be capable of being initiated promptly so as to effectively reach at the level of each distribution channel.
27. 3. The distribution records shall be readily made available to the persons designated for recalls.
27. 4. The designated person shall record a final report issued, including a reconciliation between the delivered and the recovered quantities of the products.
27. 5. The effectiveness of the arrangements for recalls shall be evaluated from time to time.
27. 6. The recalled products shall be stored separately in a secured segregated area pending final decision on them.
27 COMPLAINTS AND ADVERSE REACTIONS
28. 1. All complaints thereof concerning product quality shall be carefully reviewed and recorded according to written procedures. Each complaint shall be investigated/evaluated by the designated personnel of the company and records of investigation and remedial action taken thereof shall be maintained.
28. 2. Reports of serious adverse drug reactions resulting from the use of a drug along with comments and documents shall be forthwith reported to the concerned Licensing Authority.
28. 3. There shall be written procedures describing the action to be taken, recall to be made of the defective product.
29. SITE MASTER FILE
The licensee shall prepare a succinct document in the form of 'Site Master File' containing specific and factual Good Manufacturing Practices about the production and/or control of pharmaceutical manufacturing preparations carried out at the licensed premises. It shall contain the following : -
29. 1. General information.-
- brief information of the firm;
- pharmaceutical manufacturing activities as permitted by the licensing authority;
- other manufacturing activities, if any, carried out on the premises;
- type of products licensed for manufacture with flowcharts mentioning procedures and process flow;
- number of employees engaged in the production, quality control, storage and distribution;
- Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis;
- short description of the Quality Management system of the firm;
- products details registered with foreign countries.
29. 2. Personnel –
- organisational chart showing the arrangement for quality assurance including production and quality control;
- qualification, experience and responsibilities of key personnel;
- outline for arrangements for basic and in-service training and how the records are maintained;
- health requirements for personal engaged in production;
- personnel hygiene requirements, including clothing.
29. 3. Premises –
- simple plan or description of manufacturing areas drawn to scale;
- nature of construction and fixtures / fittings;
- brief description of ventilation systems. More details should be given for critical areas with potential risk of airborne contamination (schematic drawing of systems). Classification of the rooms used for the manufacture of sterile products should be mentioned;
- special areas for the handling of the highly toxic, hazardous and sensitizing materials;
- brief description of water systems (schematic drawings of systems), including sanitation;
- description of planned preventive maintenance programs for premises and of the recording system.
29. 4. Equipment –
- brief description of major equipment used in production and quality control laboratories (a list of equipment required);
- description of planned preventive maintenance programs for equipment and of the recording system;
- qualification and calibration, including the recording systems and arrangements for computerised systems validation.
29. 5. Sanitation –
(a) availability of written specifications and procedures for cleaning manufacturing areas and equipment.
29. 6. Documentation –
- arrangements for the preparation, revision and distribution of
- necessary documentation for the manufacture;
- any other documentation related to product quality that is not mentioned elsewhere ( e.g. microbiological controls about air and water )
29. 7. Production –
- brief description of production operations using, wherever possible, flow sheets and charts specifying important parameters;
- arrangements for the handling of starting materials, packaging materials, bulk and finished products, including sampling, quarantine, release and storage;
- arrangements for the handling of rejected materials and products;
- brief description of general policy for process validation.
29. 8. Quality control –
- description of the quality control system and of the activities of the quality control department. Procedures for the release of the finished products.
29. 9. Loan licence manufacture and licensee –
- description of the way in which compliance of Good Manufacturing Practices by the loan licensee shall be assessed.
29. 10. Distribution, complaints and product recall –
- arrangements and recording system for distribution;
- arrangements for the handling of complaints and product recalls.
29. 11. Self-Inspection –
(a) short description of the self-inspection system indicating whether an outside, Independent and experienced external expert was involved in evaluating the manufacturer's compliance with Good Manufacturing Practices in all aspects of production.
29.12. Export of drugs –
( a ) products exported to different countries;
( b ) complaints and product recall, if any.
GMP IN THE MANUFACTURING OF PHARMACEUTICALS
STERILE DOSAGE FORMS (PARENTERAL AND OPHTHALMIC)
- General –
Sterile products, being very critical and sensitive in nature, a very high degree of precautions, prevention and preparations are needed. Dampness, dirt and darkness are to be avoided to ensure aseptic conditions in all areas. There shall be strict compliance in the prescribed standards especially in the matter of supply of water, air, active materials and in the maintenance of hygienic environment.
- Buildings And Civil Works
2. 1. The building shall be built on proper foundation with standardised materials to avoid cracks in critical areas like aseptic solution preparation, filling and sealing rooms.
2. 2. Location of services like water, steam, gases etc. shall be such that their servicing or repair shall not pose any threat to the integrity of the facility. Water lines shall not pose any threat of leakage to aseptic area.
2. 3. The manufacturing areas shall be clearly separated into support areas (e.g. washing and component preparation areas, storage areas etc.), preparation areas (e.g. bulk manufacturing area, non-aseptic blending areas etc.) change areas and aseptic areas. Operations like removal of outer cardboard wrappings of primary packaging materials shall be done in the de-cartoning areas which are segregated from the washing areas. Wooden pallets, fiber board drums, cardboard and other particle shedding materials shall not be taken inside the preparation areas.
2. 4. In aseptic areas –
Walls, floors and ceiling should be impervious, non-shedding, non-flaking and non-cracking. Flooring should be unbroken and provided with a cove both at the junction between the wall and the floor as well as the wall and the celing.
- walls shall be flat,
and ledges and recesses shall be avoided. Wherever other surfaces join the wall (e.g. sterilisers, electric sockets, gas points etc.) these shall be flush
with the walls. Walls shall be provided with a cove
at the joint between
the ceiling and floor.
- ceiling shall be solid and joints shall be sealed. Light-fittings and air-grills shall be flush with the walls and not hanging from the ceiling, so as to prevent contamination.
- there shall be no sinks and drains in Grade A and Grade B areas;
- doors shall be made of non-shedding material. These may be made preferably of Aluminium or Steel material. Wooden doors shall not be used. Doors shall open towards the higher-pressure area so that they close automatically due to air pressure.
- Windows shall be made of similar material as the
doors, preferably with double panel and shall be flush with the walls. If fire escapes are to be provided, these shall be suitably fastened to the walls without any gaps.
- the furniture used shall be smooth, washable and made of stainless steel or any other appropriate material other than wood.
2. 5. The manufacturing and the support areas shall have the same quality of civil structure described above for aseptic areas, except the environmental standards which may vary in the
2. 6. Change rooms with entrance in the form of air-locks shall be provided before entry into the sterile product manufacturing areas and then to the aseptic area. Separate exit space from the
aseptic areas is advisable. Change rooms to the
aseptic areas shall be clearly demarcated into 'black', 'gray' and 'white rooms' with different levels of activity and air cleanliness. The 'black' change room shall be provided with a hand-washing sink. The sink and its drain in the un- classified (first) change rooms may be kept clean all the time. The specially designed drain shall be periodically monitored to avoid presence of pathogenic micro-organisms. Change room doors shall not be opened simultaneously. An appropriate inter-locking system and a visual and/ or audible warning system may be installed to prevent the opening of more than one door at a time.
2. 7. For communication between aseptic areas and non-aseptic areas, intercom telephones or speak-phones shall be used. These shall be minimum in number.
2. 8. Material transfer between aseptic areas and outside shall be through suitable air-locks or pass-boxes. Doors of such air-locks and pass-boxes shall have suitable interlocking arrangements.
2. 9. Personal welfare areas like rest rooms, tea room, canteen and toilets shall be outside and separated from the
sterile product manufacturing area.
2.10. Animal houses shall be away from the sterile product manufacturing area and shall not share a common entrance or air handling system with the manufacturing area.
- Air Handling System (Central Air-Conditioning)
3. 1. Air Handling Units for sterile product manufacturing areas shall be different from those for other areas. Critical areas, such as the aseptic filling area, sterilized components unloading area and change rooms conforming to Grades B, C and D respectively shall have separate Air Handling Units. The filter configuration in the air handling system shall be suitably designed to achieve the Grade of air as given in Table I. Typical operational activities for clean areas are highlighted in Table II and Table III.
3. 2. For products which are filled aseptically, the filling room shall meet Grade B conditions at rest unmanned. This condition shall also be obtained within a period of about 30 minutes of the personnel leaving the room after completion of operations.
3. 3. The filling operations shall take place under Grade A conditions which shall be demonstrated under working of simulated conditions which
shall be achieved by providing Laminar Air flow work stations with suitable HEPA filters or isolator technology.
3. 4. For products, which are terminally sterilized, the filling room shall meet Grade C conditions at rest. This condition shall be obtainable within a period of about 30 minutes of the
personnel leaving the room after completion of operations.
3. 5. Manufacturing and component preparation areas shall meet Grade C conditions.
3. 6. After completion of preparation, washed components and vessels shall be protected with Grade C background and if necessary, under Laminar Air Flow work station.
3. 7. The minimum air changes for Grade B and Grade C areas shall not be less than 20 air changes per hour in a room with good air flow pattern and appropriate HEPA filters. For Grade A Laminar Air Flow work stations, the air flow rates shall be 0.3 meter per second 20 % (for vertical flows) and 0.45 meter per second 20 % (for horizontal flows).
Air Borne Particulate Classification For Manufacture Of Sterile Products
At rest (b)
In Operation (a)
Maximum number of permitted particles per cubic metre equal to or above
0. 5 m
0. 5 m
Not defined (c)
Not defined (c)
- In order to reach the B, C and D air grades, the number of air changes shall be related to the size of the room and the equipment and personnel present in the room. The air system shall be provided with the appropriate filters such as HEPA for Grades A, B and C. The maximum permitted number of particle "at rest" condition shall approximately be as under:
Grade A corresponds with Class 100 or M 3.5 or ISO class 5; Grade B with class 1000 or M 4.5 or ISO Class 6; Grade C with Class 10000 or M 5.5 or ISO Class 7; Grade D with Class 100,000 or M 6.5 or ISO Class 8.
- The requirement and limit for the area shall depend on the nature of the
operation carried out
- Type of operations to be carried out in the various grades are given in Table II and Table III as under:
Types of Operations To Be Carried Out In The Various Grades For Aseptic Preparations
Types of operations for aseptic preparations.
Aseptic preparation and filling.
Background room conditions for activities requiring Grade A.
Preparation of solution to be filtered.
Handling of components after washing.
Types of Operations To Be Carried Out In The Various Grades For Terminally Sterilized Products
Types of operations for terminally sterilized products.
Filling of products, which
are usually at risk.
Placement of filling and sealing machines, preparation of solutions, when usually at risk. Filling of product when unusually at risk.
Moulding, blowing (pre-forming) operations of plastic containers, Preparations of solutions and components for subsequent filling.
4. Environmental Monitoring
4. 1. All environmental parameters listed under para 3.1 to 3.10 shall be verified and established at the time of installation and thereafter monitored at periodic intervals. The recommended frequencies of periodic monitoring shall be as follows:
- 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.
4. 2. There shall be a written environmental monitoring program and microbiological results shall be recorded. Recommended limits for microbiological monitoring of clean areas "in operation" are as given in the table below :
Recommended Limits For Microbiological Monitoring Of Clean Areas "In-operation"
Air sample Cfu / m3
Settle plates ( dia. 90 mm. Cfu / 2 hrs.
Contact plates (dia. 55 mm) cfu per plate
Glove points (five fingers) cfu per glove
- These are average values.
- 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.
4. 3. Appropriate action shall be taken immediately if the result of particulate and microbiological monitoring indicates that the counts exceed the limits. The Standard Operating Procedures shall contain corrective action. After major engineering modification to the HVAC system of any area, all monitoring shall be re-performed before production commences.
5. 1. This section covers garments required for use by personnel working only in aseptic areas. Outdoor clothing shall not be brought into the sterile areas.
5. 2. The garments shall be made of non-shedding and tight weave material. Cotton garments shall not be used. The garments shall shed virtually no fibers or particulate matter.
5. 3. The clothing and its quality shall be adopted to the process and the work place and worn in such a way as to protect the product from contamination. Garments shall be single piece with fastenings at cuffs, neck and at legs to ensure close fit. Trouser legs shall be tucked inside the cover boots. Suitable design of garments shall either include a hood (head-cover) or a separate hood which can be tucked inside the over-all. Pockets, pleats and belts shall be avoided in garments. Zips (if any) shall be of Plastic material. Garments with damaged zips shall not be used.
5. 4. Only clean, sterilized and protective garments shall be used at each work session where aseptic filtration and filling operations are undertaken and at each work shift for products intended to be sterilized, post-filling. The mask and gloves shall be changed at every work session in both instances.
5. 5. Gloves shall be made of latex or other suitable plastic materials and shall be powder-free. These shall be long enough to cover wrists completely and allow the over-all cuff to be tucked in.
5. 6. The footwear shall be of suitable plastic or rubber material and shall be daily cleaned with a bactericide.
5. 7. Safety goggles or numbered glasses with side extensions shall be used inside aseptic areas. These shall be sanitised by a suitable method.
5. 8. Garment changing procedure shall be documented and operators trained in this aspect. A full size mirror shall be provided in the final change room for the operator to verify that he is appropriately attired in the garments. Periodic inspection of the garments shall be done by responsible staff.
6. 1. There shall be written procedures for the sanitation of sterile processing facilities. Employees carrying out sanitation of aseptic areas shall be trained specifically for this purpose.
6. 2. Different sanitizing agents 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.
6. 3. Distilled water freshly collected directly from the distilled water plant or water maintained above 70 degree centigrade from the re-circulation loop shall be used for dilution of disinfectants. Alternately, distilled water sterilised by autoclaving or membrane filtration shall be used. The dilution shall be carried out in the 'white' change room.
6. 4. Where alcohol or Isopropyl alcohol is used for dilution of disinfectants for use as hand sprays, the preparation of the same shall be done in the bulk preparation area and the diluted solution membrane-filtered into suitable sterile containers held in aseptic area.
6. 5. Diluted disinfectants shall bear the label 'use before', based on microbiological establishment of their germicidal properties. The solutions shall be adequately labeled and documents maintained.
6. 6. Formaldehyde or any other equally effective fumigant is recommended for the fumigation of aseptic areas or after major civil modifications. There shall be Standard Operating Procedures for this purpose . Its use for routine purposes shall be discouraged and an
equally effective surface cleaning regime shall be followed.
6. 7. Cleaning of sterile processing facilities shall be undertaken with air suction devices or with non-linting sponges or clothes.
6. 8. Air particulate quality shall be evaluated on a regular basis and records maintained.
7. 1. The special equipment required for manufacturing sterile products includes component washing machines, steam sterilisers, dry heat sterilisers, membrane filter assemblies, manufacturing vessels, blenders, liquid filling machines, powder filling machines, sealing and labeling machines, vacuum testing chambers, inspection machines, lyophilisers, pressure vessels etc. Suitable and fully integrated washing-sterilizing- filling lines may be provided, depending upon the type and volume of activity.
7. 2. Unit-sterilisers shall be double-ended with suitable inter-locking arrangements between the doors. The effectiveness of the sterilization process shall be established initially by biological inactivation studies using microbial spore indicators and then at least once a year by carrying out thermal mapping of the chamber. Various sterilization parameters shall be established based on these studies and documented. For membrane filters used for filtration, appropriate filter integrity tests that ensure sterilization shall be carried out before and after filtration.
7. 3. Filling machines shall be challenged initially and then at periodic intervals by simulation trials including sterile media fill. Standard Operating Procedures and acceptance criteria for media fills shall be established, justified and documented. Special simulation trial procedures shall be developed, validated and documented for special products like ophthalmic ointments.
7. 4. The construction
for the parts which are in direct contact with products and the
manufacturing vessels may be stainless steel 316 or Boro-silicate glass (if glass containers) and the
tubing shall be capable of being washed and autoclaved.
7. 5. On procurement, installation qualification of each of the equipment shall be done by engineers with the support of production and quality assurance personnel. Equipment for critical processes like aseptic filling and sterilizers shall be suitably validated according to a written program before putting them to use.
7. 6. Standard Operating Procedures shall be available for each equipment for its calibration and operation and cleaning. Gauges and other measuring devices attached to equipment shall be calibrated at suitable intervals against a written program. Calibration status of equipment and gauges shall be adequately documented and displayed.
8.Water and Steam Systems
8. 1. Potable water meeting microbiological specification of not more than 500 cfu/ml and indicating absence of individual pathogenic micro-organisms. Escherichia
coli, Salmonella, Staphylococcus aureus and Pseudomonas aeruginosa per 100 ml sample shall be used for the preparation of purified water.
8. 2. Purified water prepared by de-mineralization shall meet the microbiological specification of not more than 100 cfu per ml and indicate
absence of pathogenic micro-organisms in 100 ml. Purified water shall also meet IP specifications for chemical quality. Purified water shall be used for hand washing in change rooms. Containers, closures and machine parts may be washed with potable water followed by suitably filtered purified water. Purified water shall be stored in stainless steel tanks or plastic tanks.
8. 3. Water for Injection (hereinafter referred as WFI) shall be prepared from potable water or purified water meeting the above specifications by distillation. Water for Injection shall meet microbiological specification of not more than 10 cfu per 100 ml. WFI shall also meet IP specification for Water for Injection and shall have an endotoxin level of not more than 0.25 EU / ml. Bulk solutions of liquid parenterals shall be made in WFI. Final rinse of product containers and machine parts shall be done with WFI. Disinfectant solutions for use in aseptic areas shall be prepared in WFI.
8. 4. Water for Injection for the manufacture of liquid injectables shall be freshly collected from the distillation plant or from a storage or circulation loop where the water has been kept at above 70 degree centigrade. At the point of collection, water may be cooled using suitable heat exchanger.
8. 5. Water for non-injectable sterile products like eye drops shall meet IP specifications for purified water. In addition, microbiological specification of not more than 10 cfu per 100 ml and absence of Pseudomonas aeruginosa and Enterobacter coli in 100 ml shall also be met.
8. 6. Water for Injection shall be stored in steam jacketted stainless steel tanks of suitable size and the tanks shall have hydrophobic bacterial retention with 0.22 microns vent filters. The filters shall be suitably sterilized at periodic intervals. The distribution lines for purified water and distilled water shall be of stainless steel 316 construction and shall not shed particles.
8. 7. There shall be a written procedure and program for the sanitation of different water systems including storage tanks, distribution lines, pumps and other related equipment. Records of sanitation shall be maintained.
8. 8. There shall be written microbiological monitoring program for different types of water. The results shall justify the frequency of sampling and testing. Investigation shall be carried out and corrective action taken in case of deviation from prescribed limits.
8. 9. Steam coming in contact with the product, primary containers and other product contact surfaces shall be sterile and pyrogen free. The steam condensate shall meet microbiological specification of not more than 10 cfu per 100 ml. The condensate shall also meet IP specification for Water for Injection and shall have an endotoxin levels of not more than 0.25 EU/ml. There shall be a suitable schedule for the monitoring of steam quality.
9. Manufacturing Process
9. 1. Manufacture of sterile products shall be carried out only in areas under defined conditions.
9. 2. Bulk raw materials shall be monitored for bio-burden periodically. Bio-burden of bulk solution prior to membrane filtration shall be monitored periodically and a limit of not more than 100 cfu per ml is recommended.
9. 3. The time between the start of the preparation of the solution and its sterilization or filtration through a micro-organism retaining filter shall be minimised. There shall be a set maximum permissible time for each product that takes into account its composition and method of storage mentioned in the
Master formula record.
9. 4. Gases coming in contact with the
sterile product shall be filtered through two 0.22 microns hydrophobic filters connected in-series. These filters shall be tested for integrity. Gas cylinders shall not be taken inside aseptic areas.
9. 5. Washed containers shall be sterilized immediately before use. Sterilized containers, if not used within an established time, shall be rinsed with distilled or filtered purified water and re-sterilized.
9. 6. Each lot of finished product shall be filled in one continuous operation. In each case, where
one batch is filled
in using more than one operation, each lot shall be tested separately for sterility and held separately till sterility test results are known.
9. 7. Special care shall be exercised while filling products in powder form so as not to contaminate the environment during transfer of powder to filling machine-hopper.
10.FORM-FILL-SEAL TECHNOLOGY OR BLOW, FILL-SEAL TECHNOLOGY
10. 1. Form-Fill-Seal units are specially built automated machines in which through one continuous operation, containers are formed from thermoplastic granules, filled and then sealed. Blow, fill - seal units are machines in which containers are moulded/blown (pre-formed) in separate clean rooms, by non continuous operations.
- These shall be installed in at least Grade C environment.
- These shall comply with the limits as recommended in Table at item 4.2.
10. 2. Form - Fill - Seal / Blow, Fill - Seal machines used for the manufacture of products for terminal sterilization shall be installed in at least Grade C environment and the filling zone within the machine shall fulfill Grade A requirements.
10. 3. Terminally Sterilized Products
- Preparation of primary packaging material such as glass bottles, ampoules and
rubber stoppers shall be done in at least Grade D environment. Where there is unusual risk to the product from microbial contamination, the above operation shall be done in Grade C environment. All the processes used for component preparation shall be validated.
- Filling of products requiring terminal sterilization shall be done under Grade A environment with a Grade C background.
10. 4. Preparation of solutions, which are to be sterilized by filtration, shall be done in Grade C environment, and if not to be filtered, the preparation of materials and products shall be in a Grade A environment with Grade B in background.
10. 5. Filtration ( Membrane )
( i ) Solutions for Large Volume Parenterals shall be filtered through a non-fiber releasing, sterilizing grade cartridge/membrane filter of nominal pore size of 0.22 microns for aseptic filling whereas 0.45 microns porosity shall be used for terminally sterilized products.
( ii ) A second filtration using another 0.22 microns sterilizing grade cartridge/membrane filter shall be performed immediately prior to filling. Process specifications shall indicate the maximum time during which a filtration system may be used with a view to precluding
microbial build-up to levels that may affect the microbiological quality of the Large Volume Parenterals.
( iii ) The integrity of the sterilized filter shall be verified and confirmed immediately after use by an appropriate method such as Bubble Point, Diffusive Flow or Pressure Hold Test.
10. 6. Sterilization ( Autoclaving )
10.6.1. Before any sterilization process is adopted, its suitability for the product and its efficacy in achieving the desired sterilizing conditions in all parts of each type of load pattern to be processed, shall be demonstrated by physical measurements and by biological indicators, where appropriate.
10.6.2. All the sterilization processes shall be appropriately validated. The validity of the process shall be verified at regular intervals, but at least annually. Whenever significant modifications have been made to the equipment and product, records shall be maintained thereof.
10.6.3.The sterilizer shall be double ended to prevent mix-ups.
10.6.4.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.
10.6.5.The use of biological indicators shall be considered as an additional method for monitoring the sterilization. These shall be stored and used according to the manufacture's instructions. Their quality shall be checked by positive controls. If biological indicators are used, strict precautions shall be taken to avoid transferring microbial contamination from them.
10.6.6.There shall be clear means of differentiating 'sterilized' and 'unsterilized' products. Each basket, tray or other carrier of products or components shall be clearly labeled with the name of the material, its batch number, and sterilization status. Indicators shall be used, where appropriate, to indicate whether a batch (or sub-batch) has passed through the sterilization process.
10.6.7.Sterilization records shall be available for each sterilization-run and may also include thermographs and sterilization monitoring strips. They shall be maintained as part of the batch release procedure.
10. 7. Sterilization ( By Dry Heat )
10.7.1. Each heat sterilization cycle shall be recorded on a time / temperature chart of a suitable size by appropriate equipment of the required accuracy and precision. The position of temperature probes used for controlling and / or recording shall be determined during the validation and, where applicable, shall also be checked against a second independent temperature probe located in the same position. The chart shall form a part of the batch record. Container mapping may also be carried out in the case of Large Volume Parenterals.
10.7.2. Chemical or biological indicators may also be used, but shall not take the place of physical validation.
10.7.3. Sufficient time shall be allowed for the load to reach the required temperature before measurement of sterilization time commences. This time shall be separately
determined for each type of load to be processed.
10.7.4. After the high temperature phase of a heat sterilization cycle, precautions shall be taken against contamination of sterilized load during cooling. Any cooling fluid or gas in contact with the product shall be sterilized unless it can be shown that any leaking container would not be approved for use. Air inlet and outlets shall be provided with bacteria retaining filters.
10.7.5.The process used for sterilization by dry heat shall include air-circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non-sterile air. Air inlets and outlets should be provided with micro-organism retaining filters. Where this process of sterilization by dry heat is also intended to remove pyrogens, challenge tests using endotoxins would be required as part of the validation process.
Sterilization (By Moist Heat)
10.8.1. Both the temperature and pressure shall be used to monitor the process. Control instrumentation shall normally be independent of monitoring instrumentation and recording charts. Where automated control and monitoring systems are used for these applications, these shall be validated to ensure that critical process requirements are met. System and cycle faults shall be registered by the system and observed by the operator. The reading of the independent temperature indicator shall be routinely checked against the chart-recorder during the sterilization period. For sterilizers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position throughout the sterilization period. There shall be frequent leak tests done on the chamber during the vacuum phase of the cycle.
10.8.2. The items to be sterilized, other than products in sealed containers, shall be wrapped in a material which allows removal of air and penetration of steam but which prevents re-contamination after sterilization. All parts of the load shall be in contact with the sterilizing agent at the required temperature for the required time.
10.8.3. No Large Volume Parenteral shall be subjected to steam sterilization cycle until it has been filled and sealed.
10.8.4. Care shall be taken to ensure that the steam used for sterilization is of a suitable quality and does not contain additives at a level which could cause contamination of the product or equipment.
10. 9. Completion / Finalisation of Sterile Products
10.9.1. All unit operations and processes in the manufacture of a batch shall have a minimum time specified and the shortest validated time shall be used from the
start of a batch to its ultimate release for distribution.
10.9.2. Containers shall be closed by appropriately validated methods. Containers closed by fusion, e.g. glass or plastic ampoules shall be subjected to 100 % integrity testing. Samples of other containers shall be checked for integrity according to appropriate procedures.
10.9.3. Containers sealed under vacuum shall be tested for required vacuum conditions.
10.9.4. Filled containers of parenteral products shall be inspected individually for extraneous contamination or other defects. When inspection is done visually, it shall be done under suitably controlled conditions of illumination and background. Operators doing the inspection shall pass regular eye-sight checks with spectacles, if worn, and be allowed frequent rest from inspection. Where other methods of inspection are used, the process shall be validated and the performance of the equipment checked at suitable intervals. Results shall be recorded.
11. Product Containers And closures
11. 1. All containers and closures intended for use shall comply with the pharmacopoeial and other specified requirements. Suitable sample sizes, specifications, test methods, cleaning procedures and sterilization procedures, shall be used to assure that containers, closures and other component parts of drug packages are suitable and are not reactive, additive, adsorptive or leachable or presents the risk of toxicity to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used.
11. 2. Plastic granules shall also comply with the Pharmacopoeial requirements including physio-chemical and biological tests.
11. 3. All containers and closures shall be rinsed prior to sterilization with water for injection according to written procedure.
11. 4. The design of closures, containers and stoppers shall be such as to make cleaning, easy and also to make an airtight seal when fitted to the bottles.
11. 5. It shall be ensured that containers and closures chosen for a particular product are such that when coming into contact they are not absorbed into the product and they do not affect the product adversely. The closures and stoppers should be of such quality substances as not to affect the quality of the product and avoid the risk of toxicity.
11. 6. Whenever glass bottles are used, the written schedule of cleaning shall be laid down and followed. Where bottles are not dried after washing, these shall be finally rinsed with distilled water or pyrogen free water, as the case may be, according to written procedure.
11. 7. Individual containers of parenteral preparations, ophthalmic preparations shall be examined against black/white background fitted with diffused light after filling so as to ensure freedom from foreign matters.
11.8.1. Shape and design of the glass bottle shall be rational and standardized. Glass bottles made of USP Type-I and USP Type-II glass shall only be used. Glass bottles shall not be reused. Before use, USP Type-II bottles shall be validated for the absence of particulate matter generated over a period of the shelf-life of the product and shall be regularly monitored after production, following statistical sampling methods. USP Type-III glass containers may be used for non- parenteral sterile products such as Otic Solutions.
11. 9. Plastic Containers
11.9.1. Pre-formed plastic containers intended to be used for the packing of Large Volume Parenteral shall be moulded in-house by one-continuous operation through an automatic machine.
11.9.2. Blowing, filling and sealing (plugging) operations shall be conducted in room(s) conforming to requirements as mentioned in Table III of Item 3.10. Entry to the area where such operations are undertaken, shall be through a series of air locks. Blowers shall have an air supply which is filtered though 0.22 microns filters. Removal of runners and plugging operations shall be conducted under a laminar airflow work station.
11.10.1. The rubber stoppers used for Large Volume Parenterals shall comply with specifications prescribed in the current edition of the
12. 1. The manufacturing records relating to manufacture of sterile products shall indicate the following details : -
- 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.
- Quantity 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.
- Temperature and humidity records whenever applicable.
- Records of plate-counts whenever applicable.
- Results of pyrogen and/or bacterial endotoxin & toxicity.
- Records 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.
- Clarification for variation in yield beyond permissible yield.
- Reference numbers of relevant analytical reports.
- Details of reprocessing, if any.
- Name of all operators carrying out different activities.
- Environmental monitoring records.
- Specimens of printed packaging material.
- Records of destruction of rejected containers and printed packaging materials.
- Signature of the competent technical staff responsible for manufacture and testing.
- Products shall be released only after complete filling and testing.
- Result of the tests relating to sterility, pyrogens, and
Bacterial endotoxins shall be maintained in the analytical records.
- Validation details and simulation trial records shall be maintained separately.
- Records of environmental monitoring like temperature, humidity, microbiological data etc. shall be maintained. Records of periodic servicing of HEPA filters, sterilizers and other periodic maintenance of facilities and equipment carried out shall also be maintained.
- Separate facilities shall be provided for filling-cum-sealing of Small Volume Injectables and Large Volume Parenterals.
- Separate facilities shall be provided for manufacture of Large Volume parenterals in glass containers and plastic containers.
ORAL SOLID DOSAGE FORMS (TABLETS AND CAPSULES)
Note : Good Manufacturing Practices for Premises and materials for pharmaceutical products shall be complied with the manufacture of oral Solid Dosage Forms (Tablets and capsules). In addition to these requirements, the following Specific Requirements shall also be followed, namely: -
1. 1. The processing of dry materials and products creates problems of dust control and cross-contamination. Special attention is, therefore, needed in the design, maintenance and use of premises and equipment in order to overcome these problems. Wherever required, enclosed dust control manufacturing systems shall be employed.
1.2. Suitable environmental conditions for the products handled shall be maintained by installation of air-conditioning wherever necessary. Effective air-extraction systems, with discharge points situated to avoid contamination of other products and processes shall be provided. Filters shall be installed to retain dust and to protect the factory and local environment.
1. 3 Special care shall be taken to protect against subsequent contamination of the product by particles of metal or wood. The use of metal detector is recommended. Wooden equipment should be avoided. Screens, sieves, punches and dies shall be examined for wear and tear or for breakage before and after each use.
1. 4. All ingredients for a dry product shall be sifted before use unless the quality of the input material can be assured. Such sifting shall normally be carried out at dedicated areas.
1. 5. Where the facilities are designed to provide special environmental conditions of pressure differentials between rooms, these conditions shall be regularly monitored and any specification results brought to the immediate attention of the Production and Quality assurance departments which shall be immediately attended to.
1. 6. Care shall be taken to guard against any material lodging and remaining undetected in any processing or packaging equipment. Particular care shall be taken to ensure that any vacuum, compressed air or air-extraction nozzles are kept clean and that there is no evidence of lubricants leaking into the product from any part of the equipments.
- Sifting, mixing and granulation
2. 1. Unless operated as a closed system, mixing, sifting and blending equipments shall be fitted with dust extractors.
2.2 Residues from sieving operations shall be examined periodically for evidence of the presence of unwanted materials.
2. 3. Critical operating parameters like time and temperature for each mixing, blending and drying operation shall be specified in a Master Formula, monitored during processing, and recorded in the batch records.
2. 4. Filter bags fitted to fluid-bed-drier shall not be used for different products, without being washed in-between use. With certain highly potent or sensitising products, bags specific to one product only shall be used. Air entering the drier shall be filtered. Steps shall be taken to prevent contamination of the site and local environment by dust in the air leaving the drier due to close positioning of the air-inlets and exhaust.
2. 5. Granulation and coating solutions shall be made, stored and used in a manner which minimises the risk of contamination or microbial growth.
- Compression (Tablets)
3. 1. Each tablet compressing machine shall be provided with effective dust control facilities to avoid cross contamination. Unless the same product is being made on each machine, or unless the compression machine itself provides its own enclosed air controlled environment, the machine shall be installed in separate cubicles.
3. 2. Suitable physical, procedural and labeling arrangements shall be made to prevent mix-up of materials, granules and tablets on compression machinery.
3. 3. Accurate and calibrated weighing equipment shall be readily available and used for in-process monitoring of tablet weight variation. Procedures used shall be capable of detecting out-of-limits tablets.
3. 4. At the commencement of each compression run and in case of multiple compression points in a compression machine, sufficient individual tablets shall be examined at fixed intervals to ensure that a tablet from each compression station or from each compression point has been inspected for suitable pharmacopoeial parameters like 'appearance', 'weight variation', 'disintegration', 'hardness', 'friability' and 'thickness'. The results shall be recorded as part of the batch documentation.
3. 5. Tablets shall be de-dusted, preferably by automatic device and shall be monitored for the presence of foreign materials besides any other defects.
3. 6. Tablets shall be collected into clean, labeled containers.
3. 7. Rejected or discarded tablets shall be isolated in identified containers and their quantity recorded in the Batch Manufacturing Record.
3. 8. In-process control shall be employed to ensure that the products remain within specification. During compression, samples of tablets shall be taken at regular intervals of not greater than 30 minutes to ensure that they are being produced in compliance with specified in-process specification. The tablets shall also be periodically checked for additional parameters such as 'appearance', 'weight variation', 'disintegration', 'hardness', 'friability ' and 'thickness' and contamination by lubricating oil.
- Coating (Tablets)
4. 1. Air supplied to coating pans for drying purposes shall be filtered air and of suitable quality. The area shall be provided with suitable exhaust system and environmental control (temperature, humidity) measures.
4. 2. Coating solutions and suspensions shall be made afresh and used in a manner, which shall minimise the risk of microbial growth. Their preparation and use shall be documented and recorded.
- Filling of Hard Gelatin Capsule
Empty capsules shells shall be regarded as 'drug component' and treated accordingly. They shall be stored under conditions which shall ensure their safety from the effects of excessive heat and moisture.
- Printing (Tablets And Capsules)
6. 1. Special care shall be taken to avoid product mix-up during any printing of tablets and capsules. Where different products, or different batches of the same product, are printed simultaneously, the operations shall adequately be segregated. Edible grade colours and suitable printing ink shall be used for such printing.
6. 2. After printing, tablets and capsules shall be approved by Quality Control before release for packaging or sale.
- Packaging (Strip and Blister)
7. 1. Care shall be taken when using automatic tablet and capsule counting, strip and blister packaging equipment to ensure that all 'rogue' tablets, capsules or foils from packaging operation are removed before a new packaging operation is commenced. There shall be an independent recorded check of the equipment before a new batch of tablets or capsules is handled.
7. 2. Uncoated tablets shall be packed on equipment designed to minimise the risk of cross-contamination. Such packaging shall be carried out in an isolated area when potent tablets or Beta-lactum containing tablets are being packed.
7. 3. The strips coming out of the machine shall be inspected for defects such as misprint, cuts on the foil, missing tablets and improper sealing.
7. 4. Integrity of individual packaging strips and blisters shall be subjected to vacuum test periodically to ensure leak proofness of each pocket strip
and records maintained.
ORAL LIQUIDS (SYRUPS, ELIXIRS, EMULSIONS AND SUSPENSIONS)
Note : The General Requirements as given in Good Manufacturing Practices for Premises and Materials for pharmaceutical products shall be complied with the manufacture of ( Syrups , Elixirs, Emulsions and Suspensions ). In addition to these requirements, the following Specific Requirements shall also be followed, namely
- Building And Equipment
1. 1. The premises and equipment shall be designed, constructed and maintained to suit the manufacturing of Oral Liquids. The layout and design of the manufacturing area shall strive to minimize the risk of cross- contamination and mix-ups.
1. 2. Manufacturing area shall have entry through double door air-lock facility. It shall be made fly proof by use of ' fly catcher' and / or 'air curtain'.
1. 3. Drainage shall be of adequate size and have adequate traps, without open channels and the
design shall be such as to prevent back flow. Drains shall be shallow to facilitate cleaning and disinfecting.
1. 4. The production area shall be cleaned and sanitised at the end of every production process.
1. 5. Tanks, containers, pipe work and pumps shall be designed and installed so that they can be easily cleaned and sanitized. Equipment design shall be such as to prevent accumulation of residual microbial growth or cross-contamination.
1. 6. Stainless Steel or any other appropriate material shall be used for parts of equipments coming in direct contact with the products. The use of glass apparatus shall be minimum.
1. 7. Arrangements for cleaning of containers, closures and droppers shall be made with the help of suitable machines/devices equipped with high pressure air, water and steam jets.
1. 8. The furniture used shall be smooth, washable and made of stainless steel.
- Purified Water
2. 1. The chemical and microbiological quality of purified water used shall be specified and monitored routinely. The microbiological evaluation shall include testing for absence of pathogens and shall not exceed 100 cfu / ml (as per Appendix 12.5 of IP 1996).
2. 2. There shall be a written procedure for operation and maintenance of the
purified water system. Care shall be taken to avoid the risk of microbial proliferation with appropriate methods like recirculation, use of UV treatment, treatment with heat and sanitizing agent. After any chemical sanitisation of the water system, a flushing shall be done to ensure that the
sanitizing agent has been effectively removed.
3. 1. Manufacturing personnel shall wear non-fiber shedding clothing to prevent contamination of the product.
3. 2. Materials likely to shed fiber like gunny bags, or wooden pallets shall not be carried into the area where products or cleaned- containers are exposed.
3. 3. Care shall be taken to maintain the homogenity of emulsion by use of appropriate emulsifier and suspensions by use of appropriate stirrer during filling. Mixing and filling processes shall be specified and monitored. Special care shall be taken at the beginning of the filling process, after stoppage due to any interruption
and at the end of the process to ensure that the product is uniformly homogenous during the filling process.
3. 4. The primary packaging area shall have an air supply which is filtered through 5 micron filters. The temperature of the area shall not exceed 30 degrees centigrade.
3. 5. When the bulk product is not immediately packed, the maximum period of storage and storage conditions shall be specified in the Master Formula. The maximum period of storage time of a product in the bulk stage shall be validated.
EXTERNAL PREPARATIONS (CREAMS, OINTMENTS, PASTES, EMULSIONS, LOTIONS, SOLUTIONS, DUSTING POWDERS AND IDENTICAL PRODUCTS)
Note : The General Requirements as given in Good Manufacturing Practices for premises and Materials for pharmaceutical products shall be complied with the manufacture of Topical Products i.e. External Preparations (Creams, Ointments, Pastes, Emulsions, Lotions, Solutions, Dusting powders and identical products used for external applications). In addition to these requirements, the following Specific Requirements shall also be followed, namely :
1.The entrance to the area where topical products are manufactured shall be through a suitable airlock. Outside the airlock, insectocutors shall be installed.
2.The air to this manufacturing area shall be filtered through at least 20 air filters and shall be air-conditioned. The area shall be ventilated.
3.The area shall be fitted with an exhaust system of
suitable capacity to effectively remove vapours, fumes, smoke or floating dust particles.
equipment used shall be designed and maintained to prevent the product from being accidentally contaminated with any foreign matter or lubricant.
5.No rags or dusters shall be used in the process of cleaning or drying the process equipment or accessories used.
6.Water used in compounding shall be Purified Water IP.
7.Powders, whenever used, shall be suitably sieved before use.
8.Heating vehicles and a
base like petroleum jelly shall be done in a separate mixing area in suitable stainless steel vessels, using steam, gas, electricity, solar energy etc.
9.A separate packing section may be provided for primary packaging of the products.
METERED – DOSE INHALERS (MDI)
The General Requirements as given inf Good Manufacturing Practices for premises and Materials for pharmaceutical products shall be complied with the manufacture of Metered-Dose-Inhalers (MDI). In addition to these requirements, the following Specific Requirements shall also be followed, namely :
Manufacture of Metered-Dose-Inhalers shall be done under conditions which shall ensure minimum microbial and particulate contamination. Assurance of the quality of components and the bulk product is very important. Where medicaments are in suspended state, uniformity of suspension shall be established.
- Building and civil works
2. 1. 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.
2. 2. All building surfaces shall be impervious, smooth and non-shedding. Flooring shall be continuous and provided with a cover between the floor and the wall as well as between the wall and the ceiling. Ceiling shall be solid, continuous and proceeded a cone with the walls. Light fittings and air-grills shall be flush with the ceiling. All service lines requiring maintenance shall be erected in such a manner that these are accessible from outside the production area.
2. 3. The manufacturing area shall be segregated into change rooms for personnel, container preparation area, bulk preparation and filling area, quarantine area and spray testing and packing areas.
2. 4. Secondary change rooms shall be provided for operators to change from factory clothing to special departmental clothing before entering the manufacturing and filling area.
2. 5. Separate area shall be provided for de-cartoning of components before they are air washed.
2. 6. The propellants used for manufacture shall be delivered to the manufacturing area distribution system by filtering them through 2 micron filters. The bulk containers of propellants shall be stored, suitably identified, away from the manufacturing facilities.
- Environmental Conditions
3. 1. Where products or clean components are exposed, the area shall be supplied with filtered air of Grade C.
3. 2. The requirements of temperature and humidity in the manufacturing area shall be decided depending on the type of product and propellants handled in the facility. Other support areas shall have comfort levels of temperature and humidity.
3. 3. There shall be a difference in room pressure between the manufacturing area and the support areas and the differential pressure shall be not less than 15 Pascals, (0.06 inches or 1.5 mm Water gauge).
3. 4. There shall be a written schedule for the monitoring of environmental conditions. Temperature and humidity shall be monitored daily.
4. 1. Personnel in the manufacturing and filling section shall wear suitable single-piece-garment made out of non-shedding, tight weave material. Personnel in support areas shall wear clean factory uniforms.
4. 2. Gloves made of suitable material having no interaction with the propellants shall be used by the operators in the manufacturing and filling areas. Preferably, disposable gloves shall be used.
4. 3. Suitable department-specific personnel protective equipment like footwear and safety glasses shall be used wherever hazard exists.
5. 1. There shall be written procedures for the sanitation of the MDI manufacturing facility. Special care should be taken to handle residues and rinses of propellants.
5. 2. Use of water for cleaning shall be restricted and controlled. Routinely used disinfectants are suitable for sanitising the different areas. Records of sanitation shall be maintained.
6. 1. Manufacturing equipment shall be of closed system. The vessels and supply lines shall be of stainless steel.
6. 2. Suitable check weights, spray testing machines and labelling machines shall be provided in the department.
6. 3. All the equipment shall be suitably calibrated and their performance validated on receipt and thereafter periodically.
7. 1. There shall be an approved master formula records for the manufacture of metered dose inhalers. All propellants, liquids and gases shall be filtered through 2 micron filters to remove particles.
7. 2. The primary packing material shall be appropriately cleaned by compressed air suitably filtered through 0.2 micron filter. The humidity of the compressed air shall be controlled as applicable.
7. 3. The valves shall be carefully handled and after de-cartoning, these shall be kept in clean, closed containers in the filling room.
7. 4. For suspensions, the bulk shall be kept stirred continuously.
7. 5. In-process controls shall include periodical checking of weight of bulk formulation filled in the containers. In a two-shot-filling process (liquid filling followed by gaseous filling), it shall be ensured that 100 % check on
weight is carried out.
7. 6. Filled containers shall be quarantined for a
suitable period established by the manufacturer to detect leaking containers prior to testing, labelling and packing.
8. 1. In addition to the routine good manufacturing practices documentation of manufacturing records shall be show the following additional information:-
( 1 ) Temperature and humidity in the manufacturing area.
( 2 ) Periodic filled weights of the formulation.
( 3 ) Records of rejections during on line check weighing.
( 4 ) Records of rejection during spray testing.
The quality and purity of the pharmaceutical product depends on the Condition maintained during the manufacturing process. The Good Manufacturing Process(GMP) concept strictly adhere to stringent specifications followed during the manufacturing process. This assure the quality of the final product. Hence GMP is very essential to provide quality products and thereby preventing the market entry for counterfit drug.
- The principal rules were published in the official gazette vide notification No. F.28-10/45-H(1) dated 21st December 1945 and last amended vide GSR 700(E) dated 28-09-2001
- The drug and cosmetic rules, 1945, as amended upto 01-05-1979 is contained in the publication of the ministry of health and family welfare (department of health) containing the drug and cosmetics act 1940 (PDGHS-61).
- Global programme for vaccines supply and quality written by Gillian Chaloner – Larsson, Roger Anderson and Anik Egan.
- A plan for total quality control by P.P. Sharma
- Companion volume to a HANDBOOK OF DRUG LAWS by M.L. Mehra