Drugs and Cosmetics Rules 1945

1
[SCHEDULE M
(See Rules 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
inspection and reference; and the manufacturing premises shall be used exclusively for
production of drugs 2[and no other manufacturing activity shall be undertaken therein except
in respect of units licensed prior to 11th December, 2001].

PART 1

GOOD MANUFACTURING PRACTICES FOR PREMISES AND MATERIALS

1 GENERAL REQUIREMENTS:
1.1. Location and surroundings.- The factory building(s) for manufacture of
drugs shall be so situated and shall have such measures as to avoid risk of contamination from
external environment including open sewage, drain, public lavatory or any factory which
produce disagreeable or obnoxious odour or fumes, excessive soot, dust, smoke, chemical or
biological emissions.
1.2. Buildings and premises.- The building(s) used for the factory shall be
designed, constructed, adapted and maintained to suit the manufacturing operations so as to
permit production of drugs under hygienic conditions. They shall conform to the conditions
laid down in the Factories Act, 1948 (63 of 1948).
The premises used for manufacturing, processing, warehousing, packaging, labelling
and testing purposes shall be
(i) compatible with other drug manufacturing operations that may be carried out
in the same or adjacent area / section;

(ii) adequately provided with working space to allow orderly and logical
placement of equipment, materials and movement of personnel so as to:

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

with raw materials, intermediates and in-process material;

(b) avoid the possibilities of contamination and cross- contamination by

providing suitable mechanism;

(iii) designed / constructed / maintained to prevent entry of insects, pests, birds,

vermins and rodents. Interior surface (walls, floors and ceilings) shall be
smooth and free from cracks, and permit easy cleaning, painting and
disinfection;

1. Subs. by G.S.R. 894(E) , dt. 11.12.2001.- applicable to manufacturers licensed to manufacture drugs, for
the period up to 31.12.2003.
2. Subs. by Act 431(E), dt. 30.6.2005.

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(iv) air-conditioned, where prescribed for the operations and dosage forms under
production. The production and dispensing areas shall be well lighted,
effectively ventilated, with air control facilities and may have proper Air
Handling Units (wherever applicable) to maintain conditions including
temperature and, wherever necessary, humidity, as defined for the relevant
product. These conditions shall be appropriate to the category of drugs and
nature of the operation. These shall also be suitable to the comforts of the
personnel working with protective clothing, products handled, operations
undertaken within them in relation to the external environment. These areas
shall be regularly monitored for compliance with required specifications;

(v) provided with drainage system, as specified for the various categories of
products, which shall be of adequate size and so designed as to prevent back-
flow and/or prevent insects and rodents entering the premises. Open channels
shall be avoided in manufacturing areas and, where provided, these shall be
shallow to facilitate cleaning and disinfection;

(vi) the walls and floors of the areas where manufacture of drugs is carried out
shall be free from cracks and open joints to avoid accumulation of dust.
These shall be smooth, washable, coved and shall permit easy and effective
cleaning and disinfection. The interior surfaces shall not shed particles. A
periodical record of cleaning and painting of the premises shall be
maintained.

1.3 Water System. - There shall be validt. system for treatment of water drawn from
own or any other source to render it potable in accordance with standards specified by the
Bureau of Indian Standards or Local Municipality, as the case may be, so as to produce
Purified Water conforming to Pharmacopoeial specification. Purified Water so produced shall
only be used for all the operations except washing and cleaning operations where potable
water may be used. Water shall be stored in tanks, which do not adversely affect quality of
water and ensure freedom from microbiological growth. The tank shall be cleaned
periodically and records maintained by the licensee in this behalf.

1.4. Disposal of waste. -

(i) The disposal of sewage and effluents (solid, liquid and gas) from the
manufactory shall be in conformity with the requirements of Environment
Pollution Control Board.
(ii) All bio-medical waste shall be destroyed as per the provisions of the Bio-
Medical Waste (Management and Handling) Rules, 1996.
(iii) Additional precautions shall be taken for the storage and disposal of rejected
drugs. Records shall be maintained for all disposal of waste.
(iv) Provisions shall be made for the proper and safe storage of waste materials
awaiting disposal. Hazardous, toxic substances and flammable materials
shall be stored in suitably designed and segregated, enclosed areas in
conformity with Central and State Legislations.

2. Warehousing Area:

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 spare parts and change items.

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2.2 Warehousing areas shall be designed and adapted to ensure good storage
conditions. They shall be clean, dry and maintained with acceptable temperature
limits. Where special storage conditions are required (e.g. temperature, humidity),
these shall be provided, monitored and recorded. Storage areas shall have appropriate
house-keeping and rodent, pests and vermin control procedures and records
maintained. Proper racks, bins and platforms shall be provided for the storage of
materials.

2.3 Receiving and dispatch bays shall protect materials and products from
adverse weather conditions.

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
segregation. Access to these areas shall be restricted to authorized persons.

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

2.6. Segregation shall be provided for the storage of rejected, recalled or

returned materials or products. Such areas, materials or products shall be suitably
marked and secured. Access to these areas and materials shall be restricted.

2.7. Highly hazardous, poisonous and explosive materials such as narcotics,

psychotropic drugs and substances presenting potential risks of abuse, fire or explosion
shall be stored in safe and secure areas. Adequate fire protection measures shall be
provided in conformity with the rules of the concerned civic authority.
2.8. Printed packaging materials shall be stored in safe, separate and secure
areas.

2.9. Separate dispensing areas for (Beta) lactum, Sex Hormones and
Cytotoxic substances or any such special categories of product shall be provided with
proper supply of filtered air and suitable measures for dust control to avoid
contamination. Such areas shall be under differential pressure.

2.10. Sampling and dispensing of sterile materials shall be conducted under

aseptic conditions conforming to Grade A, which can also be performed in a dedicated
area within the manufacturing facility.

2.11. Regular checks shall be made to ensure adequate steps are taken 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.

3. Production area:

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

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

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dedicated facilities shall be provided for the manufacture of contamination causing and potent
products such as Beta-Lactum, Sex Hormones and Cytotoxic substances.

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

3.4. Pipe-work, electrical fittings, ventilation openings and similar service lines
shall be designed, fixed and constructed to avoid 1[accumulation of dust]. Service lines shall
preferably be identified by colours and the nature of the supply and direction of the flow shall
be marked/indicated.

4. Ancillary Areas:
4.1 Rest and refreshment rooms shall be separate from other areas. These areas
shall not lead directly to the manufacturing and storage areas.

4.2 Facilities for changing, storing clothes and for washing and toilet purposes
shall be easily accessible and adequate for the number of users. Toilets, separate for males
and females, shall not be directly connected with production or storage areas. There shall be
written instructions for cleaning and disinfection of such areas.
4.3 Maintenance workshops shall be separate and away from production areas.
Whenever spares, changed parts and tools are stored in the production area, these shall be
kept in dedicated rooms or lockers. Tools and spare parts for use in sterile areas shall be
disinfected before these are carried inside the production areas.
4.4. Areas housing animals shall be isolated from other areas. The other
requirements regarding animal houses shall be those as prescribed in rule 150-C(3) of the
Drugs and Cosmetics Rules, 1945 which shall be adopted for production purposes.

5. Quality Control Area.

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

5.2 Quality Control Laboratories shall be designed appropriately for the

operations to be carried out in them. Adequate space shall be provided to avoid mix-ups and
cross-contamination. Sufficient and suitable storage space shall be provided for test samples,
retained samples, reference standards, reagents and records.
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 radioisotopes testing areas. The
laboratory shall be provided with regular supply of water of appropriate quality for cleaning
and testing purposes.
5.4. Quality Control Laboratory shall be divided into separate sections i.e. for
chemical, microbiological and wherever required, biological testing. These shall have
adequate area for basic installation and for ancillary purposes. The microbiology section
shall have arrangements such as airlocks and laminar air flow work station, wherever
considered necessary.
1. Subs. by G.S.R. 431(E), dt. 30.6.2005.

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6. Personnel:

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

6.2 The head of the Quality Control Laboratory shall be independent of the
manufacturing unit. The testing shall be conducted under the direct supervision of competent
technical staff who shall be whole time employees of the licensee.

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 personnel shall be laid and
followed strictly.

6.5. Number of personnel employed shall be adequate and in direct proportion to the
workload.

6.6. The licensee shall ensure in accordance with a written instruction that all
personnel in production area or into Quality Control Laboratories shall receive training
appropriate to the duties and responsibility assigned to them. They shall be provided with
regular in-service training.

7. Health, clothing and sanitation of workers:

7.1 The personnel handling Beta-lactum antibiotics shall be tested for Penicillin
sensitivity before employment and those handling sex hormones, cytotoxic substances and
other potent drugs shall be periodically examined for adverse effects. These personnel should
be moved out of these sections (except in dedicated facilities), by rotation, as a health
safeguard.

7.2 Prior to employment, all personnel, shall undergo medical examination including
eye examination, and shall be free from Tuberculosis, skin and other communicable or
contagious diseases. Thereafter, they should be medically examined periodically, at least once
a year. Records shall be maintained thereof. The licensee shall provide the services of a
qualified physician for assessing the health status of personnel involved in different activities.

7.3 All persons prior to and during employment shall be trained in practices which
ensure personnel hygiene. A high level of personal hygiene shall be observed by all those
engaged in the manufacturing processes. Instructions to this effect shall be displayed in
change- rooms and other strategic locations.
7.4 No person showing, at any time, apparent illness or open lesions which may
adversely affect the quality of products, shall be allowed to handle starting materials,
packaging materials, in-process materials, and drug products until his condition is no longer
judged to be a risk.

7.5 All employees shall be instructed to report about their illness or abnormal
health condition to their immediate supervisor so that appropriate action can be taken.

7.6 Direct contact shall be avoided between the unprotected hands of personnel
and raw materials, intermediate or finished, unpacked products.

7.7 All personnel shall wear clean body coverings appropriate to their duties.
Before entry into the manufacturing area, there shall be change rooms separate for each sex

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with adequate facilities for personal cleanliness such as wash basin with running water,
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[clean towels or hand dryers], soaps, disinfectants, etc. The change rooms shall be provided
with cabinets for the storage of personal belongings of the personnel.

7.8 Smoking, eating, drinking, chewing or keeping plants, food, drink and
personal medicines shall not be permitted in production, laboratory, storage and other areas
where they might adversely influence the product quality.

8. Manufacturing Operations and Control:

8.1 All manufacturing operations shall be carried out under the supervision of
technical staff approved by the Licensing Authority. Each critical step in the process relating
to the selection, weighing and measuring of raw material addition during various stages shall
be performed by trained personnel under the direct personal supervision of approved technical
staff.
The contents of all vessels and containers used in manufacture and storage during the
various manufacturing stages shall be conspicuously labelled with the name of the product,
batch number, batch size and stage of manufacture. Each label should be initialled and dt. by
the authorised technical staff.

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

8.2. Precautions against mix-up and cross-contamination:

8.2.1. The licensee shall prevent mix-up and cross-contamination of drug material
and drug product (from environmental dust) by proper air-handling system, pressure
differential, segregation, status 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 areas or isolated production
areas within the building with independent air-handling unit and proper pressure differentials.
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[The effective segregation of these areas shall be validated 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 equipment 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 left-overs of the previous packaging operations, including labels, cartons and
caps are cleared before the 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 spillages. The line clearance shall be performed according to an
approximate check list 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 rechecked at regular
intervals. All printing and overprinting shall be authorized in writing.
1. Subs. by G.S.R. 431(E), dt. 30.6.2005.

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8.2.7 The manufacturing environment shall be maintained at the required levels of

temperature, humidity and cleanliness.

8.2.8 Authorised persons shall ensure change-over into specific uniforms before
undertaking any manufacturing operations including packaging.

8.2.9 1[There shall be segregated secured areas for recalled or rejected material
and for such material which are to be reprocessed or recovered.]

9. Sanitation in the Manufacturing Premises:

9.1 The manufacturing premises shall be cleaned and maintained in an orderly

manner, so that it is free from accumulated waste, dust, debris and other similar material. A
validt. cleaning procedure shall be maintained.

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

9.3 A routine sanitation program shall be drawn up and observed, which shall be
properly recorded and which shall indicate
(a) specific areas to be cleaned and cleaning intervals;
(b) cleaning procedure to be followed, including equipment and materials to
be used for cleaning; and
(c) personnel assigned to and responsible for the cleaning operation.

9.4 The adequacy of the working and in-process storage space shall permit the
orderly and logical positioning of equipment and materials so as to minimize the risk of mix-
up between different pharmaceutical products or their components to avoid cross
contamination, and to minimise the risk of omission or wrong application of any of the
manufacturing or control steps.

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

10. Raw Materials:

10.1 The licensee shall keep an inventory of all raw materials to be used at any
stage of manufacture of drugs and maintain records as per Schedule U.

10.2 All incoming materials shall be quarantined immediately after receipt or

processing. All materials shall be stored under appropriate conditions and in an orderly
fashion to permit batch segregation and stock rotation by a in/first expiry -out
principle. All incoming materials shall be checked to ensure that the consignment corresponds
to the order placed.
10.3 All incoming materials shall be purchased from approved sources under valid
purchase vouchers. Wherever possible, raw materials should be purchased directly from the
producers.

10.4 Authorized staff appointed by the licensee in this behalf, which may include
personnel from the Quality Control Department, shall examine each consignment on receipt
and shall check each container for integrity of package and seal. Damaged containers shall be
identified, recorded and segregated.
1. Subs. by G.S.R. 431(E), dt. 30.6.2005.

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10.5 If a single delivery of material is made up of different batches, each batch

shall be considered as a separate batch for sampling, testing and release.

10.6 Raw materials in the storage area shall be appropriately labelled. 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;

(b) manufacture s name, address and batch number;

(c) the status of the contents (e.g. quarantine, under test, released, approved,
rejected); and

(d) the manufacturing date, expiry date and re-test date.

10.7 There shall be adequate separate areas for materials

and t with arrangements and equipment to allow dry, clean and orderly placement of
stored materials and products, wherever necessary, under controlled temperature and
humidity.

10.8 Containers from which samples have been drawn shall be identified.

10.9 Only raw materials which have been released by the Quality Control
Department and which are within their shelf-life shall be used. It shall be ensured that shelf
life of formulation product shall not exceed with that of active raw materials used.

10.10 It shall be ensured that all the containers of raw materials are placed on the
raised platforms/racks and not placed directly on the floor.

11. Equipment:

11.1 Equipment shall be located, designed, constructed, adapted and maintained to

suit the operations to be carried out. The layout and design of the equipment shall aim to
minimise the risk of errors and permit effective cleaning and maintenance in order to avoid
cross-contamination, build-up of dust or dirt and, in general, any adverse effect on the quality
of products. Each equipment shall be provided with a logbook, wherever necessary.

11.2 Balances and other measuring equipment of an appropriate range, accuracy

and precision shall be available in the raw material stores, production and in-process control
operations and these shall be calibrated and checked on a scheduled basis in accordance with
Standard Operating Procedures and records maintained.

11.3 The parts of the production equipment that come into contact with the
product shall not be reactive, additive or adsorptive to an extent that would affect the quality
of the product.

11.4 To avoid accidental contamination, wherever possible, non-toxic/edible grade

lubricants shall be used and the equipment shall be maintained in a way that lubricants do not
contaminate the products being produced.

11.5 Defective equipment shall be removed from production and Quality Control
areas or appropriately labelled.

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12. Documentation and Records: Documentation is an essential part of the Quality

assurance system and, as such, shall be related to all aspects of Good Manufacturing Practices
(GMP). Its aim is to define the specifications for all materials, method of manufacture and
control, to ensure that all personnel concerned with manufacture know the information
necessary to decide whether or not to release a batch of a drug for sale and to provide an audit
trail that shall permit investigation of the history of any suspected defective batch.

12.1 Documents designed, prepared, reviewed and controlled, wherever

applicable, shall comply with these rules.

12.2 Documents shall be approved, signed and dt. by appropriate and authorized
persons.

12.3 Documents shall specify the title, nature and purpose. They shall be laid out
in an orderly fashion and be easy to check. Reproduced documents shall be clear and legible.
Documents shall be regularly reviewed and kept up to date. Any alteration made in the entry
of a document shall be signed and dt..

12.4 The records shall be made or completed at the time of each operation in such
a way that all significant activities concerning the manufacture of pharmaceutical products are
traceable. Records and associated Standard Operating Procedures (SOP) shall be retained for
at least one year after the expiry date of the finished product.

12.5 Data may be recorded by electronic data processing systems or other reliable
means, but Master Formulae and detailed operating procedures relating to the system in use
shall also be available in a hard copy to facilitate checking of the accuracy of the records.
Wherever documentation is handled by electronic data processing methods, authorized
persons shall enter or modify data in the computer. There shall be record of changes and
deletions. Access shall be restricted by s other means and the result of entry of
critical data shall be independently checked. Batch records electronically stored shall be
protected by a suitable back-up. During the period of retention, all relevant data shall be
readily available.

13. Labels and other Printed Materials: Labels are absolutely necessary for identification
of the drugs and their use. The printing shall be done in bright colours and in a legible
manner. The label shall carry all the prescribed details about the product.

13.1 All containers and equipment shall bear appropriate labels. Different colour
coded labels shall be used to indicate the status of a product (for example under test,
approved, passed, rejected).

13.2 To avoid chance mix-up of printed packaging materials, product leaflets,

relating to different products, shall be stored separately.

13.3 Prior to release, all labels for containers, cartons and boxes and all circulars,
inserts and leaflets shall be examined by the Quality Control Department of the licensee.

13.4 Prior to packaging and 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 shipment received indicating receipt, control reference numbers and
whether accepted or rejected. Unused coded and damaged labels and packaging materials
shall be destroyed and recorded.

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13.6 The label or accompanying document of reference standards and reference

culture shall indicate concentration, lot number, potency, date on which containers was first
opened and storage conditions, where appropriate.

14. Quality Assurance: This is a wide-ranging concept concerning all matters that
individually or collectively influence the quality of a product. It is the totality of the
arrangements made with the object of ensuring that products are of the quality required for
their intended use.

14.1 The system of quality assurance appropriate to the manufacture of

pharmaceutical products shall ensure that:

(a) the pharmaceutical products are designed and developed in a way that takes
account of the requirements of Good Manufacturing Practices (hereinafter
referred as GMP) and other associated codes such as those of Good
Laboratory Practices (hereinafter referred as GLP) and Good Clinical
Practices (hereinafter referred 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-process controls, calibrations, and 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 the label
claim and any other provisions relevant to production, control and release of
pharmaceutical products.

15. Self Inspection and Quality audit: It may be useful to constitute a self-inspection
team supplemented with a quality audit procedure for assessment of all or part of a system
with the specific purpose of improving it.

15.1 To evaluate the manufacturer s compliance with GMP in all aspects of

production and quality control, concept of self-inspection shall be followed. The manufacturer
shall constitute a team of independent, experienced, qualified persons from within or outside
the company, who can audit objectively the implementation of methodology and procedures
evolved. The procedure for self-inspection shall be documented indicating self-inspection
results, evaluation, conclusions and recommended corrective actions with effective follow up
program. The recommendations for corrective action shall be adopted.

15.2 The program shall be designed to detect shortcomings in the implementation

of Good Manufacturing Practice and to recommend the necessary corrective actions. Self-
inspections shall be performed routinely and on specific occasions, like when product recalls
or repeated rejections occur or when an inspection by the licensing authorities is announced.
The team responsible for self-inspection shall consist of personnel who can evaluate the
implementation of Good Manufacturing Practice objectively; all recommendations for
corrective action shall be implemented.

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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.
(l) Recall procedures.
(m) Complaints management.
(n) 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 ensure that the necessary and
relevant tests are actually carried and that the materials are not released for use, nor products
released for sale or supply until their quality has been judged to be satisfactory. It is not
confined to laboratory operations but shall be involved in all decisions concerning the quality
of the product. It shall be ensured that all quality control arrangements are effectively and
reliably carried out.The department as a whole shall have other duties such as to establish,
evaluate, validate and implement all Quality Control Procedures and methods.

16.1 Every manufacturing establishment shall establish its own quality control
laboratory manned by qualified and experienced staff.

16.2 The area of the quality control laboratory may be 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 control department shall evaluate, maintain and store
reference samples.

16.4 Standard operating procedures shall be available for sampling, inspecting and
testing of raw materials, intermediate bulk finished products and packing materials and,
wherever necessary, for monitoring environmental conditions.

16.5 There shall be authorized and dt. specifications for all materials, products,
reagents and solvents including test of identity, content, purity and quality. These shall
include specifications for water, solvents and reagents used in analysis.

16.6 No batch of the product shall be released for sale or supply until it has been
certified by the 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 quantity which is at least twice the quantity of the drug required to
conduct all the tests, except sterility and pyrogen/Bacterial Endotoxin Test performed on the
active material and the product manufactured. The retained product shall be kept in its final
pack or simulated pack for a period of three months after the date of expiry.

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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 in-charge of production and countersigned by the authorised quality control
personnel before a product is released for sale or distribution.

16.9 Quality control personnel shall have access to production areas for sampling
and investigation, as appropriate.

16.10 The quality control department shall conduct stability studies of the products
to ensure and assign their shell life at the prescribed conditions of storage. All records of such
studies shall be maintained.

16.11 The in-charge of Quality Assurance shall investigate all product complaints
and records thereof shall be maintained.

16.12 All instruments shall be calibrated and testing procedures validt. before these
are adopted for routine testing. Periodical calibration of instrument and validation of
procedures shall be carried out.

16.13 Each specification for raw materials, intermediates, final products, and
packing materials shall be approved and maintained by the Quality Control Department.
Periodic revisions of the specifications shall be carried out whenever changes are necessary.

16.14 Pharmacopoeia, reference standards, working standards, references, spectra,

other reference materials and technical books, as required, shall be available in the Quality
Control Laboratory of the licensee.

17. Specification
17.1 For raw materials and packaging materials. - 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
(h) maximum period of storage before re-testing.

17.2 For product containers and closures:

17.2.1 All containers and closures intended for use shall comply with the
pharmacopoeial requirements. Suitable validt. test methods, sample sizes, specifications,
cleaning procedure and sterilization procedure, wherever indicated, shall be strictly followed
to ensure that these are not reactive, additive, 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 schedule of cleaning shall be
laid down and followed. Where bottles are not dried after washing, they should be rinsed with
de-ionised water or distilled water, as the case may be.

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17.3. For in-process and bulk products. - Specifications for in-process material,
intermediate and bulk products shall be available. The specifications should be authenticated.

17.4 For finished products. - Appropriate specifications for finished products

shall include: -

(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.

17.5 For preparation of containers and closures. - The requirements mentioned in

the Schedule do not include requirements of machinery, equipments and premises required for
preparation of containers and closures for different dosage forms and categories of drugs. The
suitability and adequacy of the machinery, equipment and premises shall be examined taking
into consideration the requirements of each licensee in this respect.

18. Master Formula Records:

There shall be Master Formula records relating to all manufacturing procedures for
each product and batch size to be manufactured. These shall be prepared and endorsed by the
competent technical staff i.e. head of production and quality control. The Master Formula
shall include: -

(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 product and batch size;
(c) name, quantity, and reference number of all the starting materials to be used. Mention
shall be made of any substance that may in the course of processing.
(d) a statement of the expected final yield with the acceptable limits, and of relevant
intermediate yields, where applicable.
(e) a statement of the processing location and the principal equipment to be used.
(f) the methods, or reference to the methods, to be used for preparing the critical
equipments including cleaning, assembling, calibrating, sterilizing;
(g) detailed stepwise processing instructions and the time taken for each step;
(h) the instructions for in-process control with their limits;
(i) the requirements for storage conditions of the products, including the container,
labelling and special storage conditions where applicable;
(j) any special precautions to be observed;
(k) packing details and specimen labels.

19. Packing Records:

There shall be authorised packaging instructions for each product, pack size and type.
These shall include or have a reference to the following: -

(a) name of the product;

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

(c) the pack size expressed in terms of the number of doses, weight or volume of the
product in the final container;
(d) 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.;
(e) reproduction of the relevant printed packaging materials and specimens indicating
where batch number and expiry date of the product have been applied;
(f) special precautions to be observed, including a careful examination of the area and
equipment in order to ascertain the line clearance before the operations begin.
(g) 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; and
(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
labelled, packed and excess returned or destroyed. Any significant or unusual
discrepancy in the numbers shall be carefully investigated before releasing the final
batch.

20. Batch Packaging Records:

20.1 A batch packaging record shall be kept for each batch or part batch
processed. It shall be based on the relevant parts of the packaging instructions, and the
method of preparation of such records shall be designed to avoid transcription errors.

20.2 Before any packaging operation begins, check shall be made and recorded
that the equipment and the work stations are clear of the previous products, documents or
materials not required for the planned packaging operations, and that the equipment is clean
and suitable for use.

21. Batch Processing Records

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

21.2 Before any processing begins, check shall be performed and recorded to
ensure that the equipment and work station are clear of previous products, documents or
materials not required for the planned process are removed and the equipment is clean and
suitable for use.
21.3 During processing, the following information shall be recorded at the time
each action is taken and the record shall be dt. and signed by the person responsible for the
processing operations: -

(a) the name of the product,

(b) the number of the batch being manufactured,
(c) dates and time of commencement, of significant intermediate stages and of
completion of production,
(d) initials of the operator of different significant steps of production and where
appropriate, of the person who checked each of these operations,
(e) the batch number and/or analytical control number as well as the quantities of each
starting material actually weighed,
(f) any relevant processing operation or event and major equipment used,
(g) a record of the in-process controls and the initials of the person(s) carrying them out,
and the results obtained,

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(h) the amount of product obtained after different and critical stages of manufacture
(yield),
(i) comments or explanations for significant deviations from the expected yield limits
shall be given,
(j) notes on special problems including details, with signed authorization, for any
deviation from the Master Formula,
(k) addition of any recovered or reprocessed material with reference to recovery or
reprocessing stages.

22. Standard Operating Procedures (SOPs) and Records, regarding:

22.1 Receipt of materials:

22.1.1 There shall be written Standard Operating Procedures and records for the
receipt of each delivery of raw, primary and printed packaging material.

22.1.2 The records of the receipts shall include;

(a) the name of the material on the delivery note and the number of containers;
(b) the date of receipt;
(c) the and/ or supplier s name;
(d) the batch or reference number;
(e) the total quantity, and number of containers, quantity in each container
received;
(f) the control reference number assigned after receipt;
(g) any other relevant comment or information.

22.1.3 There shall be written standard operating procedures for the internal labelling,
quarantine and storage of starting materials, packaging materials and other
materials, as appropriate.

22.1.4 There shall be Standard Operating Procedures available for each instrument and
equipment and these shall be placed in close proximity to the related instrument
and equipment.

22.2 Sampling:

22.2.1 There shall be written Standard Operating Procedures for sampling which
include the person(s) authorized to take the samples.

22.2.2 The sampling instructions shall include:

(a) the method of sampling and the sampling plan,

(b) the equipment to be 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 types of sample container to be used,
(g) any specific precautions to be observed, especially in regard to sampling of
sterile and hazardous materials.

22.3. Batch Numbering:

22.3.1 There shall be Standard Operating Procedures describing the details of the batch

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(lot) numbering set up with the objective of ensuring that each batch of
intermediate, bulk or finished product is identified with a specific batch number.

22.3.2 Batch numbering Standard Operating Procedures applied to a processing stage

and to the respective packaging stage shall be same or traceable to demonstrate
that they belong to one homogenous mix.

22.3.3 Batch number allocation shall be immediately recorded in a logbook or by

electronic data processing system. The record shall include date of allocation,
product identity and size of batch.

22.4. Testing:

22.4.1 There shall be written procedures for testing materials and products at different
stages of manufacture, describing the methods and equipment to be used. The
tests performed shall be recorded.

22.5 Records of analysis:

22.5.1 The records shall include the following data:

(a) name of the material or product and the dosage form,

(b) batch number and, where appropriate the manufacturer and/ or supplier,
(c) references to the relevant specifications and testing procedures,
(d) test results, including observations and calculations, and reference to any
specifications (limits),
(e) dates of testing,
(f) initials of the persons who performed the 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 person.

22.5.2 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) personnel matters including qualification, training, clothing, hygiene;
(e) environmental monitoring;
(f) pest control;
(g) complaints;
(h) recalls made; and
(i) returns received.

23. Reference Samples:-

23.1 Each lot of every active ingredient, in a quantity sufficient to carry out all the tests,
except sterility and pyrogens/Bacterial Endotoxin Test, shall be retained for a
period of 3 months after the date of expiry of the last batch produced from that
active ingredient.

23.2. Samples of finished formulations shall be stored in the same or simulated

containers in which the drug has been actually marketed.

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24. Reprocessing and Recoveries:

24.1. Where reprocessing is necessary, written procedures shall be

established and approved by the Quality Assurance Department that
shall specify the conditions and limitations of repeating chemical
reactions. Such reprocessing shall be validt..

24.2. If the product batch has to be reprocessed, the procedure shall be

authorized and recorded. An investigation shall be carried out into the
causes necessitating re- processing and appropriate corrective measures
shall be taken for prevention of recurrence. Re-processed batch shall be
subjected to stability evaluation.

24.3. Recovery of the product residue may be carried out, if permitted, in the
master production and control records by incorporating it in subsequent
batches of the product.

25. Distribution records:

25.1. Prior to distribution or dispatch of given batch of a drug, it shall be ensured

that the batch has been duly tested, approved and released by the quality
control personnel. Pre-dispatch inspection shall be performed on each
consignment on a random basis to ensure that only the correct goods are
dispatched. Detailed instructions for warehousing and stocking of Large
Volume Parenterals, if stocked, shall be in existence and shall be
complied with after the batch is released for distribution. Periodic audits
of warehousing practices followed at distribution centers shall be carried
out and records thereof shall be maintained. Standard Operating
Procedures shall be developed for warehousing of products.
25.2. Records for distribution shall be maintained in a manner 1[so as] to
facilitate prompt and complete recall of the batch, if and when necessary.
26. Validation and process validation:

26.1. Validation studies shall be an essential part of Good Manufacturing

Practices and shall be conducted as per the pre-defined protocols. These
shall include validation of processing, testing and cleaning procedures.
26.2. A written report summarizing recorded results and conclusions shall be
prepared, documented and maintained.

26.3. Processes and procedures shall be established on the basis of validation

study and undergo periodic revalidation to ensure that they remain capable
of achieving the intended results. Critical processes shall be
validt., prospectively or retrospectively.

26.4. When any new Master Formula or method of preparation is adopted, steps
shall be taken to demonstrate its suitability for routine processing. The
defined process, using the materials and equipment specified shall be
demonstrated to yield a product consistently of the required quality.

26.5. Significant changes to the manufacturing process, including any

change in equipment or materials that may affect product quality and/or
the reproducibility of the process, shall be validt..

1. Subs. by G.S.R. 431(E), dt. 30.6.2005

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27. Product Recalls:

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

27.2. There shall be an established written procedure in the form of Standard Operating
Procedure for effective recall of products distributed by the licensee. Recall
operations shall be capable of being initiated promptly so as to effectively reach at
the level of each distribution channel.

27.3 The distribution records shall be readily made available to the persons designated
for recalls.

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

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

27.6 The recalled products shall be stored separately in a secured segregated area
pending final decision on them.

28. Complaints and Adverse Reactions:.

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

28.2. Reports of serious adverse drug reactions resulting from the use of a drug along
with comments and documents shall be forthwith reported to the concerned
licensing authority.

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

29. Site Master File. The licensee shall prepare a succinct document in the form of
Master containing specific and factual Good Manufacturing Practices about the
production and/or control of pharmaceutical manufacturing preparations carried out at the
licensed premises. It shall contain the following: -

29.1 General information:

(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 with flow charts mentioning procedure
and process flow;
(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;
(g) short description of the Quality Management System of the firm; and
(h) products details registered with foreign countries.
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29.2 Personnel:

(a) organisational chart showing the arrangement for quality assurance 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; and
(e) personnel hygiene requirements, including clothing.

29.3 Premises:

(a) simple plan or description of manufacturing areas drawn to scale;

(b) nature of construction and fixtures/fittings;
(c) brief description of ventilation systems. More details should be given for critical
areas with potential risk of airborne contamination (schematic drawing of
systems). Classification of the rooms used for the manufacture of sterile products
should be mentioned;
(d) special areas for the handling of the highly toxic, hazardous and sensitizing
materials;
(e) brief description of water system (schematic drawings of systems), including
sanitation;
(f) description of planned preventive maintenance programs for premises and of the
recording system.

29.4 Equipment:

(a) brief description of major equipment used in production and Quality Control
Laboratories (a list of equipment required);
(b) description of planned preventive maintenance programs for equipment and of the
recording system; and
(c) qualification and calibration including the recording systems and arrangements for
computerized systems validation.
Sanitation:
29.5
(a) availability of written specifications and procedures for cleaning manufacturing
areas and equipment.

29.6 Documentation. -

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

(b) necessary documentation for the manufacture;
(c) any other documentation related to product quality that is not mentioned elsewhere
(e.g. microbiological controls about air and water).

29.7 Production:.

(a) brief description of production operations using, wherever possible, flow sheets
and charts specifying important parameters;
(b) arrangements for the handling of starting materials, packaging materials, bulk and

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finished products, including sampling, quarantine, release and storage;

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

29.8 Quality Control:

(a) description of the quality control system and of the activities of the Quality Control
Department. Procedures for the release of the finished products.

29.9 Loan licence manufacture and licensee:

(a) description of the way in which compliance of Good Manufacturing Practices by

the loan licensee shall be assessed.

29.10 Distribution, complaints and product recall:

(a) arrangements and recording system for distribution;

(b) arrangements for the handling of complaints and product recalls.

29.11 Self inspection. -

(a) short description of the self-inspection system indicating whether an outside,

independent and experienced external expert was involved in evaluating the
manufacture s compliance with Good manufacturing Practices in all aspects of
production.

29.12 Export of drugs. -

(a) products exported to different countries;

(b) complaints and product recall, if any.

PART IA

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 Part 1 of this Schedule relating to Requirements
of Good Manufacturing Practices for Premises and Materials for pharmaceutical products
shall be complied with, mutatis mutandis, for the manufacture of sterile products, Parenteral
preparations (Small Volume Injectables and Large Volume Parenterals) and Sterile
Ophthalmic Preparations. In addition to these requirements, the following specific
requirements shall also be followed, namely: -

1. General :
Sterile products, being very critical and sensitive in nature, a very high degree of
precautions, prevention and preparations are needed. Dampness, dirt and darkness are to be
avoided to ensure aseptic conditions in all areas. There shall be strict compliance in the
prescribed standards especially in the matter of supply of water, air, active materials and in
the maintenance of hygienic environment.

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2. Buildings and Civil Works:

2.1 The buildings shall be built on proper foundation with standardized materials
to avoid cracks in critical areas like aseptic solution preparation, filling and sealing rooms.

2.2 Location of services like water, steam, gases etc. shall be such that their
servicing or repair shall not pose any threat to the integrity of the facility. Water lines shall
not pose any threat of leakage to aseptic area.

2.3. The manufacturing areas shall be clearly separated into support areas (e.g.
washing and component preparation areas, storage areas etc.), preparation areas (e.g. bulk
manufacturing area, non-aseptic blending areas etc.) change areas and aseptic areas.
Operations like removal of outer cardboard wrappings of primary packaging materials shall
be done in the de-cartoning areas which are segregated from the washing areas. Wooden
pallets, fiber board drums, cardboard and other particle shedding materials shall not be taken
inside the preparation areas.

2.4. In aseptic areas

(a) walls, floors and ceiling should be impervious, non-shedding, non-flaking and
non-cracking. Flooring should be unbroken and provided with a cove both at
the junction between the wall and the floor as well as the wall and the ceiling.

(b) walls shall be flat, and ledges and recesses shall be avoided. Wherever other
surfaces join the wall (e,g, sterilizers, electric sockets, gas points etc.) these
shall flush the walls. Walls shall be provided with a cove at the joint between
the ceiling and the floor;

(c) ceiling shall be solid and joints shall be sealed. Light-fittings and air-grills shall
flush with the walls and not hanging from the ceiling, so as to prevent
contamination;

(d) there shall be no sinks and drains in Grade A and Grade B areas;

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

(f) Windows shall be made of similar material as the doors, preferably with double
panel and shall be flush with the walls. If fire escapes are to be provided, these
shall be suitably fastened to the walls without any gaps;

(g) The furniture used shall be smooth, washable and made of stainless steel or
any other appropriate material other than wood.

2.5. The manufacturing and support areas shall have the same quality of civil
structure described above for aseptic areas, except the environmental standards which may
vary in the critical areas.

2.6 Change rooms with entrance in the form of air-locks shall be provided before
entry into the sterile product manufacturing areas and then to the aseptic area. Separate exit
space from the aseptic areas is advisable. Change rooms to the aseptic areas shall be clearly
demarcated into . , and r with different levels of activity and air
cleanliness. The change room shall be provided with a hand-washing sink. The sink

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and its drain in the un-classified (first) change rooms may be kept clean all the time. The specially
designed drain shall be periodically monitored to avoid presence of pathogenic micro-organisms.
Change room doors shall not be opened simultaneously. An appropriate inter-locking system and a
visual and/or audible warning system may be installed to prevent the opening of more than one door at a
time.

2.7. For communication between aseptic areas and non-aseptic areas, intercom
telephones or speak-phones shall be used. These shall be minimum in number.

2.8 Material transfer between aseptic areas and outside shall be through suitable airlocks or
pass-boxes. Doors of such airlocks and pass-boxes shall have suitable interlocking arrangements.

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

2.10 Animal houses shall be away from the sterile product manufacturing area and shall not
share a common entrance or air handling system with the manufacturing area.

3. Air Handling System (Central Air-Conditioning):

3.1 Air Handling Units for sterile product manufacturing areas shall be different from
those for other areas. Critical areas, such as the aseptic filling area, sterilized components
unloading area and change room conforming to Grades B, C and D respectively shall have separate air
handling units. The filter configuration in the air handling system shall be suitably designed to achieve
the Grade of air as given in Table1. Typical operational activities for clean areas are highlighted in
Table II and Table III.

3.2 For products which are filled aseptically, the filling room shall meet Grade B conditions
at rest unmanned. This condition shall also be obtained within a period of about 30 minutes of the
personnel leaving the room after completion of operations.

3.3. The filling operations shall take place under Grade A conditions which shall be
demonstrated under working of simulated conditions which shall be achieved by providing laminar air
flow work stations with suitable HEPA filters or isolator technology.
3.4. For products, which are terminally sterilized, the filling room shall meet Grade C
conditions at rest. This condition shall be obtainable within a period of about 30 minutes of the
personnel leaving the room after completion of operations.
3.5. Manufacturing and component preparation areas shall meet Grade C
conditions.
3.6. After completion of preparation, washed components and vessels shall be protected
1
with [Grade D background and should be handled in such a way that they are not recontaminated].
3.7. The minimum air changes for Grade B and Grade C areas shall not be less than 20
air changes per hour in a room with good air flow pattern and appropriate HEPA filters. For Grade A
laminar air flow work stations, the air flow rate shall be 0.3 meter per second ± 20% (for vertical flows)
and 0.45 meter per second ± 20% (for horizontal flows).
3.8. Differential pressure between areas of different environmental standards shall be at
least 15 Pascal (0.06 inches or 1.5 mm water gauge). Suitable manometers or gauges shall be
installed to measure and verify pressure differential.

1. Subs. by G.S.R. 431(E), dt. 30.6.2005

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3.9 The final change room 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 to
3.10 Unless there are product specific requirements, temperature and humidity in
the aseptic areas 1[shall be 27 ± 2 degree centigrade and relative humidity 55% ± 5,
respectively].
1
[TABLE I
AIR BORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE
OF STERILE PRODUCTS

Grade Maximum number of permitted particles per cubic metre equal t to or above
At rest (b) In operation (a)
0.5µm 5µm 0.5µm 5µm
A 3500 0 3500 0
B (a) 3500 0 3,50,000 2,000
C (a) 350,000 2,000 35,00,000 20,000
D (a) 35,00,000 20,000 Not defined (c) Not defined (c)]

Notes :

(a) In order to reach the B, C and D air grades, the number of air changes shall be
related to the size of the room and the equipment and personnel present in the
room. The air system shall be provided with the appropriate filters such as HEPA
for Grades A, B and C. The maximum permitted number of particles in the r
condition shall approximately be as under:
1
[Grade A and B corresponds with class 100 or M 3.5 or class 5]; Grade C with Class
10,000 or M 5.5 or ISO Class 7; Grade D with Class 1,00,000 or M 6.5 or ISO Class 8.

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

(c) Type of operations to be carried out in the various grades are given in Table II and Table
III as under:

TABLE II

TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS

GRADES FOR ASEPTIC PREPARATIONS

Grade Types of operations for aseptic preparations

A Aseptic preparation and filling
B Background room conditions for activities requiring Grade A
C Preparation of solution to be filtered
D Handling of components after washing

1. Subs. by G.S.R. 431(E), dt. 30.6.2005.

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TABLE III

TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS

GRADES FOR TERMINALLY STERILIZED PRODUCTS

Grade Types of operations for terminally sterilized products.

A Filling of products, which are usually at risk.
C Placement of filling and sealing machines, preparation of solutions when 1[unusually at
risk]. Filling of product when unusually at risk.
D Moulding, blowing (pre-forming) operations of plastic containers, preparations of
solutions and components for subsequent filling.

4. Environmental Monitoring:

4.1 All environmental parameters listed under para 3.1 to 3.10 shall be verified and
established at the time of installation and thereafter monitored at periodic intervals. The
recommended frequencies of periodic monitoring shall be as follows :-

(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) Microbiological monitoring by settle plates and/or swabs in aseptic areas
Daily, and at decreased frequency in other areas.

`Note: The above frequencies of monitoring shall be changed as per the

requirements and load in individual cases.

4.2 There shall be a written environmental monitoring program and

microbiological results shall be recorded. Recommended limits for microbiological
monitoring of clean areas are as given in the table below:

TABLE
RECOMMENDED LIMITS FOR MICROBIOLOGICAL MONITORING OF CLEAN
AREAS IN OPERATI

Grade Air sample Settle plates (dia. 90mm. Contact plates Glove points
Cfu/m2 Cfu/2 hrs. (dia. 55mm) cfu per (five fingers) cfu
plate per glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 --
D 500 100 50 --

Notes:

(a) These are average values.

(b) Individual settle plates may be exposed for not less than two hours in Grade B,
C and D areas and for not less than thirty minutes in Grade A area.
1. Subs. by G.S.R. 431(E), dt. 30.6.2005.

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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 required for use by personnel working only in
aseptic area. Outdoor clothing shall not be brought into the sterile areas.

5,2 The garments shall be made of non-shedding and tight weave material.
Cotton garments shall not be used. The garments shall shed virtually no fibres or particulate
matter.

5.3 The clothing and its quality shall be adopted to the process and the work
place and worn in such a way as to protect the product from contamination. Garments shall be
single piece with fastenings at cuffs, neck and at legs to ensure close fit. Trouser legs shall be
tucked inside the cover boots. Suitable design of garments shall either include a hood (head-
cover) or a separate hood which can be tucked inside the over-all. Pockets, pleats and belts
shall be avoided in garments. Zips (if any) shall be of plastic material. Garments with
damaged zips shall not be used.

5.4. Only clean, sterilized and protective garments shall be used at each work
session where aseptic filtration and filling operations are undertaken and at each work shift
for products intended to be sterilized, post-filling. The mask and gloves shall be changed at
every work session in both instances.
5.5 Gloves shall be made of latex or other suitable plastic materials and shall be
powder-free. These shall be long enough to cover wrists completely and allow the over-all
cuff to be tucked in.
5.6. The footwear shall be of suitable plastic or rubber material and shall be daily
cleaned with a bactericide.
5.7. Safety goggles or numbered glasses with side extension shall be used inside
aseptic areas. These shall be sanitized by a suitable method.
5.8. Garment changing procedures shall be documented and operators trained in
this respect. 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:
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 agent shall be used in rotation and the concentrations of
the same shall be as per the recommendations of the manufacturer. Records of rotational use
of sanitizing agents shall be maintained.
6.3. Distilled water freshly collected directly from the distilled water plant or
water maintained above 70 degree centigrade from the re-circulation loop shall be used for
dilution of disinfectants. Alternatively, distilled water sterilized by autoclaving or membrane
filtration shall be used. The dilution shall be carried out in the change room.

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1
6.4. [Where alcohol or isopropyl alcohol is used for dilution of disinfectants for
use as hand sprays, the preparation of the same shall be done in the bulk preparation area in
grade C.]
6.5. Diluted disinfectants shall bear the label se before , based on
microbiological establishment of the germicidal properties. The solutions shall be adequately
labelled and documents maintained.
6.6. Formaldehyde or any other equally effective fumigant is recommended for
the fumigation of aseptic areas or after major civil modifications. There shall be Standard
Operating Procedures for this purpose. Its use for routine purpose shall be discouraged and an
equally effective surface cleaning regime shall be followed.
6.7. Cleaning of sterile processing facilities shall be undertaken with air suction
devices or with non-linting sponges or clothes.
6.8. Air particulate quality shall be evaluated on a regular basis and record
maintained.

7. Equipment:
7.1 The special equipment required for manufacturing sterile products includes
component washing machines, steam sterilizers, 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 inter-locking

arrangements between the doors. The effectiveness of the sterilization process shall be
established initially by biological inactivation studies using microbial spore indicators and
then at least once a year by carrying out thermal mapping of the chamber. Various
sterilization parameters shall be established based on these studies and documented. For
membrane filters used for filtration, appropriate filter integrity tests that ensure sterilization
shall be carried out before and after filtration.

7.3. Filling machines shall be challenged initially and then at periodic intervals by
simulation trials including sterile media fill. Standard Operating Procedures and acceptance
criteria for media fills shall be established, justified and documented. Special simulation trial
procedures shall be developed, validt. and documented for special products like ophthalmic
ointments.

7.4. The construction material used for the parts which are in direct contact with
products and the manufacturing vessels may be stainless steel 316 or Boro-silicate glass (if
glass containers) and the tubing shall be capable of being washed and autoclaved.

7.5 On procurement, installation qualification of each of the equipment shall be done

by engineers with the support of production and quality assurance personnel. Equipment for
critical processes like aseptic filling and sterilizers shall be suitably validt. according to a
written program before putting them to use.

7.6. Standard Operating Procedures shall be available for each equipment for its
calibration and operation and cleaning. Gauges and other measuring devices attached to
equipment shall be calibrated at suitable intervals against a written program. Calibration
status of equipment gauges shall be adequately documented and displayed.
1. Subs. by G.S.R. 431(E), dt. 30.6.2005.

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8. Water and Steam Systems:

8.1. Potable water meeting microbiological specification of not more than 500
cfu/ml and indicating absence of individual pathogenic micro-organisms. Escherichia coli,
Salmonella, Staphylococcus aureus and Pseudomonas aeruginosa per 100 ml sample shall be
used for the preparation of purified water.

8.2 Purified water prepared by de-mineralization shall meet the microbiological

specification of not more than 100 cfu per ml and indicate absence of pathogenic micro-
organisms in 100 ml. Purified water shall also meet IP specification for chemical quality.
Purified water shall be used for hand washing in change rooms. Containers, closures and
machine parts may be washed with potable water followed by suitably filtered purified water.
Purified water shall be stored in stainless steel tanks or plastic tanks.

8.3. Water for Injection (hereinafter as WFI) shall be prepared from potable water or
purified water meeting the above specifications by distillation. Water for Injection shall meet
microbiological specification of not more than 10 cfu per 100 ml. WFI shall also meet IP
specification for Water for Injection and shall have an endotoxin level of not more than
0.25 EU/Ml. Bulk solutions of liquid parenterals shall be made in WFI. Final rinse of product
containers and machine parts shall be done with WFI. Disinfectant solutions for use in aseptic
areas shall be prepared in WFI.

8.4. Water for Injection for the manufacture of liquid injectables shall be freshly
collected from the distillation plant or from a storage or circulation loop where the water has
been kept at above 70 degree centigrade. At the point of collection, water may be cooled
using suitable heat exchanger.

8.5 Water for non-injectable sterile products like eye drops shall meet IP
specifications for purified water. In addition, microbiologial specification of not more than 10
cfu per 100 ml and absence of Pseudomonas aeruginosa and Enterobacter coli in 100 ml
shall also be met.

8.6. Water for Injection shall be stored in steam jacketed stainless steel tanks of
suitable size and the tanks shall have hydrophobic bacterial retention with 0.22 µ vent filters.
The filters shall be suitably sterilized at periodic intervals. The distribution lines for purified
water and distilled water shall be of stainless steel 316 construction and shall not shed
particles.

8.7. There shall be a written procedure and program for the sanitation of different
water systems including storage tanks, distribution lines, pumps and other related equipment.
Records of sanitation shall be maintained.

8.8. There shall be written microbiological monitoring program for different types of
water. The results shall justify the frequency of sampling and testing. Investigation shall be
carried out and corrective action taken in case of deviation from prescribed limits.
1
[8.9 Steam coming in contact with the product, primary containers and other
product contact surfaces shall be sterile and pyrogen free.]

9. Manufacturing Process:

9.1. Manufacture of sterile products shall be carried out only in areas under
defined conditions.
1. Omitted by G.S.R. 431(E), dt. 30.6.2005.

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9.2. Bulk raw materials shall be monitored for bio-burden periodically. Bio-
burden of bulk solution prior to membrane filtration shall be monitored periodically and a
limit of not more than 100 cfu per ml is recommended.

9.3 The time between the start of the preparation of the solution and its
sterilization or filtration through a micro-organism retaining filter shall be minimized. There
shall be a set maximum permissible time for each product that takes into account its
composition and method of storage mentioned in the Master formula record.

9.4. Gases coming in contact with the sterile product shall be filtered through two
0.22 µ hydrophobic filters connected in-series. These filters shall be tested for integrity. Gas
cylinders shall not be taken inside aseptic areas.

9.5. Washed containers shall be sterilized immediately before use. Sterilized

containers, if not used within an established time, shall be rinsed with distilled or filtered
purified water and re-sterilized.

9.6. Each lot of finished product shall be filled in one continuous operation. In
each case, where one batch is filled in using more than one operation, each lot shall be tested
separately for sterility and held separately till sterility test results are known.

9.7. Special care shall be exercised while filling products in powder form so as not
to contaminate the environment during transfer of powder to filling machine-hopper.

10. Form-Fill-Seal Technology or Blow, Fill-Seal Technology:

10.1 Form-Fill-Seal units are specially built automated machines in which through
one continuous operation, containers are formed from thermoplastic granules, filled and then
sealed. Blow, fill-seal units are machines in which containers are moulded / blown (pre-
formed) in separate clean rooms, by non-continuous operations.

Note:
(i) These shall be installed in at least Grade C environment.
(ii) These shall comply with the limits as recommended in Table at Item 4.2.

10.2. Form-Fill-Seal/Blow, Fill-Seal machines used for the manufacture of

products for terminal sterilization shall be installed in at least Grade C environment and the
filling zone within the machine shall fulfil Grade A requirements.

10.3. Terminally sterilized products.

10.3.1. Preparation of primary packaging material such as glass bottles, ampoules

and rubber stoppers shall be done in at least Grade D environment. Where there is unusual
risk to the product from microbial contamination, the above operation shall be done in Grade
C environment. All the processes used for component preparation shall be validt..

10.3.2. Filling of products requiring terminal sterilization shall be done under Grade
A environment with a Grade C background.

10.4 Preparation of solutions, which are to be sterilized by filtration, shall be done in

Grade C environment, and if not to be filtered, the preparation of materials and products shall
be in a Grade A environment with Grade B in background.

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10.5 Filtration (Membrane).-

(i) Solutions for Large Volume Parenterals shall be filtered through a non-fibre releasing,
sterilizing grade cartridge/membrane filter of nominal pore size of 0.22 µ for aseptic
filling whereas 0.45 µ porosity shall be used for terminally sterilized products.

(ii) A second filtration using another 0.22 µ sterilizing grade cartridge / membrane filter
shall be performed immediately prior to filling. Process specifications shall indicate
the maximum time during which a filtration system may be used with a view to
precluding microbial build-up to levels that may affect the microbiological quality of
the Large Volume Parenterals.

(iii) The integrity of the sterilized filter shall be verified and confirmed immediately after
use by an appropriate method such as Bubble Point, Diffusive Flow or Pressure Hold
Test.

10.6 Sterilization (Autoclaving).

10.6.1. Before any sterilization process is adopted, its suitability for the product and
its efficacy in achieving the desired sterilizing conditions in all parts of each type of load
pattern to be processed, shall be demonstrated by physical measurements and by biological
indicators, where appropriate.

10.6.2 All the sterilization process shall be appropriately validt.. 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

of monitoring the sterilization. These shall be stored and used according to the manufacturer s
instructions. Their quality shall be checked by positive controls. If biological indicators used,
strict precautions shall be taken to avoid transferring microbial contamination from them.

10.6.6 There shall be clear means of differentiating steril and -

products. Each basket, tray or other carrier of products or components shall be clearly labelled
with the name of the material, its batch number, and sterilization status. Indicators shall be
used, where appropriate, to indicate whether a batch (or sub-batch) has passed through the
sterilization process.

10.6.7 Sterilization records shall be available for each sterilization-run and may also
include thermographs and sterilization monitoring strips. They shall be maintained as part of
the batch release procedure.

10.7. Sterilization (By dry heat).

10.7.1 Each heat sterilization cycle shall be recorded on a time/temperature chart

of a suitable size by appropriate equipment of the required accuracy and precision. The
position of temperature probes used for controlling and/or recording shall be determined
during the validation and, where applicable, shall also be checked against a second
independent temperature probe located in the same position. The chart shall form a part of the

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batch record. Container mapping may also be carried out in the case of Large Volume
Parenterals.

10.7.2 Chemical or biological indicators may also be used, but shall not take the place
of physical validation.

10.7.3. Sufficient time shall be allowed for the load to reach the required
temperature before measurement of sterilization time commences. This time shall be
separately determined for each type of load to be processed.

10.7.4. After the high temperature phase of a heat sterilization cycle, precautions
shall be taken against contamination of sterilized load during cooling. Any cooling fluid or
gas in contact with the product shall be sterilized unless it can be shown that any leaking
container would not be approved for use. Air inlet and outlets shall be provided with bacterial
retaining filters.

10.7.5. The process used for sterilization by dry heat shall include air-circulation
within the chamber and the maintenance of a positive pressure to prevent the entry of non-
sterile air. Air inlets and outlets should be provided with micro-organism retaining filters.
Where this process of sterilization by dry heat is also intended to remove pyrogens, challenge
tests using endotoxins would be required as part of the validation process.

10.8. Sterilization (By Moist Heat).-

10.8.1 Both the temperature and pressure shall be used to monitor the process.
Control instrumentation shall normally be independent of monitoring instrumentation and
recording charts. Where automated control and monitoring systems are used for these
applications, these shall be validt. to ensure that critical process requirements are met. System
and cycle faults shall be registered by the system and observed by the operator. The reading
of the independent temperature indicator shall be routinely checked against the chart-recorder
during the sterilization period. For sterilizers fitted with a drain at the bottom of the chamber,
it may also be necessary to record the temperature at this position throughout the sterilization
period. There shall be frequent leak tests done on the chamber during the vacuum phase of the
cycle.

10.8.2 The items to be sterilized, other than products in sealed containers, shall be
wrapped in a material which allows removal of air and penetration of steam but which
prevents re-contamination after sterilization. All parts of the load shall be in contact with the
sterilizing agent at the required temperature for the required time.

10.8.3. No Large Volume Parenteral shall be subjected to steam sterilization cycle

until it has been filled and sealed.

10.8.4 Care shall be taken to ensure that the steam used for sterilization is of a
suitable quality and does not contain additives at a level which could cause contamination of
the product or equipment.

10.9. Completion/finalisation of sterile products

10.9.1. All unit operations and processes in the manufacture of a batch shall have a
minimum time specified and the shortest validt. time shall be used from the start of a batch to
its ultimate release for distribution.

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10.9.2. Containers shall be closed by appropriately validt. methods. Containers

closed by fusion e.g. glass or plastic ampoules shall be subjected to 100% integrity testing.
Samples of other containers shall be checked for integrity according to appropriate
procedures.

10.9.3 Containers sealed under vacuum shall be tested for required vacuum
conditions.

10.9.4 Filled containers of parenteral products shall be inspected individually for

extraneous contamination or other defects. When inspection is done visually, it shall be done
under suitably controlled conditions of illumination and background. Operators doing the
inspection shall pass regular eye-sight checks with spectacles, if worn, and be allowed
frequent rest from inspection. Where other methods of inspection are used, the process shall
be validt. and the performance of the equipment checked at suitable intervals. Results shall be
recorded.

11. Product Containers and Closures.

11.1 All containers and closures intended for use shall comply with the
pharmacopoeial and other specified requirements. Suitable samples sizes, specifications, test
methods, cleaning procedures and sterilization procedures, shall be used to assure that
containers, closures and other component parts of drug packages are suitable and are not
reactive, additive, adsorptive or leachable or presents the risk of toxicity to an extent that
significantly affects the quality or purity of the drug. No second hand or used containers and
closures shall be used.

11.2 Plastic granules shall also comply with the pharmacopoeial requirements
including physio-chemical and biological tests.

11.3. All containers and closures shall be rinsed prior to sterilization with Water for
Injection according to written procedure.

11.4. The design of closures, containers and stoppers shall be such as to make
cleaning, easy and also to make airtight seal when fitted to the bottles.

11.5 It shall be ensured that containers and closures chosen for a particular
product are such that when coming into contact they are not absorbed into the product and
they do not affect the product adversely. The closures and stoppers should be of such quality
substances as not to affect the quality of the product and avoid the risk of toxicity.

11.6. Whenever glass bottles are used, the written schedule of cleaning shall be laid
down and followed. Where bottles are not dried after washing, these shall be finally
rinsed with distilled water or pyrogen free water, as the case may be, according to written
procedure.

11.7. Individual containers of parenteral preparations, ophthalmic preparations shall

be examined against black/white background fitted with diffused light after filling so as to
ensure freedom from foreign matters.

11.8 Glass Bottles.

11.8.1 Shape and design of the glass bottle shall be rational and standardized.
Glass bottles made of USP Type-I and USP Type-II glass shall only be used. Glass bottles
shall not be reused. Before use, USP Type-II bottles shall be validt. for the absence of
particulate matter generated over a period of the shelf -life of the product and shall be

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regularly monitored after the production, following statistical sampling methods. USP Type-
III glass containers may be used for non-parenteral sterile products such as Otic Solutions.

11.9. Plastic Containers.

11.9.1 Pre-formed plastic containers intended to be used for packing of Large

Volume Parenteral shall be moulded in-house by one-continuous operation through an
automatic machine.

11.9.2. Blowing, filling and sealing (plugging) operation shall be conducted in

room(s) conforming to requirements as mentioned in Table III of Item 3.10. Entry to the area
where such operations are undertaken, shall be through a series of airlocks. Blowers shall
have an air supply which is filtered through 0.22µ filters. Removal of runners and plugging
operations shall be conducted under a laminar airflow workstation.

11.10 Rubber Stoppers.

11.10.1 The rubber stoppers used for Large Volume Parenterals shall comply with
specifications prescribed in the current edition of the 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 Record.

(2) Name of the product
(3) Reference to Master Formula Record.
(4) Batch/Lot number
(5) Batch/Lot size.
(6) Date of commencement of manufacture and date of completion of manufacture.
(7) Date of manufacture and assigned date of expiry.
(8) Date of each step in manufacturing.
(9) Names of all ingredients with the grade given by the quality control department.
(10) Quality 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.
(18) Records of weight or volume of drug filled in containers.
(19) Bulk sterility in case of aseptically filled products.
(20) Leak test records.
(21) Inspection records.
(22) Sterilization records including autoclave leakage test records, load details, date,
duration, temperature, pressure, etc.
(23) Container washing records.
(24) Total number of containers filled.
(25) Total numbers of containers rejected at each stage
(26) Theoretical yield, permissible yield, actual yield and variation thereof.
(27) Clarification for variation in yield beyond permissible yield.
(28) Reference numbers of relevant analytical reports.
(29) Details of reprocessing, if any.

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(30) Name of all operators carrying out different activities.

(31) Environmental monitoring records.
(32) Specimens of printed packaging materials.
(33) Records of destruction of rejected containers and printed packaging materials.
(34) Signature of competent technical staff responsible for manufacture and testing.

Note: (1) Products shall be released only after complete filling and testing.

(2) Result of the tests relating to sterility, pyrogens, and Bacterial

endotoxins shall be maintained in the analytical records.

(3) Validation details and simulation trial records shall be maintained

separately,

(4) Records of environmental monitoring like temperature, humidity,

microbilogical data, etc. shall be maintained. Records of periodic
servicing of HEPA filters, sterilizers and other periodic maintenance
of facilities and equipment carried out also be maintained.
(5) Separate facilities shall be provided for filling-cum-sealing of Small
Volume Injectables and Large Volume Parenterals.

(6) It is advisable to provide separate facilities for manufacture of

Large Volume Parenterals in glass containers and / or plastic
containers.
(7) For manufacture of Large Volume Parenterals in plastic containers,
it is advisable to instal automatic (with all operations) Form Fill-
Seal machines having one continuous operation.

PART IB

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL SOLID DOSAGE

FORMS (TABLETS AND CAPSULES)

Note: - The General Requirements as given in Part 1 of this Schedule relating to

requirements of Good Manufacturing Practices for Premises 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 requirements, the following
Specific Requirement 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 equipment in order to overcome these problems. Wherever
required, enclosed dust control manufacturing systems shall be employed.

1.2. Suitable environmental conditions for the products handled shall be

maintained by installation of air-conditioning wherever necessary. Effective air-extraction
systems, with discharge points situated to avoid contamination of other products and
processes shall be provided. Filters shall be installed to retain dust and protect the factory and
local environment.

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1.3. Special care shall be taken to protect against subsequent contamination of the
product by particles of metal or wood. The use of metal detector is recommended.
Wooden equipment should be avoided. Screens, sieves, punches and dies shall be examined
for wear and tear or for breakage before and after each use.

1.4. All ingredients for a dry product shall be sifted before use unless the
quality of the input material can be assured. Such sifting shall normally be carried out at
dedicated areas.

1.5. 1[Where the facilities are designed to provide special environmental

conditions of pressure differentials between rooms, these conditions shall be regularly
monitored and any deviation shall be brought to the immediate attention of the production
and quality assurance departments].

1.6. Care shall be taken to guard against any material lodging and remaining
undetected in any processing or packaging equipment. Particular care shall be taken to ensure
that any vacuum, compressed air or air-extraction nozzles are kept clean and that there is no
evidence of lubricants leaking into the product from any part of the equipments.

2. Sifting, Mixing and Granulation:

2.1. Unless operated as a closed system, mixing, sifting and blending equipments
shall be fitted with dust extractors 1[or in a dedicated area for each operation].

2.2. Residues from sieving operations shall be examined periodically for evidence of
the presence of unwanted materials.

2.3. Critical operating parameters like time and temperature for each mixing,
blending and drying operation shall be specified in a Master Formula, monitored during
processing, and recorded in the batch records.

2.4. Filter bags fitted to fluid-bed dryer shall not be used for different products,
without being washed in-between use. With certain highly potent or sensitizing products, bags
specific to one product only shall be used. Air entering the dryer shall be filtered. Steps shall
be taken to prevent contamination of the site and local environment by dust in the air leaving
the dryer due to close positioning of the air-inlets and exhaust.

2.5. Granulation and coating solutions shall be made, stored and used in a manner
which minimizes the risk of contamination or microbial growth.

3. Compressions (Tablets):

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

3.2. Suitable physical, procedural and labelling arrangements shall be made to

prevent mix up of materials, granules and tablets on compression machinery.

3.3. Accurate and calibrated weighing equipment shall be readily available and
used for in-process monitoring of tablet weight variation. Procedures used shall be capable of
detecting out-of-limits tablets.

1. Ins. by G.S.R. 431(E), dt. 30.6.2005.

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3.4. At the commencement of each compression run and in case of multiple

compression points in a compression machine, sufficient individual tablets shall be examined
at fixed intervals to ensure that a tablet from each compression station or from each
compression point has been inspected for suitable pharmacopoeial parameters like
, , , and . The
results shall be recorded as part of the batch documentation.
3.5. Tablets shall be de-dusted, preferably by automatic device and shall be
monitored for the presence of foreign materials besides any other defects.
3.6. Tablets shall be collected into clean, labelled containers.
3.7. Rejected or discarded tablets shall be isolated in identified containers and their
quantity recorded in the Batch Manufacturing Record.
3.8 In-process control shall be employed to ensure that the products remain within
specification. During compression, samples of tablets shall be taken at regular intervals of not
greater than 30 minutes to ensure that they are being produced in compliance with specified
in-process specification. The tablets shall also be periodically checked for additional
parameters such as appearance , ight ,
and 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 environmental
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 microbial growth. Their preparation and use shall be
documented and recorded.
5. Filling of Hard Gelatin Capsule:
Empty capsules shells shall be regarded as component and treated accordingly.
They shall be stored under conditions which shall ensure their safety from the effects of
excessive heat and moisture.
6. Printing (Tablets and Capsules)
6.1. Special care shall be taken to avoid product mix-up during any printing of
tablets and capsules. Where different products, or different batches of the same product, are
printed simultaneously, the operations shall adequately be segregated. Edible grade colours
and suitable printing ink shall be used for such printing.
6.2. After printing, tablets and capsules shall be approved by Quality Control
before release for packaging or sale.
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 tablets, capsules or foils from
packaging operation are removed before a new packaging operation is commenced. There
shall be an independent recorded check of the equipment before a new batch of tablets or
capsules is handled.
7.2. Uncoated tablets shall be packed on equipment designed to minimize the risk of
cross-contamination. Such packaging shall be carried out in an isolated area when potent
tablets or Beta-Iactum containing tablets are being packed.

1. Ins. by G.S.R. 431(E), dt. 30.6.2005.

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7.3. The strips coming out of the machine shall be inspected for defects such as
misprint, cuts on the foil, missing tablets and improper sealing.
7.4. Integrity of individual packaging strips and blisters shall be subjected to
vacuum test periodically to ensure leak proofness of each pocket strip and blister and records
maintained.
PART IC

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL LIQUIDS

(SYRUPS, ELIXIRS, EMULSIONS AND SUSPENSIONS)

Note: The General Requirements as given in Part I of this Schedule relating 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 Liquids. The layout and design of the manufacturing area shall
strive to minimize the risk of cross-contamination and mix-ups.

1.2. Manufacturing area shall have entry through double door airlock facility. It
shall be made fly proof by use of and/or curtain .

1.3. Drainage shall be of adequate size and have adequate traps, without open
channels and the design shall be such as to prevent back flow. Drains shall be shallow to
facilitate cleaning and disinfecting.

1.4. The production area shall be cleaned and 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 microbial growth or cross-contamination.

1.6. Stainless steel or any other appropriate material shall be used for parts of
equipments coming in direct contact with the products. The use of glass apparatus shall be
minimum.

1.7. Arrangements for cleaning of containers, closures and droppers shall be made
with the help of suitable machines/devices equipped with the high pressure air, water and
steam jets.

1.8. The furniture used shall be smooth, washable and made of stainless steel 1[or
any other appropriate material which is scratch proof, washable and smooth].

2. Purified Water.

2.1. The chemical and microbiological quality of purified water used shall be
specified and monitored routinely. The microbiological evaluation shall include testing for
absence of pathogens and shall not exceed 100 cfu/ml (as per Appendix 12.5 of IP 1996.)
1. Added by G.S.R. 431(E), dt. 30.6.2005.

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2.2. There shall be a written procedure for operation and maintenance of the
purified water system. Care shall be taken to avoid the risk of microbial proliferation with
appropriate methods like re-circulation, use of UV treatment, treatment with heat and
sanitizing agent. After any chemical sanitisation of the water system, a flushing shall be done
to ensure that the sanitizing agent has been effectively removed.
3. Manufacturing:
1
3.1. [Manufacturing personnel shall wear wherever required, non-fiber shedding
clothing to prevent contamination of the products].
3.2. Materials likely to shed fibre like gunny bags, or wooden pallets shall not be
carried into the area where products or cleaned-containers are exposed.
3.3. Care shall be taken to maintain the homogenecity of emulsion by use of
appropriate emulsifier and suspensions by use of appropriate stirrer during filling. Mixing and
filling processes shall be specified and monitored. Special care shall be taken at the beginning
of the filling process, after stoppage due to any interruption and at the end of the process to
ensure that the product is uniformly homogenous during the filling process.
3.4. The primary packaging area shall have an air supply which is filtered through
5 micron filters. The temperature of the area shall not exceed 30 degrees centigrade.
3.5. When the bulk product is not immediately packed, the maximum period of
storage and storage conditions shall be specified in the Master Formula. The maximum period
of storage time of a product in the bulk stage shall be validt..
PART ID
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 to
Requirements of Good Manufacturing Practices for Premises and Materials for
pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of
Topical Products i.e. External preparations (Creams, Ointments, Pastes, Emulsions, Lotions,
Solutions, Dusting powders and identical products used for external applications). In
addition to these requirements, the following Specific Requirements shall also be followed,
namely: -
1. The entrance to the area where topical products are manufactured
shall be through a suitable airlock. Outside the airlock, insectocutors shall be
installed.
2. The air to this manufacturing area shall be filtered through at least 20µ
air filters and shall be air-conditioned. 2 [***].
3. The area shall be fitted with an exhaust system of suitable capacity to
effectively remove vapours, fumes, smoke, floating dust particles.
4. The equipment used shall be designed and maintained to prevent the
product from being accidentally contaminated with any foreign matter or
lubricant.
5. 3[Suitable cleaning equipment and material] shall be used in the process
of cleaning or drying the process equipment or accessories used.
1. Subs. by G.S.R. 431(E), dt. 30.6.2005.
2. The words The air shall be ventilated. omitted by G.S.R. 431(E), dt. 30.6.2005.
3. Subs. by G.S.R. 431(E), dt. 30.6.200 .

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6. Water used in compounding shall be Purified Water IP.

7. Powders, wherever used, shall be suitably sieved before use.
8. Heating vehicles and a base like petroleum jelly shall be done in separate
mixing area in suitable stainless steel vessels, using steam, gas, electricity, solar
energy, etc.
9. A separate packing section may be provided for primary packaging of the
products.
PART 1E

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF

METERED-DOSE-INHALERS (MDI)
Note: The General Requirements as given in Part I of this Schedule relating to
Requirements of Good Manufacturing Practices for Premises and Materials for
pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of
Metered-Dose-Inhalers (MDI). In addition to these requirements, the following Specific
Requirements shall also be followed, namely: -

1. General:

Manufacture of Metered-Dose-Inhalers shall be done under conditions which shall

ensure minimum microbial and particulate contamination. Assurance of the quality of
components and the bulk product is very important. Where medicaments are in suspended
state, uniformity of suspension shall be established.

2. Building and Civil Works:

2.1. The building shall be located on a solid foundation to reduce risk of cracking
walls and floor due to the movement of equipment and machinery.

2.2 All building surfaces shall be impervious, smooth and non-shedding.

Flooring shall be continuous and provided with a cove between the floor and the wall as well
as the wall to the ceiling. Ceiling shall be solid, continuous and covered to walls. Light
fittings and air-grills shall be flush with the ceiling. All service lines requiring maintenance
shall be erected in such a manner that these are accessible from outside the production area.

2.3. The manufacturing area shall be segregated into change rooms for personnel,
container preparation area, bulk preparation and filling area, quarantine area and spray testing
and packing areas.

2.4. Secondary change rooms shall be provided for operators to change from
factory clothing to special departmental clothing before entering the manufacturing and filling
area.

2.5. Separate area shall be provided for de-cartoning of components before they
are air washed.

2.6. The propellants used for manufacture shall be delivered to the manufacturing
area distribution system by filtering them through 2µ filters. The bulk containers of
propellants shall be stored, suitably identified, away from the manufacturing facilities.

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3. Environmental Conditions:

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

3.2. The requirements of temperature and humidity in the manufacturing

area shall be decided depending on the type of product and propellants handled in the
facility. Other support areas shall have comfort levels of temperature and humidity.

3.3. There shall be a difference in room pressure between the manufacturing

area and the support areas and the differential pressure shall be not less than 15 Pascals (0.06
inches or 1.5 mm water gauge).

3.4. There shall be a written schedule for the monitoring of environmental

conditions. Temperature and humidity shall be monitored daily.

4. Garments:

4.1. Personnel in the manufacturing and filling section shall wear suitable single-
piece-garment made out of non-shedding, tight weave material. Personnel in support areas
shall wear clean factory uniforms.

4.2. Gloves made of suitable material having no interaction with the propellants
shall be used by the operators in the manufacturing and filling areas. Preferably, disposable
gloves shall be used.

4.3. Suitable department-specific personnel protective equipment like footwear

and safety glasses shall be used wherever hazard exists.

5. Sanitation:

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

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

6. Equipment:

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

6.2. Suitable check weights, spray testing machines and labelling machines shall
be provided in the department.

6.3. All the equipment shall be suitably calibrated and their performance validt.
on receipt and thereafter periodically.

7. Manufacture:

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

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7.2. The primary packing material shall be appropriately cleaned by compressed

air suitably filtered through 0.2µ filter. The humidity of compressed air shall be controlled as
applicable.

7.3. The valves shall be carefully handled and after de-cartoning, these shall be
kept in clean, closed containers in the filling room.

7.4. For suspensions, the bulk shall be kept stirred continuously.

7.5. In-process controls shall include periodical checking of weight of bulk

formulation filled in the containers. In a two-shot-filling process (liquid filling followed by
gaseous filling), it shall be ensured that 100% check on weight is carried out.

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

8. Documentation-

8.1. In addition to the routine good manufacturing practices documentation,

manufacturing records shall show the following additional information:-

(1) Temperature and humidity in the manufacturing area.

(2) Periodic filled weights of the formulation.
(3) Records of rejections during on-line check weighing.
(4) Records of rejection during spray testing.

PART 1F

SPECIFIC REQUIREMENTS OF PREMISES, PLANT AND MATERIALS FOR

MANUFACTURE OF ACTIVE PHARMACEUTIAL INGREDIENTS
(BULK DRUGS)

Note: The General Requirements as given in Part I of this Schedule relating to

Requirements of Good Manufacturing Practices for premises and Materials for
pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of
active pharmaceutical ingredients (Bulk Drugs). In addition to these requirements, the
following Specific Requirements shall also be followed, namely: -

1. Building and Civil Works:

1.1. Apart from the building requirements contained in Part I, General ante, the
active pharmaceutical ingredients facilities for manufacture of hazardous reactions, Beta-
Lactum antibiotics. Steroids and Steroidal Hormones / Cytotoxic substances shall be provided
in confined areas to prevent contamination of the other drugs manufactured.

1.2. The final stage of preparation of a drug, like isolation/filtration/drying/

milling / sieving and packing operations shall be provided with air filtration systems including
pre-filters and finally with a 5 micron filter. Air handling systems with adequate number of air
changes per hour or any other suitable system to control the air borne contamination shall be

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provided. Humidity / Temperature shall also be controlled for all the operations wherever
required.

1.3. Air filtration systems including pre-filters and particulate matter retention air
filters shall be used, where appropriate, for air supplies to production areas. If air is re-
circulated to production areas, measures shall be taken to control re-circulation of floating
dust particles from production. In areas where air contamination occurs during production,
there shall be adequate exhaust system to control contaminants.

1.4. Ancillary area shall be provided for Boiler-house. Utility areas like heat
exchangers, chilling workshop, store and supply of gases shall also be provided.

1.5. For specified preparation like manufacture of sterile products and for certain
antibiotics, sex hormones, cytotoxic and oncology products, separate enclosed areas shall be
designed. The requirements for the sterile active pharmaceutical ingredient shall be in line
with the facilities required for formulation to be filled aseptically.

2. Sterile Products:

Sterile active pharmaceutical ingredient filled aseptically shall be treated as

formulation from the stage wherever the process demands like crystallization, lyophilisation,
filtration etc. All conditions applicable to formulations that are required to be filled aseptically
shall apply mutatis mutandis for the manufacture of sterile active pharmaceutical ingredients
involving stages like filtration, crystallization and lyophilisation.

3. Utilities / Services:

Equipment like chilling plant, boiler, heat exchangers, vacuum and gas storage
vessels shall be serviced, cleaned, sanitized and maintained at appropriate intervals to prevent
mal-functions or contamination that may interfere with safety, identity, strength, quality or
purity of the drug product.

4. Equipment Design, Size and Location:

4.1. Equipment used in the manufacture, processing, packing or holding of an

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 maintenance.

4.2. If equipment is used for different intermediates and active pharmaceutical

ingredients, proper cleaning before switching 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 suitability of the cleaning agent 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/
filtration, dryer/fluid bed dryer, rotocone proton dryer, vacuum dryer, frit
mill, multi-mill/jet mills/sewetters cut sizing;
(d) test for absence of intermediate or active pharmaceutical ingredient in the
final rinse.

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4.4. Written 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 ingredients. These procedures shall include but should
not be limited to the following :

(a) assignment of responsibility for cleaning and maintaining equipment;

(b) maintenance and cleaning program schedules, including where appropriate,
sanitizing schedules;
(c) a complete description of the methods and materials used to clean and
maintain equipment, including instructions for de-assembling and re-
assembling each article of equipment to ensure proper cleaning 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 time that may elapse between completion of
processing and equipment cleaning as well as between cleaning and
equipment reuse.
4.5. Equipment shall be cleaned between successive batches to prevent
contamination and carry-over of degraded material or contaminants unless otherwise
established by validation.

4.6. As processing approaches the final purified active pharmaceutical ingredient,

it is important to ensure that incidental carry over between batches does not have adverse
impact on the established impurity profile. However, this does not generally hold good for
any 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:

5.1. In-process control for chemical reactions may include the following:

(a) reaction time or reaction completion;

(b) reaction mass appearance, clarity, completeness or pH 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.

5.2. In-process control for physical operations may include the following:

(a) appearance and colour;

(b) uniformity of the blend;
(c) temperature of a process;
(d) concentration of a solution;
(e) processing rate or time;
(f) particle size analysis;
(g) bulk/tap density;
(h) pH determination;
(i) moisture content.

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6. Product Containers and Closures:

6.1. All containers and closures shall comply with the pharmacopoeial 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 leachable to an extent that significantly affects the quality or
purity of the drug.

6.2. The drug product container shall be 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/drug master file number (whichever
applicable), batch number;
(c) date of manufacture and date of expiry;
(d) method for container disposal (label shall give the methodology, if
required);
(e) storage conditions, if specified and name and address of the manufacturer, if
available.
6.6. Areas for different operation of active pharmaceutical ingredients (bulk
drugs) section shall have appropriate area which may be suitably partitioned for different
operations.
PART II
REQUIREMENTS OF PLANT AND EQUIPMENT
1. External Preparations:
The following equipment is recommended for the manufacture of
Ointments, Emulsion, Lotions, Solutions, Pastes, Creams, Dusting powders
and such identical products used for external applications, whichever is applicable, namely :-
1
(1) [Mixing and storage tanks preferably of stainless steel or any other appropriate
material].
2
(2) [Stainless steel container] (steam, gas or electrically heated).
(3) Mixer (electrically operated).
(4) Planetary mixer.
(5) A colloid mill or a suitable emulsifier.
(6) A triple roller mill or an ointment mill.
1. Subs. by G.S.R. 431(E), dt. 30.6.200
2. Subs. by G.S.R. 431(E), dt. 30.6.2005

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(7) Liquid filling equipment (electrically operated).

(8) Jar or tube filling equipment 1 [***]
Area. - (1) A minmum area of thirty square meters for basic installation and ten
square meters for Ancillary area is recommended.
(2) Areas for formulations meant for external use and internal use shall be
separately provided to avoid mix-up.
2
[Note: The requirement for ancillary area in this part shall not apply to units registered
before 1st January, 2002.]
2. Oral Liquid Preparations:
The following equipments are recommended for the manufacture of oral/internal use
preparations i.e. Syrups, Elixirs, Emulsions and Suspensions, whichever is applicable,
namely: -
3
(1) [Mixing and storage tanks preferably of Stainless steel or any other
appropriate material].
(2) Jacketted Kettle / Stainless steel tank (steam, gas or electrically heated).
(3) Portable stirrer (electrically operated).
(4) A colloid mill or suitable emulsifier (electrically operated).
(5) Suitable filtration equipment (electrically operated).
(6) Semi-automatic/automatic bottle filling machine.
(7) Pilfer proof cap sealing machine.
(8) Water distillation unit or deionizer.
(9) Clarity testing inspection units.
Area. - A minimum area of thirty square meters for basic installation and ten square
meters for Ancillary area is recommended.
2
[Note: The requirement for ancillary area in this part shall not apply to units registered
before 1st January, 2002.]
3. Tablets:
The Tableting section shall be free from dust and floating particles and may be air-
conditioned. For this purpose, each 4[tablet compression machine] shall be isolated into
cubicles and connected to a vacuum dust collector or an exhaust system. 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 wherever required).
(d) Coating section (wherever required).

3.1. The following electrically operated equipments are recommended for 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 granulator.

mitted by G.S.R. 431(E), dt. 30.6.2005.

2. Ins by G.S.R. 431(E), dt. 30.6.2005.
3 Subs. by G.S.R. 431(E), dt. 30.6.2005,
4. Subs. by G.S.R. 431(E), dt. 30.6.2005,

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1
(4) [Granulator wherever required].
(5) Thermostatically controlled hot air oven with trays (preferably mounted on a
trolley)/Fluid bed dryer.
(6) Weighing machines.
(b) Compression section:

(1) Tablet compression machine, single/multi punch/rotatory.

(2) Punch and dies storage cabinets.
(3) Tablet de-duster
(4) Tablet inspection unit/belt.
1
(5) [Dissolution test apparatus wherever required].
(6) In-process testing equipment like single pan electronic balance, hardness tester,
friability and disintegration test apparatus.
(7) Air-conditioning and dehumidification arrangement (wherever necessary)
(c) Packaging section:

(1) Strip/blister packaging machine.

(2) Leak test apparatus (vacuum system).
(3) Tablet counters (wherever applicable).
(4) Air-conditioning and dehumidification arrangement (wherever applicable).
Area. A minimum area of sixty square meters for basic installation and twenty
square meters for Ancillary area is recommended for un-coated tablets.
(d) Coating section:

(1) Jacketted kettle 2[stainless steel container or any other appropriate material]
(steam, gas or electrically heated for preparing coating suspension).
(2) 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.
2
[Note: The requirement for ancillary area in this part shall not apply to units registered
before 1st January, 2002.]
3.2. 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 meters for coating section for
basic installation and ten square meters for Ancillary area is recommended.
Separate area and 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.
2
[Note: The requirement for ancillary area in this part shall not apply to units registered
before 1st January, 2002.]

3.3. 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.
1. Subs. by G.S.R. 431(E), dt. 30.6.2005.
2. Ins. by G.S.R. 431(E), dt. 30.6.2005.

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3.4. The manufacture of effervescent and soluble 1 [***] tablets shall be carried out in air-
conditioned and dehumidified areas.
4. Powders:
The following equipment is recommended for the manufacture of powders, namely:-

(1) Disintegrator.
(2) Mixer (electrically operated).
(3) Sifter.
(4) Stainless steel vessels and scoops of suitable sizes.
(5) Filling equipment 1[***].
(6) Weighing balance.
In the case of operation involving floating particles of fine powder, suitable exhaust
system shall be provided. Workers should be provided with suitable masks during operation.
Area. A minimum area of thirty square meters 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.
2
[Note: The requirement for additional room in this part shall not apply to units registered
before 1st January, 2002.]
5. Capsules:

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

(1) Mixing and blending equipment (electrically or power driven).

(2) Capsules filling units 1[***].
(3) Capsules counters (wherever applicable).
(4) Weighing balance.
(5) Disintegration test apparatus.
(6) Capsule polishing equipment.
Separate equipment and, filling and packaging areas shall be provided in penicillin
and non-penicillin sections. In case of operations involving floating particles of fine powder, a
suitable exhaust system shall be provided. Manufacture and filling shall be carried out in air-
conditioned area. The room shall be dehumidified.

Area. A minimum area of twenty-five square meters for basic installation and ten
square meters for Ancillary area each for penicillin and non-penicillin sections is
recommended.
2
[Note: The requirement for ancillary area in this part shall not apply to units registered
before 1st January, 2002.]
6. Surgical Dressing:
The following equipment is recommended for the manufacture of Surgical Dressings
other than Absorbent Cotton Wool, namely:-

(1) Rolling machine.

1. Omitted by G.S.R. 431(E), dt. 30.6.2005.

2. Ins. by G.S.R. 431(E), dt. 30.6.2005.

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(2) Trimming machine.

(3) Cutting equipment.
(4) Folding and pressing machine for gauze.
(5) Mixing tanks for processing medicated dressing.
(6) Hot air dry oven.
(7) Steam sterilizer or dry heat sterilizer or other suitable equipment.
(8) Work 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. Ophthalmic Preparations:.

For the manufacture of Ophthalmic preparations, separate enclosed areas with airlock
arrangement shall be provided. The following equipment is recommended for the manufacture
under aseptic conditions of Eye-Ointment, Eye-Lotions and other preparations for external
use, namely:-
(1) Thermostatically controlled hot air ovens (preferably double ended).
(2) Jacketted kettle/stainless steel tanks (steam, gas or electrically heated).
(3) Mixing and storage tanks of stainless steel/Planetary mixer.
(4) Colloid mill or ointment mill.
(5) Tube filling and crimping equipment (semi-automatic or automatic filling machines).
(6) Tube cleaning equipment (air jet type).
(7) Tube washing and drying equipment, if required.
(8) Automatic vial washing machine.
(9) Vial drying oven.
(10) Rubber bung washing machine.
(11) Sintered glass funnel, Seitz filter and filter candle (preferably cartridge and membrane
filters).
(12) Liquid filling equipment (semi-automatic or automatic filling machines).
(13) Autoclave (preferably ventilator autoclave).
(14) Air conditioning and dehumidification arrangement (preferably centrally air-
conditioned and dehumidification system).
(15) Laminar airflow units.
Area. (1) A minimum area of twenty-five square meters for basic installation and
ten square meters for Ancillary area is recommended. Manufacture and filling shall be carried
out in air-conditioned areas under aseptic conditions. The rooms shall be further dehumidified
as considered necessary if preparations containing antibiotics are manufactured.
(2) Areas for formulations meant for external use and internal use shall be separately
provided to avoid mix up.
1
[Note: The requirement for ancillary area in this Part shall not apply to units registered
before 1st January, 2002.]
8. Pessaries and Suppositories:

(i) The following equipment is recommended for manufacture of Pessaries and

Suppositories, namely: -
(1) Mixing and pouring equipment
(2) Moulding equipment.
(3) Weighing devices.
1. Ins. by G.S.R. 431(E), dt. 30.6.2005.

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

(ii) In the case of pessaries manufactured by granulation and compression, the

requirements as indicated under 3 of shall be provided.

9. Inhalers and Vitrallae:

The following equipment is recommended for manufacture of inhalers and vitrallae,

namely: -

(1) Mixing equipment.

(2) Graduated delivery equipment for measurement of the medicament during filling.
(3) Sealing equipment.

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

10. Repacking of drugs and pharmaceutical chemicals:

The following equipment is recommended for repacking of drugs and

pharmaceuticals chemicals, namely:-
(1) Powder disintegrator.
(2) Powder sifter (electrically operated).
(3) Stainless steel scoops and vessels of suitable sizes.
(4) Weighing and measuring equipment.
(5) Filling equipment (semi-automatic / automatic machines).
(6) Electric sealing machine.

Area. An area of minimum thirty square metres is recommended for the basic
installation. In case of operations involving floating particles of fine powder, a suitable
exhaust system shall be provided.

11. Parenteral Preparations

The whole operation of manufacture of parenteral preparations (small volume

injectables and large volume parenterals) in glass and plastic containers may be divided into
the following separate areas/rooms, namely: -

11.1 Parenteral preparations in glass containers:

(1) Water management area: This includes water treatment and storage.
(2) Containers and closures preparation area: This includes washing and drying of
ampoules, vials, bottles and closures.
(3) Solution preparation area: This includes preparation and filtration of solution.
(4) Filling, capping and sealing area: This includes filling and sealing of ampoules and/or
filling, capping and sealing of vials and bottles.
(5) Sterilization area
(6) Quarantine area
(7) Visual inspection area.
(8) Packaging area

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The following equipment is recommended for different above-mentioned areas,

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 area:

(1) Automatic rotary ampoule/vial/bottle washing machine having separate 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 cabinets.
(6) Stainless steel benches/stools.

(c) Solution preparation area:

(1) Solution preparation and mixing stainless steel tanks and other containers.
(2) Portable stirrer.
(3) Filtration equipment with cartridge and membrane filters/bacteriological filters.
(4) Transfer pumps.
(5) Stainless steel benches/stools

(d) Filling, capping and sealing area:

(1) Automatic ampoule/vial/bottle filling, sealing and capping machine under laminar air
flow workstation.
(2) Gas lines (Nitrogen, Oxygen, Carbon dioxide) wherever required.
(3) Stainless steel benches / stools.

(e) Sterilization area:

(1) Steam sterilizer (preferably with computer control for sterilization cycle along with
trolley sets for loading/unloading containers before and after sterilization).
(2) Hot air sterilizer (preferably double ended).
(3) Pressure leak test apparatus.
(f) Quarantine area.

(1) Storage cabinets.

(2) Raised platforms/steel racks.
(g) Visual inspection area:

(1) Visual inspection units (preferably conveyor belt type and composite white and black
assembly supported with illumination).
(2) Stainless steel benches/stools.
(h) Packaging area. -
(1) Batch coding machine (preferably automatic).

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(2) Labelling unit (preferably conveyor belt type).

(3) Benches/stools.
Area. (1) A minimum area of one hundred and fifty square meters for the basic
installation and an Ancillary area of one hundred square meters for Small Volume Injectables
is recommended. For Large Volume Parenterals, an area of one hundred and fifty square
meters each for the basic installation and for Ancillary area is recommended. These areas
shall be partitioned into suitable enclosures with airlock arrangements.
(2) Areas for formulations meant for external use and internal use shall be separately
provided to avoid mix up.
(3) Packaging materials for large volume parenteral shall have a minimum area of
100 square meters.
1
[Note: The requirement for ancillary area in this part shall not apply to units registered
before 1st January, 2002.]

11.2 Parenteral preparations in plastic containers by Form-Fill-Seal/Blow, Fill-

Seal Technology.-The whole operation of manufacture of large volume parenteral
preparations in plastic containers including plastic pouches by automatic (all operations in one
station) Form-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) Containers moulding-cum-filling and sealing area.
(4) Sterilization area.
(5) Quarantine area .
(6) Visual inspection area.
(7) Packaging area.

The following equipment is recommended for different above mentioned areas

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

(b) Solution preparation area:

(1) Solution preparation and storage tanks.

(2) Transfer pumps.
(3) Cartridge and membrane filters.

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

(1) Sterile Form-Fill-Seal machine (all operations in one station with built-in laminar air
flow workstation having integrated container output conveyor belt through pass box).
(2) Arrangement for feeding plastic granules through feeding-cum-filling tank into the
machine.
1. Ins. by 431(E), dt. 30.6.2005.

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 Drugs and Cosmetics Rules 1945

(d) Sterilization area: Super heated steam sterilizer (with computer control for
sterilization cycle along with trolley sets for loading/unloading containers for
sterilization).

(e) Quarantine area:- Adequate number of platforms/racks with storage system.

(f) Visual inspection area. - Visual inspection unit (with conveyor belt and composite
white and black assembly supported with illumination).
(g) Packaging area:

(1) Pressure leak test apparatus (pressure belt or rotating disc type).
(2) Batch coding machine (preferably automatic).
(3) Labelling unit (preferably conveyor belt type).

Area. (1) A minimum area of two hundred and fifty square meters for the basic
installation and an Ancillary area of one hundred and fifty square metres for large volume
parenteral preparations in plastic containers by Form-Fill-Seal technology is recommended.
These areas shall be partitioned into suitable enclosures with airlock arrangements.

(2) Areas for formulations meant for external use and internal use shall be separately
provided to avoid mix up.

(3) Packaging materials for large volume parenteral shall have a minimum area of
100 square meters.]

1
[Note: The requirement for ancillary area in this part shall not apply to units registered
before 1st January, 2002.]
1
[Note I: There are certain categories of drugs such as chemicals and pharmaceutical aids,
gauzes and bandages, medicinal gases, empty gelatin capsules, non- chemical/mechanical
contraceptives, diagnostic kits and reagents, medical devices, new dosage forms and their
delivery systems, disinfectant fluids, antacids, raw-materials manufactured from sea bittern,
veterinary biologicals including poultry vaccines, re-packing of drugs, etc. for which this
Schedule does not prescribe specific requirements of space and equipments. The Licensing
Authority, as the case may be, in respect of such categories of drugs, have the discretion to
modify the requirements of this Schedule, if he is of the opinion that having regard to the
nature off the products and extent of manufacturing operations and for reasons to be recorded
in writing, it is necessary to relax or alter them in the circumstances of a particular case and
direct the manufacturer to carry out necessary modifications in them and the modifications
having been made, approve the manufacturer of such categories of the drugs.

Note II: In case of manufacturers licensed to manufacture drugs prior to the 11th December,
2001, the requirements of this Schedule shall also apply to them from 1st July, 2005.]
1. Ins. by G.S.R. 431(E), dt. 30.6.2005.

478