MINISTRY OF HEALTH AND FAMILY WELFARE (Department of Health)-The Drugs Technical Advisory Board, propose to make, in exercise of the powers conferred by sections 12 and 33 of the Drugs and Cosmetics Act, 1940 (23 of 1940), is hereby published as required by the said sections for the information of all persons likely to be affected thereby

REGD. No D, L,-33004/99 The Gazette of India

EXTRAORDINARY

PART II—Section 3—Sub-section (1)

PUBLISHED BY AUTHORITY

No. 8 ] NEW DELHI, THURSDAY, JANUARY 4,2001/PAUSA 14,1922

39 GI/2001

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T HE G A Z E T TE OF I N D IA • E X T R A O R D I N A RY2 2X

THE GAZETTE OF INDIA. EXTRAORDINARY

[PART II—She 3(i)l29 M) THE GAZETTE OF INDIA . EXTRAORDINARY [PART II—SFc.^(i)| 31 M THE GAZETTE OF INDIA EXTRAORDINARY ' [PART II—SEC 3(i)] 3 V1GI/2001 —EU THE GAZETTE OF INDIA EXTRAORDINARY [PARI 11—SH-l(i)| ^ E OF A. A

[PART II—SEC\.<37 38 THE GAZETTE OF INDIA: EXTRAORDINARY [PART II—SEC.3(J)} 39 40 THE GAZETTE OF INDIA: EXTRAORDINARY [PART II—SEC.3(i)] 41 39GI/20Q1—642 THE GAZETTE OF INDIA : EXTRAORDINARY P^ART II—SEC. 3(i)1

MINISTRY OF HEALTH AND FAMILY WELFARE

(Department of Health)

NOTIFICATION

New Delhi, the 4th January, 2001

G. S. R. 8(E).—The following draft of certain rules further to amend the Drugs and Cosmetics Rules, 1945, which the Central Government, after consultation with the Drugs Technical Advisory Board, propose to make, in exercise of the powers conferred by sections 12 and 33 of the Drugs and Cosmetics Act, 1940 (23 of 1940), is hereby published as re- quired by the said sections for the information of all persons likely to be affected thereby; and notice is hereby given that the said draft rules shall be taken into consideration after the expiry of forty five days from the date on which the copies of the Gazette of India in which the notification is published, are made available to the public;

Objections or suggestions may be addressed to the Secretary, Ministry of Health and Family Welfare, Government of India, Nirman Bhavan, New Delhi-110011.

Any objections or suggestions which may be received from any person with respect to the said rules within the expiry period specified above shall be taken into consideration by the Central Government.

DRAFT RULES

1.(1) These rules may be called the Drugs and Cosmetics (Amendment) Rules, 2000.

(2) They shall come into force on the date of their final publication in the Official Gazette.

(3) Notwithstanding contained anything in sub-rule (2), these rules shall not apply to the manufacturers, who are having licence for manufacture of drugs, for a period of two years from the date of such commencement.

2 In the Drugs and Cosmetics Rules, 1945, for Schedule M, the following Schedule shall be substituted, namely •—

"SCHEDULE M

(See rule 71, 74, 76, and 78)

GOOD MANUFACTURING PRACTICES AND REQUIREMENTS OF PREMISES, PLANT AND EQUIPMENT FOR PHARMACEUTICAL PRODUCTS

Note : To achieve the objectives listed below, each licensee shall evolve appropriate

methodology, systems and procedures which shall be documented and maintained

for i ispection and reference; and the manufacturing premises shall be used-exclu-

sively for production of drugs and no other manufacturing activity shall be under-

taken therein.

PART - I

(Good Manufacturing Practices for Premises and Materials)

1 GENERAL REQUIREMENTS -

1.1. Location and surroundings.- The.factory building(s) for manufacture of d u ur shall be located, preferably in an industrial area and 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 such as 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, 1940 (63 of 1948). The premises used for manufacturing, processing, warehousing, packaging, labeling and testing purposes shall be\- (i) compatible with other diug manufacturing operations that may bo carried out in the same or adjacent area / section ;

(n) adequately provided with working space to allow orderly and logical placement of equipment, materials and movement of,p*ersonnel to .

(a) avoid risk of mix-up between different categories of dnujs or

with raw materials, intermediates and in-process material,

(b) avoid the possibilities of contamination mid cross- conlamiikilKm

by providing suitable mechanism,

(iii) designed/constructed/maintained to prevent entry of insects, posts, birds, vermins and rodonls. Interior surface (walls, floois and ceilings) shall be smooth ana free from cracks, and permit easy cleaning painting and disinfection,

(iv) air conditioned, where prescribed for the operations and dosage for in- under production. The production and dispensing areas shall be won lighted, effectively ventilated, with air control facilities and may have proper Air Handling Units (wherever applicable) to maintain define; classes of conditions including temperature and, wherever necessaiy, humidity. 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 validated to ensure •compliance with required specifications,

(v) provided with drainage system, preferably underground, which shall bo44 THE GAZETTE OF INDIA EXTRAORDINARY [PART II—SEC 3(I)1 of adequate size and so designed as lo prevent back-flow and /or to prevent insects / rodents entering the premises Open channels shall be avoided in manufacturing areas but if inevitable, these shall bo 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 a 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 It shall be free from pathogenic micro-organisms 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 —

(0 The disposal of sewage and effluents (solid liquid 'and gas) from the manufactory shall bo in conformity with the requirements of Environment Pollution Control Board

(n) All bio-medical waste shdll be destroyed as per the provisions of the Bio Medical Waste (Management and Handling) Rules, 1996

(in) Additional precautions shall be taken for the storage and disposal or 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 a suitably designed and segregated enclosed areas in conformity with Conlial and State Legislation

2. Warehousing Area —

2 1 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 parts spare items

2.2 Warehousing areas shall be designed or adapted to ensure good storage conditions. They shall be clean, dry and maintained within acceptable temperature limits Where special ripr^ge conditions are required ( eg 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 maintained45 2.3. Receiving and dispatch bays shall protect materials and products from adverse weather conditions. Receiving areas shall be closed and shall be designed and equipped to allow containers of incoming materials to be cleaned before transfer to warehousing aiea Receiving and dispatch bays shall be provided with exhaust fans to prevent back flow of air into the production area.

2.4. 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 status. Access to these areas shall be restricted to authorised persons .

2.5. There shall be a separate sampling area in the warehousing area for starting materials. "If sampling is performed in any area, it shall be conducted in such a way as to prevent contamination, cross-contamination and mix-up.

2.6. Segregation shall be provided for the storage of rejected, recalled or leturned materials or products. Such areas, materials or products shall be suitably marked and secured, Access to these areas and /or materials shall be restricted.

2.7. Highly hazardous, poisonous and explosive materials such as, narcotics, psychotrppic 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 rules of the civic authority concerned.

2.8. Printed packaging materials sh'all be stored In safe separate and secure areas, 2.9. Separate dispensing areas for p (Beta) Lactum Antibiotics and/or Hormonal or any such special categories of products shall be provided with proper supply of filtered air and suitable measures for dust corilrol.to avoid-contamination. Such areas shall be under differentiatpressnre.

2.10.Sampling and dispensing of sterile materials shall be conducted under aseptic conditions conforming to Class 100, which can also be performed iPfledicated area within the manufacturing facility.

2.11. Regular checks shall be made to ensure steps against spillage, breakage and leakage of containers.

2.12. Rodent treatments (pest control) should be done regularly and at least once in a year and record maintained. In particular, adequate steps shall be taken to prevent contamination of productin materials by rodent-urine, leading to Leptospirosis.

2.13.The licensees shall take steps to follow Good Warehousing Practices arid Guidelines.

3. Produttfon area —

3.1. The production area shall be designed to allow the production in uni-flow and with logical sequence.

3.2. In order to avoid the risk of cross-contamination, separate dedicated and self- contained facilities shall be made available for the production of sensitizing pharmaceutical product like penicillin or biological preparations with live micro-organisms. Separate dedicated facilities shall be provided for the manufacture of cross-contamination causing and potent products.

3.3. Working and in-process warehousing space shall be adequate to permit orderly and logical positioning of equipment and materials and movement of personnel so as to avoid cross-contamination and to minimize the risk of omission or wrong application of any of the manufacturing and control measures.

3.4. 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 flow-direction shall be marked.

4. Ancillary areas;—

4.1. Rest and refreshment rooms shall be separate from other areas. These areas shall not lead directly to Jthe manufacturing and storage areas.

4.2. Facilities for changing, storing clothes and for washing arid 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.

4.3. Maintenance workshops shall be separate and away from production areas. Whenever spares, changed parts antl lools 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 bo disinfected before these are carried.inside in the production areasr - -

4.4. Areas housing animals shall bo isolated from other areas. The other requirements r e g a r d^ animal houses shall be those as prescribed in rule 150-C(3) of the Drugs and Cosmetics~Kules, 1945 which shall be adopted for production puiposes,

5. Quality Control area —

5.1. Quality Control Laboratories shall be independent of the production areas. Separate areas shall be provided each for physico-chemical, biological, microbiological or radioisotope analysis. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis,

5.2. Quality Control Laboratories shall be designed appropriately for the operations to be carried out jn.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.

5.3. 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 radioisotope testing areas. The laboratory shall be provided with regular supply of water of appropriate quality for cleaning and testing purposes.

6. Personnel —

6.1. The manufacture shall be conducted under the active direction and personal supervision of competent technical staff with prescribed qualifications and practical experience in the relevant dosage form and/or active pharmaceutical products.

6.2. The Head of the Quality Control Laboratory shall be independent of the manufacturing unit. The testing shall be conducted under the active direction and personal supervision of competent technical staff who shall be whole time employees of the licensee.

6.3. Personnel for Quality Assurance and Quality Control operations shall be suitably qualified and experienced.

6.4. Written duties of technical and Quality Control personnels shall be laid and followed strictly.

6.5. Each technical person shall be suitably trained to perform the assigned

responsibilities. They shall be subjected to regular in-service training.

6.6. Number of personnels employed shall be adequate and in direct proportion to the workload.

6.7. The licensee shall ensure in accordance with a written instruction that all personnels in production area or into Quality Control Laboratories shall receive training appropriate to the duties and responsibility assigned to them.

7. Health, clothing and sanitation of workers —

7.1. The personnels 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 personnels should be rotated out of the sections at suitable intervals.

7.2. All persons prior to employment, shall undergo medical examinations including eye examination and shall be free from Tuberculosis , skin and other communicable and contagious diseases. Thereafter, they should be medically examined periodically, at least once in 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 the practices of personal 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 an 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 product.

7.7. All personnel shall wear clean body coverings (single-suit) appropriate to their duties. Before entry to manufacturing area, there shall be change-rooms separate for each sex with adequate facilities for personal cleanliness such as washbasin with running water, disposable 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_pth" areas where - . - - - -• they might adversely influence the product quality. -

8. Manufacturing Operations and Controls —

8.1. All manufacturing operations and controls shall be carried out under the supervision of competent 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 the manufacture and storage during various manufacturing stages shall be conspicuously labelled with the name of the product, batch no., batch size and stage of manufacture. Each label should be initialed and dated by the approved technical staff.

Products not prepared under asceptlve conditions are required to be free from pathogens like Salmonella, Escherichla coli, Pyocyanea etc.

8.2. Precautions against mlx-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 labelling 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 cytotoxic substances in segregated area or isolating 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 labelled to demonstrate their status. All equipments used for production shall be labelled with their current status.

8.2.4. Packaging lines shall be independent and adequately segregated. It shall be ensured that all the left-over of previous packaging operations, including labels, cartons and caps, are cleared before closing hour.

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 contaminations. 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 checked and recorded. Attention shall be paid to manual printingT which 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 degree required of temperature, humidity and cleanliness.

8.2.8. Authorized 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. Dedicated and self-contained facilities shall be provided for the production of particular Pharmaceuticals products.

9.2. 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 protocol shall be maintained.

9.3. The manufacturing areas shall not be used for storage of materials, except for material being processed. It shall not be used as a general thoroughfare.

9.4. A routine sanitation programme shall be drawn up and observed, which shall be properly recorded and which shall indicate —

3qc;i/2Q01— 7 A ,, A A i [PARTII—SEC. 3(i)] (a) specific areas to be cleaned and cleaning intervals; (b) cleaning procedure to be followed, including equipment and materials lo be used for cleaning; and

(c) personnel assigned to and responsible for cleaning operation.

9.5. The adequacy of the woiking and in-process storage space shall peimit the orderly and logical positioning of equipment and materials so as to minimise the risk of confusion between different pharmaceutical products or their components to avoid cross- contamination, and to minimise the risk of emission or wrong application of any of the manufacturing or control steps.

9.6. Production areas shall be well lit, particularly where visual on-line controls are carried out.

9.7. Records of compliance in respect of sanitation shall be maintained for inspection.

10. Raw materials ^*v

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 and finished products shall be quarantined immediately after receipt or p/ocessing. All materials and products shall be stored under appropriate conditions and in an orderly fashion to permit batch segregation and stock rotation by a 'fir st- in' 'first-out' principle. All incoming materials shall be checked to ensure that the consignment corresponds to the ordei placed.

10.3. Starting mateiials shall be purchased from authentic sources under valid purchase vouchers. Whenever possible, law materials should be purchased directly from the producers and suppliers.

10.4. Authorised staff appointed by 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 and underweight containers shall be identified, recorded and segregated.

10.5. If a single delivery of a 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 ;

(a) designated name of the product and the internal code reference, where applicable, and analytical reference number; \6) manufacturer's name, address and batch number; (c) the status of the contents (e.g. quarantine, under test, released, approved, rejected);

(d) the manufacturing date, expiry date and re-test date51 10.7. There shall be adequate separate partitioned areas for materials "undei test' "approved¹, and rejected "with arrangements and equipment to allow dry, clean and ordoily placement of stored materials and products, whenever necessary, under controlled temperature and hutnidity.

10.8. Containers from which p.'uiiplus have L^cn drawn shall be identified 10.9. Only materials whicn nave been released by the Quality Control Uepnilmpnt and which are within their shelf-life shall be used. In lieu of testing by the manufactuier, a certificate of analysis may be accepted from the validated supplier, provided the manufacturer establishes the reliability of the supplier's analysis through appropriate validation of the supplier's test results.

10.10. It shall be ensured that all containers of raw materials.aie placed un \\v; raised plat-forms or in steel racks.

11. Equipment-

11.1. Equipments shall be located, designed, constructed, adapted, and maintained iu suit the operations to be carried out. The layout and design of equipment shall aim to minimize 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 equipments of an appropriate range, accuracy and precision shall be available in the raw-material stores, production and in-piocess conliol 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 pioduct shall not be reactive, additive, or adsoiplive to an extent that would affect the quality of the product. All contact parts shall be made of stainless steel (3IC grade)

11.4. To avoid accidental contamination, wheie ever possible, non-toxic/edible grade lubricants shall be used and the equipment shrill be maintained in a way Hint lubricants do not contaminate the pioducl being pioduced.

11.5. Defective equipments shall bu removed from production and Quality Conliol areas or appropriately labelled.

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 manufacluie know the informations necessary to decide whether or not to release a batch of a diug for sale and to provide an audit trail thnt 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 authoiized persons.

12.3. Documents shall specify Iho title, nature and purpose They shall be laid out in an orderly fashion and be easy to check Repioduced documents shall be clear and legible Documents shall be regularly reviewed and knpt up to flate. 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 Mastes Formulae and detailed operating procedures relating to the system in use shall be available in a hard copy and the accuracy of the records shall be checked. Wherevei documentation is handled by electronic data processing methods, authorized persons shall enter or modify data in the computer. There shall be a 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. Duiing the period of retention, all relevant data shall be readily available.

13. Labels and other Printed Materials.- Labels are absolutely necessaiy for identification of the drugs and their use. The printing should 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 mix-up of printed and packaging materials, product leaflets, relating to different products, should bo stoied 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 labelling 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 shiprQ£,nt 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 refoience culture shall indicate concentration, date of manufacture, expiry date, where appropuale, date on which container was first opened and stoiage conditions, where appiopriale 14. Quality Assurance.- It is a wide rouging modern concept concerning all mntters that individually or collectively influence Iho quality of a product. It is the totality of tho 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 appiopuate to the manufacture of pharmaceutical products shall ensure that

(a) the pharmaceutical products are designed and developed in a way that takes account of the requirements of Gaod Manufacturing Practices (hereinafter referred as GMP) and other associated codes such as those of Good Laboratory Piaclicos (heieinaftcr icfened as GLP) and Good Clinical Practices (hereinafter leferred as GCP), (b) adequate arrangements are made for manufacture, supply, and use of

the correct starting and packaging materials,

(c) adequate controls on starting materials, intermediate products, and bulk products and other in-piocess controls, calibrations, ami validations are carried out;

(d) the finished product is correctly processed and checked in accordance

with established procedures

(e) 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 tho label claim and any other provision relevant to production, control and lelcase of pharmaceutical products;

15. Self inspection and Quality audit.- It may be useful to constitute the self inspection team supplemented with a quality audit procedure for assessment of all oi part of a system with the specific purpose of impiovinn it54 THE GAZETTE OF INDIA : EXTRAORDINARY [PART II—SEC. 3(i)l 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 implementations of methodology and procedures evolved. The procedure for self-inspection shall be documented indicating self-Inspection results, evaluation and conclusions and recommended corrective actions with effective follow-up programme. The recommendations for corrective action shall be adopted.

15.2 The programme shall be designed to detect shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections shall be performed routinely and on specific occasions, like product recalls or repeated rejections 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 GMP 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.-

(a) Personnel (b) Premises including personnel facilities (c) Maintenance of buildings and equipment (d) Storage of starting materials and finished products (e) Equipment (f) Production and In-process controls (g) Quality control (h) Documentation

(i) Sanitation and hygiene (j) Validation and revalidation programmes (k) Calibration of instruments or measurement systems (I) Recall procedures

(m) Complaints management (rr) Labels control (o) 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 ensured that the necessary and relevant tests are actually carried and that materials are not released for use, nor products were 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 manned by qualified and experienced staff.

16.2. The area of the quality control laboratory shall be suitably divided into Chemical. Instrumentation. Microbiological and Biological testing.

16.3. Adequate area having the required storage conditions shall be provided for keeping reference samples. The quality conlrol department shall evaluate, maintain and store Reference Standard.substances.

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 on identity, content, purity and quality. This shall include specifications for water, solvents and reagents used in production and analysis.

16.6. No batch of the product is to be released for sale or supply until it has been certified to comply with the prescribed standards by the authorized 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.

16.8. Assessment of records pertaining to finished products shall include all relevant factors, including the production conditions, the results of in-process 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 incharge of production and countersigned by the Head of the Quality Control Department 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 incharge of Quality Control shall investigate all product complaints and records thereof shall be maintained

16.12. All equipments and testing procedures shall be validated before they are adopted for routine testing. Periodical validation of equipment and procedures shall be carried out.

16.13. Each specifications for raw materials, intermediates, final products and packing mat$rals 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. Pharmacopoeias, technical books, reference standards, reference spectia and other reference materials shall be available in the Quality Control Laboratory of the licensee.

17. Specification —

17.1 For Raw materials and Packaging maletials:-

They shall include, - (a) the designated name and internal code reference; (b) reference , if any, to a pharmacopoeial monograph, (c) qualitative and quantitative requirements with acceptance limits; (d) name and address of manufacturer or supplier and original manufacturer of the material;

(e) specimen of printed material, (f) directions for sampling and testing or reference to procedures; (g) storage conditions and specifications and (h) maximum period of storage before re-testmg.

17.2. For Product Containers and Closures —

17.2.1 All containers and closures intended for use shall comply with the pharmacopoeial or other pharmacopoeial requirements. Suitable validated test methods, sample sizes, specifications, test methods, cleaning procedure and sterilization procedure, wherever indicated, shall be followed strictly to-ensure that these are not reactive, additive, adsorptive, absorptive 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 scheduled 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 validated and authenticated.

17.4. For Finished Products.- Appropriate specifications for finished products shall include:-

(a) the designated name of the product and the code reference; (b) the formula or a reference to the formula and the pharmacopoeial reference;

(c) directions for sampling and testing or a reference to procedures; (d) a description of the dosage form and package details; (e) the qualitative and quantitative requirements, with the acceptance ^" limits for release;

(f) the storage conditions and precautions, where applicable and (g) the shelf-life.

Note: It is advisable that each batch of tho finished products is 'Bar Coded ' for easy tiacahihiy.

The licensee shall register with EAN India, an autonomous unit unclet tho Ministry of Commerce which shall allot the 'Bar Code'.

18. Master Formula Records.- There shall be Master Formula records relating to all manufacturing procedmos 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-

(a) the name of the product together with product reference code

relating to its specifications;

(b) the patent or proprietary name of the product along with the generic name, a description of the dosage form, strength, composition of the (c) product and batch size;

name, quantity, batch number and reference number of all the starting materials to be used. Mention shall be made of any (d)¹ substance that may 'disappear' in the course of processing;

a statement of the expected final yield with the acceptable limits, and (e) of relevant intermediate yields, where applicable;

a statement of the processing location and the principal equipment to (f) be used;

the methods, or reference to the methods, to be'used for preparing the critical equipment" including cleaning assembling, calibrating, (g) sterilizing;

detailed stepwise processing instructions and the time taken for each (h) step; (i) the instructions for in-process controls with their limits;

the requirements for storage conditions of the products, including the (j) container, labelling and special storage conditions where applicable, (k) any special precautions to be observed;

Packing details and specimen labels

19. Packaging and Batch Processing Records.- There shall be authorised packaging instructions for each pioduct, pack size and type These shall include or have a reference to the following.-

(a) name of the product,

(b) description of the dosage form, strength and composition;

(c) the pack size expressed in teims of the number or doses, weiuht or

volume of the product in the final container,

(d) a 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;

.''^l/JOON-H

(e)¹ reproduction of the relevant printed packaging materials, and specimens indicating where batch number and expiry date of the product have been applied;

(0 special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin,

(g) a description of the packaging operation, including any significant subsidiary operations and equipment to be used;

(h) details of in-process controls with instructions for sampling and acceptance;

(i) upon completion of the packing and labelling operation, a reconciliation shall be made between number of labelling and packaging units issued, number of units labeled and packed and excess returned or destroyed. Any significant or unusual discrepancy in the numbers shall be carefully investigated before releasing the final batch.

19.1 There shall be Batch Processing Record for each product. It shall be based on the relevant parts of the currently approved Master Founula. The method of preparation of such records included in Master Formula shall be designed to avoid transcription errors;

19.2 Before any processing begins, check shall be performed and recorded that the equipment and work station aie clear of previous products, documents or materials not required for the planned piocess, are lemoved and that equipment is clean and suitable for use.

19.3 During processing, the following information shall be rccoided at the time each action is taken and, the record shall bo dated and signed by the person responsible for the processing opeiations.

(a) the name of the pioduct, (b) the number of the batch being mariufactuicd, (c) dates and lime of commencement, of significant intermediate stages and of completion of production,

(d) name and designation of the person lesponsible for each stage of production;

(e) initials of the operator of different significant steps of pioduclion and, where appropriate, of the person who checked each of these operations;

(f) .the batch number and/or, analytical control number as well as the quantities of each starting material actually weighed,59 (g) any relevant processing operation or event nn

(h) a records of the in-process controls and the initials of llic peison(s) carrying them out, and the results obtained;

(i) the amount of product obtained nflei different and cutical stages of manufacture (yield);

(j) comments or explanations for significant deviations fmm the expected yield limits shall be given,

(k) notes on special problems including details, with signed authorization, for , any deviation from the master formula;

(I) addition of any recovered or reprocessed material with icfeienco to recovery or reprocessing stages.

20, Batch Packaging Records ,

20.1 A Batch packaging recoid shall be kept for each batch oi pait batch processed It shall be based on the lelevanl 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 operation begins, checks shall be made and recorded that the equipments and woik stations are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use

21. Standard Operating Proccdurrr- (SOPs) and Records, Regarding. -

21.1 Receipt of Mateiials-

21.1.1 There shall be written Standard Opeiating Procedures and recoids for the receipt of each delivery of raw, primary and printed packaging material 21.1.2 The records of the receipts shall include,-

(a) the name of the material on the delivery note and the number or containers;

(hj the dale 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 contiol refoiHu r- MIIMIIHT -J'-.^KUVHI n!l"i icc^ipt, (g) any other mlovanl coinni':n( or un'oiIH'IIKMi.

21.1.3, There shall bo wiillon standard operating pioceduros for the internal labelling, quarantine anil storage of starling materials, packaging materials and other materials, as appropriate

21.1.4. There shall be Standard Operating Pioceduies available for each instrument and equipment and shall bo placed in close proximity to the equipment.

21.2 Sampling;

21.2 1 There shall be written "Standmd Operating -Piocedmes for sampling, which include the person(s) authorized to take samples

21 2 2 The sampling instructions shall include.-

(a). thp method of sampling and the sampling plan, (b). the equipment to bo used, (c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality,

(d), the quantity of samples to be taken, (e). instructions for any required sub division or pooling of

the samples,

(f). the typo of ••-.nmple c ontainor to be used, (g) any specific precautions to bo obseivod, especially in iegaid to sampling of slnrilc ut ha/aidous material.

21.3 Batch Numbering.

21.3 1 There shall be Standard Opei citing Procedures describing the details of the batch (lot) numbering set up with the objective of ensuring that each batch of intermediate, bulk or finished pioduct is identified with a specific batch number.

2 13 2 Batch numbering standard operating pioceduies applied to a processing stage and-to the respective packaging stage shall be i elated to each other

21.3.3 Batch number allocation shall be immediately recorded, in a logiiook. The record shall include dale of allocation, product identity and size of batch.

21.4 Testing —

21.4 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 bo recorded

2 1 .5 Records of analysis ^

21.5.1 The records shall include the following data-61 (a) name of the malci ijl ur product and the dosaye form (b) batch numbci and, whfcie appropriate the manufacturer and/or supplier, (c) references to the iclevant specifications and testing proccduies (d) test results mcludinq obseivdtions and calculations, and tefeienco to any specifications (limits)

(e) dates of testing (f) initials of the persons who performed tho testing, (g) initials of the persons who verified the* testing and the detailed calculations,

(h) a statement of release or rejection, and (i) signature and date of the designated responsible peison

2 15 2 There shall be written standard operating procedures and the associated records of actions taken for (a) equipment assembly and validation (b) analytical apparatus and calibration (c) maintenance, cleaning and sanitation, (d) pe/3onnel matters including qualification training, clothing hygiene, (e) environmental monitoring, (f) pest control, (g) complaints, (h) recalls made, (t) returns received

22 Reference samples; -

22 1 Each lot of every active ingredient, in a quantity sufficient to cairy out all the tests except sterility and pyrocjens / Bartenal Endotoxin Test shall be retained for a period of 3 months a fH the date of expiry of the last batch produced from that active ingredient

22 2 Samples of finished formulations shall be stored in the same containers in which the drug has been actually marketed

23. Reprocessing And Recoveries —

23 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

23 2 If the product batch has to be processed, reprocessing 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 fur prevention of recurrence Re-processed batch shall be subjected to stability evaluation62 THE GAZETTE OF INDIA : EXTRAORDINARY [PART II—SEC. 3(i)J 23.3 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.

24. Distribution Records —

24.1 Prior to distribution or dispatch of a 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 the correct goods are only 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.

24.2 Records for distribution shall be maintained in a manner that finished batch of a drug is traced to end-user to facilitate prompt and complete recall of the batch, if arid when necessary.

25. Validation And Process Validation —

25.1 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.

25.2 A written report summarizing recorded results and conclusions shall be prepared, documented and maintained.

25.3 Processes and procedures shall be established on the basis of validation study and undergo periodic revaluation to ensure that they remain capable of achieving the intended results. Critical processes shall be validated, prospectlvely or retrospectively.

25.4 When any new master formula,or method of preparation are adopted, steps shall be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipments, specified, shall be demonstrated to yield a product consistently of required quality.

25.5 Significant changes to the manufacturing process, including any change In Equipments or materials that may affect product quality and/or the reproducibility of the process, shall be validated.

26. Product recalls —

26.1 A prompt and effective product recall system of defective products shall be devised for timely information of all concerned stockists, wholesalers, suppliers, and end-users within the shortest period. The licensee may make use of both print and electronic media in this regard.

26.2 There shall be 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 initiated promptly down to the level of each distribution channel.

26.3 The distribution records shall be readily made available to the person designated for recalls.

26.4 The designated person shall record a final report ' issued including a reconciliation between the delivered and recovered quantities of the products.

26.5 The effectiveness of the arrangements for recalls shall be evaluated from time to time.

26.6 The recalled products shall be stored separately in a sectored segregated area pending final decision on them,.

27. Complaints and Adverse Reactions —

27.1 All complaints theregf concerning product quality shall be carefully reviewed and recorded according to written procedures. Each complaint shall be investigated / evaluated by die designated personnel of the Company and records of investigation and remedial action taken thereof shall be maintained.

27.2 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.

27.3 There shall be written procedures describing the action to be taken, recall to be made of the defective product

28. Site Master File.- The licensee shall prepare a succint 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:-

28 1 General information -—

(a) brief information of the firm, (b) pharmaceutical manufacturing activities as permitted by the licensing authority,

(c) other manufacturing activities if any, carried out on the premises, (d) type of products licensed for manufacture and mentioning the ways they aie being manufactured,

(e) number of employees engaged in the production, quality control, storage and distribution,

(f) Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis,

(h) short description of the Quality Management system of the firm , (i) details of punitive actions, if any taken against the firm, (j) product details registered with Government institutions, (k) products details registered with foreign countries

28 2 Personne\ —

(a) organisational chait showing the arrangement for quality assuiance, including production and quality control

(b)( qualification, experience and responsibilities of key personnel, (c) outline for arrangements for basic and in service training and how the records are maintained,

(d) health requirements for personnel engaged in production, (e) personnel hygiene requirements, Including clothing

28 3 Premises ;—

(a) simple plan or description of manufacturing areas with the help of scale, (b) nature of construction and fixures/fittings, (c) brief description of ventilation systems More details should be given foi critical areas with potential risks of airborne contamination (schemetic drawings of systems) Classification of the rooms used for the manufacture of sterile products should be mentioned,

(d) special areas for the handling of highly toxic, hazardous and sensitizing materials,

(e) brief description of water systems (schemetic drawings of systems), including sanitation,

(f) description of planned preventive maintenance programmes for premises and of the recording system

28 4 Equipment .—

(a) brief description of major equipment used in piocluction and control laboratories (a list of equipment required)

(b) description of planned preventive maintenance programmes for equipment and of the recording system

(c) qualification and calibration, including the recording systems and

arrangements for computerised systems validation

28 5 Sanitation .—

(a) availability of written specifications and procedures for cleaning

manufacturing aieas and equipment65 28.6 Documentation .—

(a) arrangements for the preparation, revision and distribution of necessary documentation for the manufacture;

(b) any other documentation related to product quality that is not mentioned elsewhere (e.g. microbilogical controls about air and water).

28.7 Production —

(a) brief description of production operations using, wheiever possible, flow sheets and charts specifying important paiameters;

(b) arrangements for the handling of starting materials, packaging materials.

and bulk and finished products, including sampling, quarantine, release, and storage.

(c) arrangements for the handling of rejected materials and pioducts; (d) brief description of general policy for process validation

28.8 Quality control r-

(a) description of the quality control system and of the activities of tho quality control department Procedures for the release of finished pioducts.

28.9 Loan licence manufacture) and licensee .-

(a) description of the way in which the Good Manufacturing Piactices compliance of the loan licensee is assessed.

28.10 Distribution, complaints, and product lecnll.-

(a) arrangements and iecoiiliny system for disliibulion; (b) arrangements for the handling of complaints and product recalls.

28.11 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.

28.12 Export of drugs —

(a) details of products expoited to different countries, (b) complaints and product recall, if any.

PART I-A

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF STERILE

PRODUCTS, PARENTERAL PREPARATIONS (SMALL VOLUME

INJECTABLES AND LARGE VOLUME PARENTERALS) AND STERILE

OPHTHALMIC PREPARATIONS

Note: The General Requirements as given in'Pait I of this Schedule relating io Requirements of Good Manufacturing Piactices for Premises and Materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of Stoule products, Paronteial piepamtions (Small Volume Injectablos and Large Volume Paienterals) and Stenlr Opffitilmic Preparations, In addition to these requirements, the following Specific Requirements shall also be followed, namely:-

i General,

Sterile products, being of voiy uitical and sensitive nature, a veiy high degree of piecaulions, preventions and preparations are needed Dampness, dirt and daikness are to be avoided at all cost to ensure aseptic conditions in all areas There shall be no let-up in the prescribed standards specially in the matter of supply of water, air, active materials and in the maintenance of hygienic environment

2. Buildings And Civil Works --

2.1 The building shall be built on a proper foundation with standardised materials to avoid cracks in critical areas like aseptic solution preparation, filling and sealinq rooms

2 2 Locatnn of services like wnler, 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 2fe-cartoning areas wh.ch are segregated from the washing aieas Wooden pallets shall not be *F \en inside the preparation areas.

2,4 In aseptic rreas,-

(a) walls, floors and ceiling should be impervious, non-shedding, non-flaking and non-cracking. Flooring should be continuous and coved to walls;

(b) walls shall be flat, ledges and recesses shall be avoided. Wherever other surfaces join the wall (eg. sterilisers, electric sockets, gas points etc ), these shall be flushed to the wall. Wall shall be coved at the joint with the ceiling and the floor.

(c) ceiling shall be solid and continuous Light-fittings and air-grills shall be flushed and not hanging fiom the ceiling;

(d) there shall be no drains;

(e) doors shall be made of non-shedding material. These shall be made preferably of Aluminium or Steel material. Wooden doors shall not be used. Doors shall open towards the higher pressure area so that these close automatically due to air pressure. Doors shall not have handles on them;

(0 Windows shall be m?de of similar material as doors, preferably with double panel and sh. II be flu J ie with the walls. If fire escapes are to be provided, tt.ase shall be suitably sealed to the walls without any gaps;

(g) the furniture used shall be smooth, washable and made of Steel.

2 5 The manufacturing and support areas shall have Ihe same quality of civil structure described above for aseptic areas except the enviionmnntil standards varying from critical aiea

2 ,6 Change rooms with sepaiate entrance and exu space in the form of an locks shall be provided before entry into the sterile produ t manufacturing are^is and then to the aseptic area Change rooms to aseptic areas shall be cleaily demarcated into 'black¹, 'gray and 'white' rooms with different levels of activity and air cleanliness The 'black' change mom shall be provided with a hand- washing sink The sink and its dmin in the un-ciassmed (first) change rooms shall be kept clean dll HIP 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 noivaseptic areas, hand-fiee intercom telephones shall be used These shall be minimum in number 2 8 Material transfer between aseptic areas and outside shall be thiough suitable air-locks and pass-boxes Doors of such air-locks and pass-boxes shall have suitable interlocking arrangements

2.9 Personnel welfare areas like rest*rooms, tea room, canteen and toilets shall be outside and separated from sterile product manufacturing area

2.10 Animal houses shall be away from 'he sterile product manufacturing aiea and shall not shaie a common entrance or air handling system with the manufacturing area

3. Air Handling System (Central Air-Conditionlng) r -

3.1 Air Handling Units for sterile product manufacturing area shall be different from those for other areas Critical areas, such as aseptic filling area, stenlized components unloading area, change rooms conforming to Grades D, C and B respectively shall have separate Air Handling Units The filter configuration In the air handling system shall be according to the Grade of air as given in Table I, Table II and Table III below

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 15 minutes of personnel leaving the room and filling operations stopped.

3.3 The filling operations shall take place under Grade A conditions which shall be demonstrated under working or simulated working conditions The Grade A conditions shall be achieved by providing Laminar Air Flow Modules with suitable HEPA filters68 THE GAZETTE OF INDIA : EXTRAORDINARY [PART II—SEC. 3(i)] 3.4 For products which are toiminally sterilized, the filling room shall meet Grade C conditions at rest. This condition shall be obtainable within a period of about 15 minutes of personnels leaving the mom and filling operations stopped.

3.5 Manufacturing and component preparation areas shall meet Grade C conditions within a period of about 30 minutes of personnels leaving the area 3.6 After completion of preparation, washed components and vessels shall be protected with Grade C background and, if necessary, under Laminar Air Flow.

3.7 The minimum air changes foi 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 stations, the air flow rates shall be 0,3 melie per second |2O% (for vertical flows) and 0.45 metre per second ±20% (for horizontal flows)

3.8 Differential pressures between areas of different environmental standards shall be at least 15 Pascal (0.06 inches or 1.5 mm water gauge) Suitable manometers shall be installed to measure and verify pressuie differential.

3.9 The final change rooms shall have the same class of air as specified for the aseptic area. The pressure differentials in the change rooms shall be in the descending order from 'white' to black'

3.10 Unless there are pioduct specific requirements, temperature and humidity in the aseptic areas shall be 25 degree centigrade and humidity 55%, respectively.

TADLEI Air Classification System For Manufacture Of Sterile Products

3,500,000 20,000 500

D (Class 100,000)

Notes: (a) In order to reach Class 100, 10,000 and 100,000 in clean levels, the number of air changes shall be related to the size of the equipment and the personnel present in the room. It shall be ensured that the air shall be provided with appropriate efficient HEP A filters for class 100 and class 10,000.

(b) The requirement and limit for the area shall depend on the nature of operation carried out.

TABLE II Types Of Operations To Be Carried Out In The Various Grades For Aseptic Preparations

T A B LE III Types of operations To Be Carried Out In The Various Grades For Terminally Sterilized Products

Note : Use M 3.5, M 5.5 and M 6.5 as the terms for Class 100, 10,000 and 100,000 respectively.

4. Environmental Monitoring r-

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: (a) Particulate monitoring in air - 6 Monthly (b) HEPA filter integrity testing (smoke testing) - Yearly (c) Air change rates - 6 monthly (d) Air pressure differentials - Daily (e) Temperature and humidity - Daily (f) Mfcrpbiological monitoring by settle plates and/or swabs in aseptic areas / at decreased frequency in other areas - Daily.

Note: The above frequencies of validations shall be changed as per the requirements and load in individual cases.

4.2 There shall be a written environmental monitoring programme and microbiological results shall be recorded Recommended limits for microbiological monitoring of clean areas "in operation" are as given in the table below

TABLE

Recommended Limits for microbiological monitoring of clean areas "in operation

Notes (a) These are average values (b) Individual settle plates may be exposed for not less thanVour hours

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 Garments.—

5 1 This section covers garments requnecl for use by personnel working only in aseptic areas Outdoor clothing shall not be brought into the sterile areas

5 2 These 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 over boots Suitable design of garments shall either include hood (head- cover) or separate hood which can be tucked inside the over-all Pockets, pleats and belts shall be avoided in garments Zips shall be of plastic material Garments with damaged zips shall not be used71 5.4 Only clean, sterilized and protective garments shall be used at each work session.

5.5 Gloves shall be made of latex and shall be powder-free. These shall be long enough to cover wrists completely and allow the over-all cuff to be tucked in. The use of disposable and single-use gloves is necessary.

5.6 The footwear shall be of suitable "plastic or rubber material and shall be daily cleaned with a bactericide. Footwear covers made of same fabric as that of garments shall be used to cover the boots and these shall be washed and sterilized after each day of use The use of disposable and single-use foot wears is advisable.

5.7 Safety goggles or numbered glasses with side extensions shall be used inside aseptic areas. These shall be sanitized by a suitable method.

5.8 Garment changing procedure shall be documented and operators trained in this aspeqf. 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. Sanitation p-

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 re-circulation loop shall be used for dilution of disinfectants. Alternately, distilled water sterilized 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 may be done in the bulk preparation area and the diluted solution membrane-filtered into suitable sterile containers held in the aseptic area.

6.5 Diluted disinfectants shall bear 'use before' based on microbiological establishment of their germicidal properties. The solutions shall be adelfliately labeled and documents maintained.

6.6 Formaldehyde or any other equally effective fumigant is recommended for the fumigation of new aseptic areas or after major civil modifications. There shall be Standard Operating Procedures for this purpose. Its use72 THE GAZETTE OF INDIA : EXTRAORDINARY [PART II—SEC. 3(i)l for routine use shall be discouraged and equally effective surface cleaning regime shall be followed

6.7 Cleaning of sterile processing facilities shall be undei taken with air suction devices.

6.8 Air particulate quality shall bo evaluated on a regular basis and lecoids maintained.

7. EQUIPMENT.

7.1 The special equipment requned for manufacturing steiile products includes component washing machines, steam sterilisers, dry heat sterilizers, membrane filter assemblies, manufacturing vessels, blenders, liquid filling machines, powder filling machines, sealing and labelling 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-sterilizers shall be double ended with suitable interlocking arrangements betwnnn the doois Sterilization effectiveness shall be established initially and then periodically by carrying out thermal mapping of the chamber and biological inactivalion studies using micjobial spore indicators Various sterilization parameters shall be established based on these studies and documented. For membrane filters used for filtration, steiilization, appropriate filter integrity tests, 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 material of construction foi the pails which are in direct contact with products and manufacturing vessels may be stainless steel 316 or Boro- silicate glass (in the case of glass containers) and 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 sterilisers .shall be suitably validated according to a written programme 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 programme. Calibration status of equipment and gauges73 shall be adequately dociiniGnl^cl anr| displayed

8 Water and Steam System ,

8 1 Potable water meeting microbiological s-pecificaliun of not moie than 500 cfu / ml and absence of individual pathogenic micio-oryanisms - Eschenchla coli, Salmonclln Staphylococcus nuieus and Pseudomonas aeiugmosa per 100 ml sample shall bo used for the propaiation of purified water

8 2 Purified water prepared by de-mineralizatlon shall meet microbiological specification of not more than 100 cfu per ml and 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 and initial container and machine parts washing

8 3 Water for Injection (hereinafler mfeiied as Wl-I) shall be prepared fiom potable water or puufied waiter meeting the above specifications by distillation "Water for Injection shall meet microbiologiacal specification of not more than 10 cfu per 100 ml WFI shall also meet IP specification for Water for Injection and have an endotoxin levels of not more than 0 25 EU/ml Bulk solutions of liquid parenterals shall be made in WFI Final rinse of product contact containers and machine parts shall l}e 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 above 80 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 Enterobactena coll in 100 ml shall also be met

8 6 Purified water and Distilled water shall be stored in steam jackelted stainless steel tanks of suitable size and the tanks shall have hydrophobic bacterial retention with 0 2 ^ vent fillers The filters shall be suitably sterilised 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 programme for the sanitation of different water systems including storage tanks, distribution lines, pumps ana' oiner related equipments Records of sanitation shall be maintained and periodically validated

8 8 There'shall be written microbiological monitoring programme-for different types of water The results shall justify the frequency of sampling and iOGI/2001 —1074 THE GAZETTE OF INDIA : EXTRAORDINARY [PART II—SEC. 3(ij] testing Investigation rh-ill I if? f ; , m i " i| out and ouirective nclmM l;ikrn in case of deviation frmti p r r ^ u i b ' vl limit';

8.9 Steam corning in contact with product, piimaty containers find other product contact surfaces shall be sterile and pyrogon 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 Watei for Injection and have an endotoxin levels of not more than 0 25 KU/ml There shall be a suitable schedule for the monitoring of steam qunlily

9. Manufacturing Process.

9.1 Manufacture of sterile products shall be carriod out only in aieas under

defined conditions

9 2 Bulk raw materials slinll lie monitoiod for bio-burden periodically. Bio- burden of bulk solution prior lo momhrane filtration shall be monitored and a limit of not more than 100 cfu per ml is recommended.

9.3 Bulk solutions shall be sterile-filtered within 12 houis of preparation and the filtered sterile-bulk shall be filled within a short period or time but not exceeding 72 hours.

9.4 Gases coming in contact with sterile product shall be filtered through two 0.2 n hydrophobic membrane Tillers in scries These membrane filteis shall be tested for integrity. Gas cylinders shall not be taken inside aseptic areas.

9.5 Washed containers shall be sterilised immediately before use. Sterilised containers, if not used, shall be rinsed with distilled or filtered purified water and re-sterilised.

9.6 Each lot of finished product shall be filled in one continuous operation. In case of filling of one batch in 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 excercised while filling powder products so as not to contaminate the environment during transfer of powder to filling machine- hopper.

10. FLOW-FILL-SEAL TECHNOLOGY OR BLOW-FILL-SEAL TECHNOLOGY; -

10.1 Flow-Fill-Seal or Blow-NII-Seal units are specially built foreign machines in which in one-continuous-operation, containers are formed from a tnermoplastlc granulate, filled and then sealed, all by one-automatic- machine. Both types of machines used for aseptic production shall be fitted with an effective Class 100 (Grade A) air shower.

Note:

(i) These shall be installed in at least Class 10,000 envimnment (u) These shall comply with the viable and non-vmblo limits 'at test" end shall be opeiatod at only the viable limit

10 2 Flow-Fill-Seal/Blow-Fill-Seal machines used for the manufacture of products for terminal sterilization shall be installed in at least a Class 100,000 environment and Ihe filling zone within the machine shall fulfil Class 100 requirements

10 3 Terminally Sterilized Products.-

10 3 1 Preparation of primary packaging material such as glass bottles, ampoules, rubber stoppers shall be done in at least Class 100.000 environment Where there is unusual risk to the pioduct because of microbial contamination, the above operation shall be done in Class 10,000 environment All the processes used for component preparation shall be validated

10 3 2 Filling of products requiring terminal sterilization shall be done under Class 100 environment with a Class 10,000 background

10 4 Preparation of solutions which are to be sterilized by filtration shall be done in Class 10,000 environment, and if not to be filtered, tfie preparation of materials and products shall bo in a Class 100 environment with Class 100 in background

10 5 Filtration (Membrane),

(i) Solutions for Large Volume Parenterals shall be filtered through a non-fiber releasing, sterilizing grade cartridge filter of nominal pore size of 0 22 n for aseptic filling whereas 0 45 \i porosity shall be used for terminally sterilized products

(M) A second filtration using another 0 22 |i, sterilizing grade cartridge filter shall be performed immediately prior to filling Process specifications shall indicate the maximum time during which a filtration system may be used Such time length shall preclude microbial build-up to levels that may affect the microbiological quality of the Large Volume Parenterals

(in) The integrity of the sterilized filter shall be verified befoie use and shall be confirmed immediately after use by an appropriate method such as a Bubble Point Diffusive How or Pressuie Hold Test 10 6 Sterilization (AulocUwiiui),

10 6 1 Before any sterilization PKKCSS 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 'unsterjlized.' products. Each basket, tray or other carrier of products or components shall be "lea/ly labelled with the name of the material, its batch number, and sterilization status. , Indicators shall be used, where appropiiate, 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 ?hall 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, shap 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 case of Large Volume Parenterale.

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 bg allowed for the load to reach the required temperature before measurement of sterilizing time commences. This time shall be determined for each type of load to be processed

10.7.4 Afle'r the high temperature phase of a heat sterilization cycle, precautions shall be taken against contamination of sterilised load during cooling. Any cooling fluid or gas in contact with the product shall be sterilised 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-slenle air. Air inlets and outlets should be provided with micro-organism retaining filters. Where this process of sterilization by dry head is also intended to remove pyrogens, challenge tests using Endotoxins would be required as part of the validation.

10.8 Sterilization ( By Moist Heat) -

10.8.1 .Both temperature and piessure 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 requirement are met. System and cycle faults shall be legistered 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 on the chamber when vacuum phase is part 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 loa~d 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 steam used for sterilization is of 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 processos in the manufacture of a batch shall have a minimum time specified and the shortest validated time shall be used from 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 appiopriate procedures.

10.9.3 Containers sealed under vacuum shall be tested for requiied vacuum conditions78 THE GAZETTE OF INDIA : EXTRAORDINARY [PART II—SEC. 3(i)l 10.9.4 Filled containers of parenleial products sh.'ill bo inspected individually for extraneous contamination oi other defects When inspection is done visually, it shall be done under suitably and controlled conditions of illumination and backgiound Operatoi? doing the inspection shall pass regular eye-sight chocks, with spectacles, if worn, and be allowed frequent rest from inspection. Wlu-if oih^i method;; of inspection mo used, the process shall be vahdnl"(l and the poifmmance of the equipment checked at suitable inlcivals. Resulh sh.ill hu ICCOILIPII

11. Product Containers And Closures .

11.1 All containeis and closuies intended for use shall comply with the pharmacopoeial and other specified requirements. Suitable validity test, sample sizes, specifications, test methods, cleaning piocedmes and sterilization procedures, shall be used to assure that containers, closures and other component parts of drug packages are suitable and aie not reactive, additive, adsoiplive or leachable or to piesent a risk of toxicily to an extent that significantly affects the quality or puuty of the drug. No second hand or used containers and closures shall be used

11.2 Plastic granules used in Tonn fill-soril machines for the packing of Laige Volume Parcnleral shall be tested for freedom from bacterial endotoxin. These shall also comply \|ith the pharmacopoeial requirements including physico-chemical and biological tests

11.3 All containers and closures before use, shall be rinsed finally with distilled water 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 adveisely. The closuies and stoppers should be of such quality substances as not to affect the quality of 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 parenterals,. Oplhalmic preparations shall be examined against block/white background fitted with defused light after filling so as to ensure freedom from contamination and foreign matters.

11.8 Glass bottles—

11.8.1 Shap^j'and design of the glass bottle shall be rational and standardized. Glass bottles made of USP Type - I and USP Type-ll 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 generation over a period of the shelf-life of the product and shall be regularly monitored after79 production following statistical sampling methods

11.9 Plastic Containers,

11.9 1 Pre-formed plastic containers intended to be used for the packing, of Large Volume Parenteral shnll 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 at-least Class 10,000 environment. Entry to the area where such operations are undertaken, these shall be through a series of air locks, Blowers shall have an air supply which is filtered though 0 2 fi filters. Removal of runners and plugging opeiations shall be conducted under a laminar airflow bench.

11.10 Rubber stoppers,

11.10.1 The rubber stoppers used foi I arye: Volume Paienterals shall be only of BromobulyUrubbei or CMoiobufyl rubber Othet rubber stoppers including lacquer-coated rubber stoppers shnll not be used

11.10.2 The rubber stoppers shall comply to specifications prescribed in current edition of Indian Pharmacopoeia.

12 Documentation —

12.1 The manufacturing records relating to manufacture of sterile products shall indicate the following details:-

(1) -Serial number of the Batch Manufacturing Recoid (2) Name of the product (3) 'Reference to Master Formula Record (4) Batch / Lot number (5) Batch / Lot size (6) Date of commencement of manufactuie and dale of completion of manufacture.

(7) Date of manufacture and assigned dale of expiry. (8) Date of each step in manufacturing. (9) Names of all ingredients with grade of quality. (10? Quantity of all ingredients. (11) Control reference numbers for all ingredients, (12) Time and duration of blending, mixing etc. whenever applicable. (13) ' pH of solution whenever applicable. (14) , Filter integrity testing records. (15) Temperature and humidity records whenever applicable. (16; Records of plate-counts whenever applicable, (17) Results of pyrogen and/or bacterial endotoxin & Toxicity, (T8) Records of weight or volume of drug filled in containers. (19) Bulk sterility. (20) Leak test records80 THE GAZETTE OF INDIA : EXTRAORDINARY [PART II—SEC, 3(i)1 (21) Inspection records (22) i Sterilization records including autoclave leakage test records, lontJ

details, date, duialion, Icmpnifilure, pressure etc

(23) Container washing IOCOU^ (24) Total number of containers fillnd (25) Total number of contniners iej<\;led at each stage. (26) Theoretical yield, permissible yield and actual yield and

variation theieof

(27) Clarification for variation ir yield beyond permissible yield (28) Reference numbers of relevant analytical repot Is (29) Details of reprocessing, if any. (30) Name of all operators carrying out different activities. (31) Environmental monitoring records (32) Specimens of printed packaging material (33) Records of destruction of rejected containers and printed

packaging mateiials

(34) Signature of the competent technical staff responsible for manufacture and counlersiynaluie of competent staff responsible for testing

Notes: (1) Products chnll hb n:l<:u:sru] only after complete filling and testing

(2) Sterility, Pyrogens, Bacterial undoloxins tests shall be^maintained in the analytical records.

(3) Validation details and simulation tnal tecoids shall bo maintained separately.

(4) Records of environmental monitoring like tempeiature, humidity, microbiological data etc. shall bo maintained . Records of periodic servicing of HEP A filters, sterilizers and other periodic maintenance of facilities and equipment carried out shall also be maintained.

(5) Separate facilities shall be provided for filling-cum-sealing of Small Volume Injectables -and Laiye Volume Paienterals.

(6) Separate facilities shall be provided for manufacture of Large volume pamnterals in glass containers and/or plastic containers.

(7) For manufacture of Large volume patenterals in plastic containers, it is advisable to install automatic, (with all operations) Flow-Fill-Seal machines having one-continuous operation.

PART I-B

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL SOLID

DOSAGE FORMS (TABLETS AND CAPSULES)

Note: The General Requiiements as given in Pait I of this Schedule relating to Requirements of Good Manufacturing Practices for Piemises and Materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of Oral Solid Dosage Forms (Tablets and capsules). In addition to these requiiements, the following Specific Requirements shall also be followed, namely:-

1. General —

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 equipments in order to overcome these problems. Wherever possible, 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 necessaty. Effective air-extraction systems, with dischaiyc points sited lo 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 mchl or wood. The use of metal detectors is recommended. Woodeli equipment should be avoided. Screens, sieves, punches and dies shall be examined for wear or 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 piovide special environmental conditions or pressure differentials between rooms, these conditions shall be regularly monitored and any out of specification tesulls brought to the immediate attention of the Production and Quality assuiance departments which shall be immediately attended to

1.6 Care shall be taken to yuard against any material lodging and remaining undetected in any processing or packaging equip;.>^nt Particular care shall bo taken to ensure that any vacuum, compressed air or air-extraction nozzles ate kept clean and that there is no evidence of lubricants leaking into the product from any contact part uf IIi

2. Sifting, mixing anil granulation.

2.1 Unless operated as a closed system, mixing, sifting and blendiny equipments shall be fitted with dust extractors.

V5GI/2OO1 —1182 THE GAZETTE OF INDIA : EXTRAORDINARY [PART II—SEC. 3(i)] 2.2 Residues from sieving operations shall be examined periodically for evidence of the presence of unwanted maleiials

2.3. Critical'operating parameters like time, power 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 coatiny solutions shall be made, stored and used in a manner which minimises the risk of contamination or miciobN growth

3 Compression (Tablets).

3.1. Each tablet compressing machines shall be provided with effective dust control facilities and be sited to avoid product mix-up, Unless the same product is being made on each machine, or unless the compression machine itself provides its own enclosed air controlled environment, the machines shall be installed in separate cubicles

3.2. Suitable physical, proceduial and labelling arrangements shall be made to prevent mix-up of mateiials, 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-limils tablets

3.4. At the commencement of each compiession inn and in case of multiple compression points in a compression machine, sufficient individual tablets shall be examined at fixed intervals to ensuie that a tablet from each compression station or from each compression point has been inspected for suitable pharmacupoeial parameters like 'appearance¹, 'weight variation', 'dismlegtation', 'dissolution', 'hardness', 'friability' and 'thickness'. The results shall be lecorded as part of the batch documentation

3.5 Tablets shall be de ducfod, pmferably by automatic device, and shall be monitored for the pic r^nv.r- of f'>ificjn nuilotuls besides any other defects

3.6 Tablets shall bo collected into r'ean, hbelnd containers

3.7 Rejected or discarded lablph shall bu isolated in identified containers and their quantity recorded in the? Bnirh Mnnufncliinnrj Rpford83 3.8 In-process control shall bo employed to ensure that the products remain within specification During compression, samples of tablets shall be taken at tegular 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', 'dissolution¹, 'hardness', 'filability' and 'thickness' , and contamination by lubricating oil

4. 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 environment control (temperature, humidity) measures

4.2 Coating solutions and suspensions shall be made afresh and used in a manner, which shall minimize the risk of mictobinl giowth Their preparation and use shall be documented and roi'uulfMJ

5. Filling of Haid Gelatin Capsulo.

Empty capsules shells shall be regarded as 'dmg component' and treated accordingly They shall be stored under conditions which shall onsine then safety from the effects of excessive heat and moisture

6. Printing (Tablets And Capsules),

6 1 Special care shall bo taken to avoid pioduct mix-up dunny any punting of tablets and capsules Where different products, or different batches of the same product, are punted nmulteineously the operations shall adequately be segregated Edible grade colonia and Mutable printing ink shall be used for such printing.

6.2 After printing, tablets and capsules shall be appioved by Quality contiol before release for packaging or sale

7. 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 a packaging operation are removed before a new packaging operation is commpliced. There shall be an independent recoided 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 minimize the nsK of cross-contamination Such packaging shall be carried out in an isolated aien when potent tablets or beta lactum containing tablets are being packed 7.3. The strips coming out of the machine shall be inspected on the conveyor belt itseifVor defects such ac. mispnnl, cuts on the foil, missing tablets and improper sealing

7,4 Integrity of individual packaging slnps and blisters shall be subjected to vacuum test periodically to ensuie leak pmnfness of each pocket strips and blisters and records maintained84 THE GAZETTE OF INDIA : EXTRAORDINARY PART II—SEC. 3(i)1

PART I-C

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL LIQUIDS (SYRUPS, ELIXIRS, EMULSIONS AND SUSPENSIONS)

Note: The General Requirements as given in Pait I of 1his Schedule minting to Requirements of Good Manufacturing Practices for Premises and Materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of (Syrups, Elixirs, Emulsions and Suspensions). In addition to these requirements, the following Specific Requirements shall also be followed, namely:-

1. Building And Equipment;

1.1 The premises and equipment shall be designed, constructed and maintained to suit the manufacturing of Oral Li'quids, The layout and design of the manufacturing area shall stiive 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, ^raps, without open channels and design shall be such so as to prevent back" flow, Drains shall be shallow to facilitate cleaning" and disinfecting.

1.4 The production area shall be cleaned and sanitized 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 microbia! 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 automatic maohines equipped with high pressure air, water and steam jets.

1.8 The furniture used shall be smooth, washable and made of stainless steel, 2. PurlflecLWater —

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 he wnltrn pmttdurc for opmation mid iiuiiiituiianrc of punfied waler system 5 le circulation Lii.o of UV treatment lie UIIKMII with heat and snniti/nvj nijr.nl After any rhnnncfil sanitisation of the watci system, a flushing slull be done lo en^uie Mini s^nili/ing agnnt has I icon effectively removed

3 Manufacturing. -

3 1 Manufactunng personnels shdll i v nr non fiber shedding clothing to prevent contamination of the produr I

3 2 Materials likely lo shed fihei like gunny-bags wooden pallets shall not lj<^ carried into the aren wheie prorkif Is or cleaned containeis 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 Mjxmg and filling process shall be specified and monitored Special care shall be taken at the beginning of filling process after stoppage and at the end of the process to ensure that the product is uniformly homogenous during the filling process

3 4 The primary packaging aiea shall have an air supply which is filtered thiough 5 micron filters Tim temperature of the area shall not exceed 25 dngiee centigrade

3 5 When the bulk product ic nut immediately packed, the maximum periud of storage and the storage conditions shall be specified in the Mastet rounula The maximum period of storage time of a product in the bulk stage shall tie validated

PART I-D

Specific Requirements for Manufacture of Topical Products i.e. External

Preparations (Creams, Ointments, Pastes, Emulsions, Lotions,

Solutions, Dusting powders and identical products ).

Note: The General Requirements as given in Part I of this Schedule relating lo Requirements of Good Manufacturing Practices fot Piemises and Materials fot pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of Topical Products i e External Preparations (Creams, Ointments, Pastes, Emulsion, Lotions, Solutions, Dusting powders and identical products used for external applications) In addition to these (*$Quirements, the following Specific Requnements 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 .suitable msectocutors shall be installed86 THE GAZETTE OF INDIA EXTRAORDINARY [PART II—SEC 3(i)] 2 "The air to this mariiiradiiimrj ,nc,i kill be M lonsl filtered Ihionyh A) |i nil filtnis and shdll bo an conditional I he r 1 r•—-1 • lutll bo suilnbly ventilated

3 The area shall be filled with ^uiUiltln (ripauly ovlicinsl ^yMnin to pffpilivcly KMIIUVP vapours, fume; smoke flonlinu dir I pnilu ler,

4 Equipment used sluill ho d< oic|n< d mid ninint-iinnd to piPVPiil Urn prochlet finm being accidentally conUunin.ilod with riny foieiyn ninitnr oi lubiiL.inl

5 No rags or dusters shall be used in the piocess of cKinmy or dtyiny the process equipment or accessories used

6 Water used in the compounding shall be Purified Walci IP which shall be fieshly boiled and cooled Alternatively fieshly collcotpd Distilled water may be used 7 Powders,, whenever used, shall bo suitably sieved hofore use

8 Heating of base and vehicles like petroleum jolly shall bn done in sppninte mixing area In jacketed vessels using steam oi electricity

9 Separate packing section shall bo provider] for primdiy packaging of the piodu' h

PART I-E

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF METERED-DOSE INHALERS (MDI)

Note: The Goneial Requitements as givon in Pail I of (his Schrdulp lelalmy to Requirements of Good Manufacturing Piaclices for Premises and Materials for pharmaceutical piodutts shall he compliod with mutali<; mutandis, for the manu^utuio of Metorcd Dose Inhalers (MDI) In addition to these requirements, the following Spcufic Requirements shall also be followed, namely -

1 General,—

Manufacture of Metered-Dose-lnhalers shall be done under conditions which shall ensure minimum nncrobial and participate contamination Assurance of the quality of components and the bulk product is very important Where medicaments are in suspended slate, uniformity of suspension shall be established

2 Building and civil w o r k ^.

2 1 The building shall be located on a solid foundation to reduce risk of cracking of walls and floor due to movement of equipments and machinery

2 2 All building surfaces shall be impervious, smooth and non-shedding Flooring shall be continuous and coved to walls Ceiling shall be solid, continuous and87 coved to walls, Light fittings and air-grills shall be flushed to 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 aiea, bulk preparation and filling area, quarantine niea and spray testing and packing aiea

2.4 Secondary change roomr. shall be piovidc-d for operatois to change from factory clothing to special dopnilniPiilal clothing before entering the manufacturing and filling area.

2.5 Separate area shall be piovided for de-cailoning 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 through 2 n filters The bulk containers- of propellarits shall be stored, suitably identified, away from the manufacturing facilities.

3. Environmental Conditions,

3.1 Where products or clean components are exposed, the area shall be supplied with filtered air of Class C

3.2 The requirement of temperatuie and humidity in the manufacturing area shall be decided, depending on the type of pioduct 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 aiea and the support areas and the differential pressuie 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 monitoiing of environmental conditions, Temperature and humidity shall be monitored daily

4. Garments —

4.1 Personnel in the manufacluiiny and filling section shall wear suitable single - piece-garment made out of nun shedding, lighl weave material. Personnel in support areas shall wear clean factoty 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 foot wear and goggles shall be used by the peisonnels.

5. Sanitation —

5.1 There shall be written procedures for the sanitation of the MDI manufacturing facility. Special care shall be taken to handle residues and rinses of propellants.

5.2 Use of water for cleaning shall be resliicted and controlled. Routinely used disinfectants are suitable fur sairtising the different areas. Records of sanitation shall be maintained

6. Equipment^—

6.1 Manufacturing equipments shall be of closed system. The vessels and supply lines shall be of stainless steel.

¹6.2 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 there after periodically

7. Manufacture —

7.1 There shall be an approved Master Fonnula Records for the manufacture of metered dose inhalers. All propellants, liquids and gases, shall be filtered through 2 (.i filters to remove particles.

7.2 The primary packing material shall be appropriately cleaned and dried by compressed air suitably filtered' through 0.2 ji filter. The humidity of the compressed air shall be controlled as applicable.

7.3 The values shall be carefully handled and after de-cm toning 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 ensuied that 100% weight checking is carried out.

7.6 Filled containers shall be quarantined for suitable period established by the manufacturer to detect leaking containers prior to testing, labelling and packing -89 8 Documentation. -

8 1 in addition to the miitiuo good manufacturing pipctices documentation, manufacturing records shall show the following additional informations (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

PART I-F

SPECIFIC REQUIREMENTS OF PREMISES, PLANT AND MATERIALS FOR

MANUFACTURE OF ACTIVE PHARMACEUTICAL INGREDIENTS (BULK

DRUGS).

Note: The General Requncmwits as gi\en in Part I of this Sdmdule relating to Requirements of Guod Manufacturing Practices for Promises and Mateuals for pharmaceutical produUs shall bo complied with, mutatis mutandis, for the manufacture of Active Pluvmaceutical Ingredients (Bulk Dftigs) In addition to these requirements the fullowng Specific Reqimements shall also be followed, namely -

1 Buildings and civil works.

1 1 Apart from the building lequirements vontained in Pail I, General ante, the active pharmaceutical ingredients facilities for manufacture of hazardous reactions, Beta-Lactum antibiotics and Steroids and Steroidal Hormones/ Cytotoxic substances shall be provided in confined areas to prevent contamination of manufacture from other drugs

12 l he final stage of preparation of a drug like isolation/ Alteration / drying/ milling/ sieving and packing operations shall be provided with an Alteration systems including pre filters and final 5 micron filter Air dandling systems with adequate number of air changes per hour or any other suitable system to control the air borne contamination shall be provided Humidity/ Tempeiature shall also be controlled for all the operations wherevei requited

1 3 Air Alteration systems includiny pre-Alters and particulate matter air filters shall be u s ^, where appropnate on air supplies to production areas If air is re- circulated to production areas, measures shall be taken to control re- circulation' of floating dust paitides fiom production In areas where air contamination occurs during pioduction there shall be adequate exhaust system to control contaminants

ir)Gi/?noi—1?

1 4 Ancillary aiea shall be pioviclt >\ ki RoiN t-hou^e Utility service aieas like heat exchangers chilling woiMmi -IUIP rind supply of gases shall also he provided

1 5 For specified preparation like manurndntp of stciile pioducts and for certain antibiotics, hormones, cyloU we and oncology products, separate enclosed areas shall be designed The requirements for the sterile active pha-maceutical ingredient shall be in line with the facilities required for formulations to be filled aseptically

2 Sterile Products - Sterile active pharmaceutical ingredient filled asepttcally shall be treated as formulation from the stage wherever the p-ocess demands like crystallisation, lyophilisation, Alteration etc All conditions applicable to formulations to be filled aseptically shall apply mutatis mutandis for the manufacture of sterile active phaimaceutical ingredient involving the stages like filter jtion, crystallisation and lyophilisation

3 Utilities/ Services.- Equipments like Chilling Plant, Boiler, Heat exchangers, Vaccum and Gas , Storage Vessels shall be serviced, cleaned, sanitised and maintained at appropriate intervals to prevent mal-functions or contamination that may interfere with the safety, identity, strength, quality or purity of the drug product

4 Eqi pnVent Design, Size and Location

4 1 Equipme it used in the manufacture, processing, packing or holding of on active pharmaceutical ingredient shall be of appropriate design, adequate size and suitably located to facilitate operations for its intended use and for its cleaning and main'enance

4 2 If equipment is used for different intermediates and active pharmaceutical ingredient, proper cleaning from one product to another becomes particularly important If cleaning of a specific type of equipment is difficult, the equipment may need to be dedicated to a particular intermediate or active pharmaceutical ingredient

4.3 The choice of cleaning methods, detergents and levels of cleaning shall be defined and justified Selection of cleaning agents (e g solvents) should depend on,

(a) the cleaning agent stability to remove residues of raw materials, intermediates, precursors, degradation products and isomers as appropriate

(b) whether the cleaning agent leaves a residue itself, (c) compatibility with equipment construction materials like centrifuge/ Alteration, dnef-^fTuid bed dryer, rotocone proton dryer, vaccum dryer, frit mill, multi-mill/ jet mills sewetters for cuf sizing,

(d) test for absence of ntcr.nec atr or active pharmaceutical ingredient in the f nal rinse91 4.4 Wiitten procedures shall be established and followed for cleaning and maintenance of equipment including utensils used in the manufacture processing, packing or holding of active pharmaceutical ingredient These procedures shall include but should not be limited to the following.

(a) assignment of responsibility for cleaning and maintaining equipment, (b) maintenance and cleaninq pmrjmmmes .Schedules including wheic appropriate sanitizing schedules;

(c) a complete description of the methods and materials used to clean and maintain equipment including instructions for dis-assembling and le- assembling each article of equipment to ensuie pioper defining and maintenance,

(d) removal or obliteration of previous batch identification; (e) protection of clean equipment from contamination prior to use; (f) inspection of equipment for cleanliness immediately before use; (g) establishing the maximum times that may elapse between the completion 01 processing and equipment Honning ns well as between cleaning and equipment reuse

4.5 Equipment shall be donned between successive batches to prevent contamination and cfiny-ovut of derjmded material or contaminants.

4.6 As processing approaches the final purified active pharmaceutical ingredient, it is important to ensure that incidental carryover between batches does not have adverse impact on the established impurity profile. However, this does not generally hold good for biological active pharmaceutical ingredient where many of the processing steps are accomplished aseptically and where it is necessary to clean and sterilize equipment between batches

5. In- process Controls r-

5.1 In-process controls for chemical reactions may include the following;

(a) reaction time or reaction completion, (b) reaction mass appearance, clarity, completeness or pH of solutions; (c) reaction temperature; (d) concentration of a reactant; (e) assay or purity of the product; (f) process completion check by TLC/any other means/specific requirements 5.2 In-process controls for physical operations may include the following:

(a) appearance and color (b) uniformity of the blend (c) temperature of a process (d) concentration of a solution (e) proc&ssing rate or time (f) particle size analysis (g) bulk/tap density (h) pH determination (i) moisture content92 THE GAZETTE OF INDIA: EXTRAORDINARY [PART II—SEC. 3(I)]

6. Product containers and closures.—

6.1 All containers and closures shall comply with the pharmacopoeia! or any other requirement, suitable sampling methods, sample sizes, specifications, test methods, cleaning procedures and sterilization procedures, when indicated shall be used to assure that containers, closures and other component parts of drug packages are suitable and are not reactive, additive, adsorptive or teachable to an extent that significantly affects the quality or purity of the drug.

6.2 The drug product container shall be-re-tested or re-examined as appropriate and approved or rejected and shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which these are unsuitable.

6.3 Container closure system shall provide adequate protection against foreseeable external factors in storage /transportation and use that may cause deterioration or contamination of the active pharmaceutical ingredient.

6.4 Bulk containers and closures shall be cleaned and where indicated by the nature of the active pharmaceutical ingredient sterilized to ensure that they are suitable for their intended use.

6.5 The container shall be conspicuously marked with the name of the product and the following additional information concerning: (a) quality and standards, if specified, (b) manufacturing licence number, batch number, Drug Master File number (c) date of manufacture and date of expiry, if specified, (d) method for container disposal(labe! shall give the methodology) (e) storage¹ conditions, if specified and name and address of the manufactuter, if available.

PART II

Requirements of Plant and Equipment

External Preparations.- The following equipment is recommended for the rnanufacture of 'External preparations" i.e. Ointments, Emulsions, Lotions, Solutions, Pastes, Creams, Dusting Powders and such identical products used for external applications whichever is applicable, namely,-

[1) Mixing and storage tanks (Stainless steel). [2) Jacketted Kettle (steam, gas or electrically heated). [3) Mixer (Electrically operated ) [4) P^nejary mixer [5) A'colloid mill or a suitable emulsifier ;6) A triple roller mill or an ointment mill [7) Liquid filling equipment (Electrically operated ) [8) Jar or tube filling equipment (Electrically operated )

A r e a .- A m i n i m um i i i ' \i of i t n i 'y r n ' i r > i^ in"ii<->-. foi l ^ r - ic inr'l93 2 Oral Liquid Preparations.- The followiny equipment is iscommentlod foi Ihe manufacture of oral/ internal uso preparations ie Syrups, Elixus. r-Iiniilsionp ami Suspensions, whichever is applicable, namely ,

(1) Mixing and storage tanks (Stainless steel) (2) Jacketted Kettle/ Stainless steel tank (steam, gas or electrically healed) (3) Portable stirrer (Electrically operated ). (4) .A colloid mill or suitable emulsifier (Electrically operated ). (5) Suitable filteralion ct|inpment (Electrically operated ) (6) Semi-automatic/ automatic bottle filling machine. (7) Pilfer pioof cap scaling machine (8) Water distillation unit or cloioniser. (9) Clarity testing inspection units

Area.- A minimum area or fifty square metres for basic installation and ten sqimie metres for Ancillary area is recommended.

3. Tablets.- For effective operations, the tablet production department shall be divided into four distinct and separate sections as follows:

(a) Mixing, Granulation and Drying section. (b) Tablet compression section. (c) Packaging section (strip/blister machine wheiever required) (d) Coaling section (wherever requiied)

3.1 The following electrically, operated equipments are recommended foi the manufacture of compressed tablets and hypodermic tablets, in each of the above sections, namely,-

(a) Granulation - cum - Drying section ,-

(1) Disintegrator and sifter (2) Powder mixer. (3) Mass mixer/ planetary mixer / Rapid mixer yianulntor. (4) Granulator (non-oscillating type) (5) Thermostatically controlled hot aii oven with tiays (prefeiably

mounted on a trolley) / Fluid bed diyer

(6) Weighing machines

(b) Compression section ,

(1) Tablet compression machine, single/multl punch / rotatory. (2) Punch and dies storaye cabinets. (3) Tablet deduster. (4) Tablet counters (wherever applicable) (5) Tablet Inspection unit/belt. (6) Dissolution test apparatus. (7) In-process testing equipment like single pan electronic balance,

hardness tester, friability and disintegration lest apparatus.

(8) Alr-condltioning and dehumidificalion arrangement (wherever

necessary),

3.2 The Tableting section shall be free from dust and floating particles and may be air-conditioned. For this purpose, each tablet machine shall be isolated into cubicles and connected to a vacuum dust collector or an exhaust system.

(c) Packaging section' ,-

(1) Strip/ blister packaging machine (2) Leak test apparatus (vacuum system)

(3) Air condilioning and Dehumidification Arrangement (wheiever 39GI/2001-I3 applicable)94 THE GAZETTE QF INDIA: EXTRAORDINARY [PART II—SEC. 3(i)1 Area.- A minimum area of sixty square metres for basic Installation and twenty square metres for Ancillary area is recommended for un-coated.tablets.

(d) Coating Section ,-

(1) Jacketted kettle (steam, gas or electrically heated for pieparing coating suspension).

Q) Coating pan (Stainless steel). (3) Polishing pan where applicable. (4) Exhaust system (including vacuum dust collector) (5) Air conditioning and Dehumidification Arrangement. (6) Weighing balance.

3.3 THe Coating section shall be made dust free with suitable exhaust system to remove excess powder and fumes resulting from solvent evaporation. It shall be air- conditioned and dehumidified wherever considered necessary.

Area.- A minimum additional area of thirty square metres for coating section for basic Installation and ten square metres for Ancillary area is recommended.

Separate area & equipment for mixing, granulation, drying, tablet compression , coating and packing shall be provided for Penicillin group of drugs on the lines indicated above. In case of operations involving dust and floating particles, care shall be exercised to avoid cross- contamination

3.4 The manufacture of Hypodermic tablets shall be conducted under aseptic conditions in a separate air conditioned room, the walls of which shall be smooth and washable. The granulation, tableting and packing shall be done in this room.

3.5 The manufacture of effervescent and solcible/dlspersible tablets shall be carried out under air-conditioned and dehumidified area.

4. Powders.-The following equipment is recommended for the manufacture of powder namely,-

(1) Disintegrator. (2) Mixer (Electrically operated ) (3) Sifter. (4) Stainless steel vessels and scoops of suitable sizes. (5) Filling equipment (electrically operated). (6) Weighing balance.

In the case of operation involving floating particles of fine powder, a suitable exhaust system shall be provided. Workers should be provided with suitable masks during operation.

Area.- A minimum area of thirty square metres is recommended to allow for the basic Installations. Where the actual blending is to be done on the premises, an additional room shall be provided for the purpose.

5. Capsules.- For the manufactuie of capsules, separate enclosed area suitably air- conditioned with airlock arrangement shall be provided. The following equipment is recommended for filling of Hard Gelatin Capsules, namely,-

(1) Mixing and blending equipment (electrically or power driven). (2) Capsule filling units (preferably semi-automatic or automatic filling machines).

(3) Capsules counters (wherever applicable). (4) Air-conditioning and Dehumidification arrangement (preferably centrally air-condijjoned and dehumidification system).

(5) Weighin'g balance .

(6) Disintegration test apparatus. (7) Capsule polishing equipment.

Separate equipments, filling and packaging areas shall be provided for penicillin and non-penicillin sections. In case of operations involving floating particles of fine powder, a suJtable exhaust system shall be provided. The manufacture and filling shall be carried out in air conditioned areas. The room shall be dehumidified.

Area.- A minimum area of twenty five square metres for basic Installation and ten square metres for Ancillary area each for penicillin and non-penicillin section is recommended.

6. Surgical dressing.- The following equipment is recommended for the manufacture of surgical dressings other than Absorbent Cotton Wool, namely,-

(1) Rolling machine. (2) Trimming machine. (3) Cutting equipment. (4) Folding and pressing machine for guaze. (5) Mixing tanks for processing medicated dressing. (6) Hot air dry oven. (7) Steam sterilizer or dry heat sterilizer or other suitable equipment. (8) Working tables / benches for different operations.

Area.- A minimum area of thirty square meters is recommended to allow for the basic Installations In case medicated dressings are to be manufactured, another room with a minimum area of thirty square meters shall be provided.

7. Opthalmic preparations.- For the manufacture of Opthalmic preparations, separate enclosed areas with air lock arrangement shall be provided. The following equipment is recommended for manufacture under aseptic conditions of Eye-Oiiilmonl, Eyo- lotions and other preparations foi external use, namely -

(1) Thermostatically contiolled hot air ovens (piefeiably double ended) (2) Jacketted Kettle/ Stainless steel tanks (steam, gas or electrically honied) (3) Mixing and storage tanks of stainless stool/ Planetaiy mixer. (4) Colloid mill or ointment mill (5) Tube filling and crimping equipment (semi-automatic or automatic filling machines).

(6) Tube cleaning equipment (ail jet lype) (7) Tube washing and drying equipment. (8) Automatic vial washing machine (9) Vials drying oven. (10) Rubber bung washing machine. (11) Sintered glass funnel, seitz filter or filter candle (pieferably cailiidge and membrane filters).

(12) Liquid filling equipment (semi-automatic or automatic filling machines) (13) Autoclave (preferably ventilator autoclave) (14) Air-conditioning and Oehumidificalion ananyement (piefeiably centrally air-conefftioned and d^humidificntion system)

(15) Laminar air flow units

Area.- A minimum area of twenty five squaie metres foi basic installation and ten square metres for Ancillary area is recommended The manufacfliie and filling shall be carried out in an air-conditioned areas under aseptic conditions. The looms shall be further dehumidified if piennmliuns containing antibiotics are manufactured as necessary.

8 Pessaries and Suppositories.- (i) The following equipment Is recommended foi manufacture of Pessaries and Suppositions, namely -

(1) Mixirig and pouring equipment (2) Moulding equipment (3) Weighing devices

Area.- A minimum area of twenty five square meters is recommended to allow for the basic Installation.

(ii) In the case of pessaries rnanufactuied by granulation and compression if the licensee does not have a tablet section, the requirements as indicated under "item 3 of Tablet",shall be provided

9. Inhalers and Vltrallae.- The following equipment is recommended for manufactuie of Inhalers and vitrallae, namely,- (1) Mixing equipment. (2) Qjpduated delivery equipment for measurement of the medicament (3) Sealing equipment

Area.- An area of minimum twenty square meters is recommended for the basic installations.

10 Repacking of drugs and pliainiacoutlcal chemicals.- The following equipment K recommended for repacking ol thugs nml plmmncoulicals chemirnls namely, (1) Powder disintegrator (2) Powder sifter (Electrically npeialnd) (3) Stainless steel scoops and vessels nf suitable sires (4) Weighing and measuring equipment (5) Filling equipment (semi / automatic machine) (6) Electric sealing machine

Area.- An area of minimum thirty fivp square meters is recommended for the basic installation In case of operations involving floating particle^ of fine powdei a suitable exhaust system shall be provided

11 Parenteral Preparations.- The whole operation of manufactuie of paienteial preparations (small volume injoclables and large volume parenterals) in glass and plastic containers may be divided into following separate arc?W rooms, namely,-

11.1 Parentaral preparations in glass contalneis,-

(1) Water management area - This includes water tiealment and storage (2) Containers and closures prepaiation area- This irtrdudes washing and drying of ampoules, vials, bottles and closuies

(3) Solution preparation area- I his includes picpaialion and filtration of solution

(4) Filling, capping and sealing area - This includes filling and sraling of ampoules and/or filling, capping and sealing of vials and hollies

(5) Sterilization area (6)" Quarantine area (7) Visuallnspection aiea (8) Packaging area n- 3ml

** •

•—

The following equipment is recommended for different above mentioned aieas, namely: -

(a) Water management area.-

(1) De-ionised water treatment unit (2) Distillation (multi column with heat exchangers) unit (3) Thermostatically controlled water storage tank (4) Transfer pumps (5) Stainless steel service lines for carrying water into user areas.

(b) Containers and closures preparation aiea,-

(1) Automatic rotary ampoule/vial/bottle washing machine having sepaiate air, water, distilled water jets

(2) Automatic closures washing machine (3) Storage equipment for ampoules, vials, bottles and closures (4) Dryer/sterilizer (double ended)

(5) Dust proof storage cabinils. (6) Stainless steel benchcs/stoolr.

(c) Solution preparation area,-

(1) Solution preparation ntul mixing Stainless steel tanks and olhei containers. (2) Portable stirrer (3) Filteration equipment with cartridge and membrane filiters/bacleriologicnl filters.

(4) Transfer pumps. (5) Stainless steel benches/stools

(d) Filling, capping and sealing area ,-

(1) Automatic ampoule/vial/boUle filling, sealing and capping machine under laminar air flow work station.

(2) Stainless stenl bonchos/slools

(1) Supei heated steeam sterilizei (preferably with computer conliol for sterilization cycle alongwith trolley sets for loading/unloading containers before and after sterilization).

(2) Hot Air Sterilizer (preferably double ended). (3) Pressure leak test apparatus

(0 Quarantine area,-

(1) Storage cabinets- (2) Raised platforms/iron racks

(g) Visual inspection area,-

(1) Visual inspection units (piefeiably conveyor belt type and composile while and black assembly supported with illumination)

(2) Stainless steel benches/stoolsZo OA OF INDIA:, LAORDINARY [PART II—SBC. 3(1)1 (h) Packaging area,-

(1) Batch coding machine (preferably automatic) (2) Labelling unit (preferably conveyor belt type) (3) Bar coding equipment (4) Stainless steel benches/stools

Area.- A minimum area of one hundred and fifty square metres for the basic installation and an Ancillary area of one hundred square metres for Small Volume Injectables is recommended. For Large Volume Parenlerals, an area of one hundred and fifty square metres each for the basic installation and for Ancillary area is recommended. These areasrshall be partitioned into suitable enclosures with airlock arrangements.

11.2 Parenteral preparations In Plastic c o n t a i n er by Flow-Fill-Seal technology.- The whole operation of manufacture of Inige volumn parenteial preparations in plastic containers including plastic pouches by automatic (all operations in one station) How- Fill-Seal machine or by semi-automatic blow moulding, filling-cum-sealing machine may be divided into following separate areas/ rooms, namely -

(1) Water management area (2) Solution preparation area (3) Container moulding -cum -Filling and pealing area (4) Sterilization area (5) Quarantine area (6) Visual inspection area (7) Packaging area

The following equipment is recommended for diffeient above mentioned areas, namely :

(a) Water management area ,-

(1) De-ionised water tiontment unit (2) Distillation unit (mulli column with heat exchangers) (3) Thermostatically controlled water storage tank

(4) Transfer pumps (6) Stainless steel service lines for carrying water into usei aieas.

(b) Solution preparation area -

(1) Solution preparation and storage tanks (2) Tlansfer pumps (3) Cartridge and membrane filters

(c) Container moulding -cum -filling and sealing area,-

(1) Sterile flow-fill-seal machine (all operations in one station with built-in Laminar air flow work station having integrated container oulput conveyer belt through pass-box)

(2) Arrangement for feeding plastic granules thiouyh feeding -cum- filling tank into the machine

(d) Sterilization area.- Super heated steam sterlizet (with computer contiol for sterilization cycle alongwith trolley sets for loading/unloading containers for sterilization)

(e) Quarantine area.- Adequate number of platforms/racks with stoiage system (f) Visual inspection area.- Visual inspection unit (with conveyer belt and composite white £hd black assembly r.uppniled with illumination)99 (g) Packaging area,-

(1) Pressure leak test apparatus (piessure belt or rotating disc type); (2) Batch coding machine (preferably automatic); (3) Labelling unit (preferably conveyor belt type); (4) Bar coding equipment

Area.- A minimum area of two hundred and fifty square metres for the basic installation and an Ancillary area of one hundred square metres for large volume parenteral preparations in plastic containers by Flow-Fill-Seal technology is recommended. These areas shall be partitioned into suitable enclosures with air- lock arrangements,

Note I. The requirements mentioned in this Schedule do not include requirement of machinery, equipment and premises required for preparation of containers and closures for different dosage forms and categories of drugs. The Licensing Authority shall have the discretion to examine the suitability and adequacy of the machinery, equipment and premises taking into consideration the requirements of the licensee in this respect.

Note II. The requirements mentioned in this Schedule are made subject to the modification at the discretion of the Licensing Authority, if he is of the opinion that havipg regard to the nature and extent of the manufacturing operations, it is necessary to relax or alter them in the circumstances of a particular case.

Note III. This Schedule gives equipments and area for basic installation required for certain categories of drugs only. There are, in addition, Qther categories of drugs such as basic drugs, Pharmaceuticals and chemicals, medicinal gases, empty gelatin capsules, mechanical contraceptives, new dosage forms, surgical dressing (except -sterile) gauge, bandages, disinfectant fluids and products to be repacked etc which are not listed in this Schedule. The Licensing Authority shall, in respect of such categories of drugs, have the discretion to examine the adequacy or otherwise of factory premises, area, plant and machinery and other requisites, having regard to the nature and extent of the manufacturing operations involved and direct the manufacturer to carry out necessary modifications in them and on the modifications having been made approve the manufacture of such categories of drugs. Any drug as permitted to be manufactured by the Licensing Authority shall be deemed to be additional category of drug for the purpose of this Schedule and sub-rule (5) of rule 69.

Note IV, Areas for formulations meant for external use and areas for formulations meant for interna¹! use shall be separately provided to avoid mix-up even though they are from the same category of formulations.

Note V. (a) Excipients, Packaging materials (in general) and Packaging materials for Large Volume Parenterals shall have a minimum area of thirty, fifty and one hundred square metres respectively.

(b) Quality Control Laboratory shall be divided into separate three sections i.e. Chemicals, Microbiological and Biologiocal testing. These shall have a minimum area of sixty, thirty and fifteen square metres respectively for basic100 THE GAZETTE OF INDIA: EXTRAORDINARY [PART II—SEC. 3(i)] installation and an Ancillary area of Ihirty, ten and twenty five square metres respectively is recommended. These sections shall have airlock arrangement and Laminar air-flow work station wherever considered necessary

(c) Active Pharmaceutical Ingredients (Bulk drugs) section shall have additionally a minimum area of one hundred square metres, which may be suitably partitioned for different operations.

Note VI. The licensees and/or manufactures are advised to replace the old and existing equipments, instruments, machines and devices with the latest and new ones, under intimation to the Licensing Authonty "

[F No X 11014/5/2000-DMS &PFA]

DEEPAK GUPTA, Jt. Secy.

Foot Note : The Principal Rules were published in the official Gazette vide notification No. F 28-10/45-H(l) dated 21st December, 1945 and last amended vide GSR 904(E), dated 1-12-2000. The Drugs and Cosmetics Rules, 1945 as amended up to 1-5-1979 is contained in the publication of the Ministry of Health and Family Welfare (Department of Health) containing the Drugs and Cos- metics Act 1940 (PDGHS-61)

Printed by the Manager, QovL of India Proa, Ring Road, Mayapun, New Delhi-110064

and Publiihod by the Contrpller of Publication, Dolhi-110054 — 2 0 0 1.