[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 and no other manufacturing activity shall be undertaken therein.

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 environmental including open sewage, drain, public lavatory or any factory
which product disagreeable or obnoxious odour, fumes, excessive soot, dust, smoke,
chemical or biological emissions.

1.2. Building and premises.- The building(s) used for the factory shall be
designed, constructed, adapted and maintained to suit the manufacturing operations so as
to permit production of drugs under hygienic conditions. They shall conform to the
conditions laid down in the Factories Act, 1948 (63 of 1948)

The premises used for manufacturing, processing, warehousing, packaging

labeling and testing purposes shall be –
________________________________________________________________________
_
● Omitted by G.O.I.Notification No.G.S.R.462(E) dt.22.06.1982.
●●Ins.by G.O.I.Notification NoG.S.R.864(E) dt.11.12.2001.- applicable to manufacturers
licensed to manufacture drugs, for the period upto 31.12.2003.

(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;

(iv) air-conditioned, where prescribed for the operations and dosage froms
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 insets 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, covered and shall permit easy and
effective cleaning and dis-infection. The interior surfaces shall not shed
particles. A periodical record of cleaning and painting of the premises
shall be maintained.

1.3 Water System. - There shall be validated system for treatment of water
drawn from own or any other source to render it potable in accordance with standards
specified by the Bureau of Indian Standards or Local Municipality, as the case may be, so
as to produce Purified Water conforming to Pharmacopoeial specification. Purified Water
so produced shall only be used for all 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.

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 β (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 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 services

lines shall be designed, fixed and constructed to avoid creation of recesses. Services 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 purpose.

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 basis installation and for ancillary purposes. The microbiology section
shall have arrangements such as airlocks and laminar air flow work station, wherever
considered necessary.

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 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
following 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,
packing materials, in-process materials, and drug products until his condition is no longer
judged to be a risk.

7.5 All employees shall be instructed to report about their illness or abnormal
health condition to their immediate supervisor so that appropriate action can be taken.
 7.6 Direct contact shall be avoided between the unprotected hands of
personnel and raw materials, intermediate or finished, unpacked products.

7.7 All personnel shall wear clean body coverings appropriate to their duties.
Before entry into the manufacturing area, there shall be change rooms separate for each
sex with adequate facilities for personal cleanliness such as wash basin with running
water, clean towels, hand dryers, soaps, disinfectants, etc. The change room shall be
provided with cabinets for the storage of personal belongings of the personnel.

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

8. Manufacturing Operations and Controls. -

8.1 All manufacturing operations shall be carried out under the supervision of
technical staff approved by the Licensing Authority. Each critical step in the process
relating to the selection, weighing and measuring of raw material addition during various
stages shall be performed by trained personnel under the direct personal supervision of
approved technical staff.

The contents of all vessels and containers used in manufacture and storage during
the various manufacturing stages shall be conspicuously labeled with the name of the
product, batch number, batch size and stage of manufacture. Each label should be
initialled and dated by the auhorised 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 labeling and cleaning. Proper records and
Standard Operating Procedures thereof shall be maintained.

8.2.2 The licensee shall ensure processing of sensitive drugs like Beta-Lactum
antibiotics, sex hormones and cytotoxic substances in segregated areas or isolated
production areas within the building with independent air-handling unit and proper
pressure differential. The effective segregation of these areas shall be demonstrated with
adequate records of maintenance and services.

8.2.3 To prevent mix-ups during production stages, materials under process

shall be conspicuously labeled to demonstrate their status. All equipment used for
production shall be labeled with their current status.
 8.2.4 Packaging lines shall be independent and adequately segregated. It shall
be ensured tat 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.

8.2.7 The manufacturing environment shall be maintained at the required levels

of temperature, humidity and cleanliness.

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

8.2.9 There shall be segregated enclosed areas, secured for recalled or rejected
material and for such materials which are to e 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 validated cleaning procedure shall be maintained.

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

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 ‘first in/first expiry’ – ‘first-
out’ principle. All incoming materials shall be checked to ensure that the consignment
corresponds to the order placed.

10.3 All incoming materials shall be purchased from approved sources under
valid purchase vouchers. Wherever possible, raw materials should be purchased directly
from the producers.

10.4 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.

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

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

10.6 Raw materials in the storage area shall be appropriately labeled. Labels
shall be clearly marked with the following information:

(a) designated name of the product and the internal code reference, where
applicable, and analytical reference number;

(b) manufacturer’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 “under test”,
“approved” and “rejected” with arrangements and equipment to allow dry, clean and
orderly placement of stored materials and products, wherever necessary, under controlled
temperature and humidity.

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

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

11. 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 labeled.

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

assurance system and, as such, shall be related to all aspects 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 bath of drug for sale and
to provide an audit trail that shall permit investigation of the history of any suspected
defective batch.

12.1 Documents designed, prepared, reviewed and controlled, wherever

applicable, shall comply with these rules.

12.2 Documents shall be approved, signed and dated by appropriate and

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

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

12.5 Data may be recorded by electronic data processing systems or other

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

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

13.1 All containers and equipment shall bear appropriate labels. Different
colour coded tablets 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 labeling of a given batch of a drug, it shall be

ensured by the licensee that samples are drawn from the bulk and duly tested, approved
and released y the quality control personnel.

13.5 Records of receipt of all labeling and packaging materials shall be

maintained for each shipment received indicating receipt, control reference numbers and
whether accepted or rejected. Unused coded and damaged labels and packaging materials
shall be destroyed and recorded.
 13.6 The label or accompanying document of reference standards and reference
culture shall indicate concentration, lot number, potency, date on which 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 requirement of Good Manufacturing
Practices (herein referred as GMP) and other associated codes such
as those of Good Laboratory Practices (hereinafter referred as
GLP) and Good Clinical Practices (herein after referred as GCP);

(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
as been produced and controlled in accordance with the
requirements of the label claim and any other provisions relevant
to production, control and release of pharmaceutical products.

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

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

production and quality control, concept of self-inspection shall be followed. The
manufacturer shall constitute a team of independent, experienced, qualified persons from
within or outside the company, who can audit objectively the implementation of
methodology and procedures evolved. The procedure for self-inspection shall be
documented indicating self-inspection results; evaluation, conclusions and recommended
corrective actions with effective follow up program. The recommendations for corrective
action shall be adopted.
 15.2 The program shall be designed to detect shortcomings in the
implementation of Good Manufacturing Practice and to recommend the necessary
corrective actions. Self-inspections shall be performed routinely and on specific
occasions, like when product recalls or repeated rejections occur or when an inspection
by the licensing authorities is announced. The team responsible for self-inspection shall
consist of personnel who can evaluate the implementation of Good Manufacturing
Practice objectively; all recommendations for corrective action shall be implemented.

15.3 Written instructions for self-inspection shall be drawn up which shall

include the following: -

(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 n 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 manner by qualified and experience 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 dated specifications for all materials,
products, reagents and solvents including test of identity, content, purity and quality.
These shall include specifications for water, solvents and reagents used in analysis.

16.6 No batch of the product shall be released for sale or supply until it has
been certified by the 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.

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 validated 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 wherever changes are
necessary.

16.14 Pharmacopoeiae, 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 validated test methods, sample sizes,
specifications, cleaning procedure and sterilization procedure, wherever indicated, shall
be strictly followed to ensure that these are not reactive, additive, 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.

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 ‘disappear’ in the courts 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, labeling and special storage conditions where applicable;
(j) any special precautions to be observed; and
(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;

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

20. Batch Packaging Records.

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

20.2 Before any packaging 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 dated and signed by the person responsible for
the processing operations: -

(a) the name of the product

(b) the number of the batch being manufactured,
(c) dates and time of commencement, of significant intermediate stages and of
completion of production,
(d) initials of the operator of different significant steps of production and where
appropriate, of the person who checked each of these operations,
(e) the batch number and/or analytical control number as well as the quantities of
each starting material actually weighed,
(f) any relevant processing operation or event and major equipment used,
(g) a record of the in-process controls and the initials of the person(s) carrying
them out, and the results obtained,
(h) the amount of product obtained after different and critical stages of
manufacture (yield),
(i) comments or explanations for significant deviations from the expected yield
limits shall be given.
(j) notes on special problems including details, with signed authorization, for any
deviation from the Master Formula.
(k) addition of any recovered or reprocessed material with reference to recovery
or reprocessing stages,

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

22.1 Receipt of materials:

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

22.1.2 the records of the receipts shall include;

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

22.1.3 There shall be written standard operating procedures for the internal
labeling, 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 instruction 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 poling of the samples,
(f) The types of sample containers 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 (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) reference 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 quality sufficient to carryout all the
tests, except sterility and pyrogens / Bacterial Endotoxin Test, shall be
retained for a period of 3 months after the date of expiry of the last batch
produced from that active ingredient.

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

containers in which the drug has been actually marketed.

24. Reprocessing and Recoveries. -

24.1. Where reprocessing is necessary, written procedures shall be established

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

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

24.3. Recovery of 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 ensure

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 such that finished
batch of a drug can be traced to the retain level to facilitate prompt and
complete recall of the batch, if and when necessary.

26. Validation and process validation. -

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

Practices and shall b conducted as per the pre-defined protocols. These shall
include validation of processing, testing and cleaning procedures.

26.2. A written report summarizing recorded results and conclusions shall be

prepared, documented and maintained.

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

study and undergo periodic revalidation to ensure that they remain capable
of achieving the intended results. Critical processes shall be validated,
prospectively for 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 changes in

equipment or materials that may affect product quality and/or the
reproducibility of the process, shall be validated.
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 procedure describing the action to be taken, recall to
be made of the defective product.

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

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) personal 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; and
(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.

29.5 Sanitation. -

(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 finished products, including sampling, quarantine, release and
storage;
(c) arrangements for the handling of rejected materials and products; and
(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; and

(b) arrangements for 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 export was involved in
evaluating the manufacturer’s compliance with Good manufacturing
Practices in all aspects of production.
 29.12 Export of drugs. -

(a) products exported to different countries; and

(b) complaints and product recall, if any.

PART I-A

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF STERILE PRODUCTS,

PARENTERAL PREPARATIONS (SMALL VOLUME INJECTABLES AND LARGE
VOLUME PARENTERALS) AND STERILE OPHTHALMIC PREPARATIONS.

Note. - The general requirements as given in 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 and 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.

2. Building and Civil Works. -

2.1 The building 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, fiberboard drugs, 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 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 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 ‘black’. ‘gray’, and ‘white rooms’ with different levels of
activity and air cleanliness. The ‘black’ change room shall be provided with a hand-
washing sink. The sink and its drain in the un-classified (first) change rooms may be kept
clean all the time. The specially designed drain shall be periodically monitored to avoid
presence of pathogenic microorganisms. 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 rook after completion of operations.

3.5. Manufacturing and component preparation areas shall meet Grade C

conditions.

3.6. After completion of preparation, washed components and vessels shall be

protected with Grade C background and if necessary, under laminar air flow work station.

3.7. The minimum air changes for Grade B and Grade C areas shall not be less
than 20 air changes per hour in a room with god 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 1.5mm water gauge). Suitable manometers or
gauges shall be installed to measure and verify pressure differential.

3.9 The final change room shall have the same class or air as specified for the
aseptic area. The pressure differentials in the change roods shall be in the descending
order from ‘white’ to ‘black’.

3.10 Unless there are product specific requirements, temperature and humidity
in the aseptic areas shall not exceed 27 degree centigrade and relative humidity 55%,
respectively.

TABLE I
AIRBORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE
OF STERILE PRODUCTS.
Grade At rest (b) In Operation (a)
Maximum number of permitted particles per cubic metre equal to or above.

0.5µm 5µm 0.5µm 5µm

A 3520 29 3500 29
B (a) 35,200 293 3,52,000 2,930
C (a) 3,52,000 2,930 35,20,000 29,300
D (a) 35,20,000 29,300 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 Grade A, B and C. the maximum permitted number of particles in the “at rest”
condition shall approximately be as under:
Grade A corresponds with Class 100 or M 3.5 or ISO Class 5; Grade B with Class
1000 or M 4.5 ISO Class 6; Grade C with Class 10,000 or M 5.5 or ISO Class 7;
Grade D with Class 100,000 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

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 usually
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 “in operation” are as given in the table below:

TABLE
RECOMMENDED LIMITS FOR MICROBIOLOGICAL MONITORING OF CLEAN
AREAS “ IN OPERATION”

Grade Air sample Settle plates (dia. 90mm. Contact plates (dia. Glove points
 Cfu/m2 Cfu/2 hrs. 55mm) cfu per plate (five fingers)
cfu 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.

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 ‘white’ change
room.

6.4. Where alcohol or isopropyl alcohol is used for dilution of disinfectants for
use as hand sprays, the preparation of the same shall be done in the bulk preparation area
and diluted solution membrane filtered into suitable sterile containers held in aseptic area.

6.5. Diluted disinfectants shall bear the label ‘use before’, based on
microbiological establishment of the germicidal properties. The solutions shall be
adequately labeled and documents maintained.

6.6. Formaldehyde or any other equally effective fumigant is recommended for

the fumigation of aseptic areas or after major civil modifications. There shall be Standard
Operating Procedures for this purpose. Its use for routine 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 labeling machines, vacuum testing chambers, inspection machines,
lyophilisers, pressure vessels etc. suitable and fully integrated washing sterilizing filling
lines may be provided, depending upon the type and volume of activity.

7.2. Unit-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, validated 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
validated according to a written program before putting them to use.

7.6. Standard Operating Procedures shall be available for each equipment for
its calibration and operation and cleaning. Gauges and other measuring devices attached
to equipment shall be calibrated at suitable intervals against a written program.
Calibration status of equipment gauges shall be adequately documented and displayed.

8. Water and Steam Systems –

8.1. Potable water meeting microbiological specification of not more than 500
cfu/ml and indicating absence of individual pathogenic microorganisms, 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 met 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 100ml and absence of Pseudomonas aeruginosa and Enterobacter coli in
100 m 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 0.2 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.

8.9 Steam coming in contact with the product, primary containers and other
product contact surfaces shall be sterile and pyrogen free. The steam condensate shall
meet microbiological specification of not more than 10 cfu per 100ml. the condensate
shall also meet IP specification for Water for Injection and shall have an endotoxin levels
of not more than 0.25 EU/ml. there shall be a suitable schedule for the monitoring of
steam quality.

9. Manufacturing Process –

9.1. Manufacture of sterile products shall be carried out only in areas under
defined conditions.

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

9.3 The time between the start of the preparation of the solution and its
sterilization or filtration through a micro-organism retaining filter shall be 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 fulfill 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 process used for component preparation shall be
validated.

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.

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 validated. The validity
of the process shall be verified at regular intervals, but at least annually. Whenever
significant modifications have been made to the equipment and product, records shall be
maintained thereof.

10.6.3 The sterilizer shall be double ended to prevent mix-ups.

10.6.4 Periodic bio-burden monitoring of products before terminal sterilization

shall be carried out and controlled to limits specified for the product in the Master
Formula.

10.6.5 The use of biological indicators shall be considered as an additional

method 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 t avoid transferring microbial
contamination from them.

10.6.6 There shall be clear means of differentiating ‘ sterilized’ and ‘un-

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

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

10.7. Sterilization (by dry heat).-

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

chart of a suitable size by appropriate equipment of the required accuracy and precision.
The position of temperature probes used for controlling and/or recording shall be
determined during the validation and, where applicable, shall also be checked against a
second independent temperature probe located in the same position. The chart shall form
a part of the batch record. Container mapping may also be carried out in the case of Large
Volume Parenterals.

10.7.2 Chemical or biological indicators may also be used, but shall 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 validated to ensure that critical process requirements are met.
System and cycle faults shall be registered by the system and observed by the operator.
The reading of the independent temperature indicator shall be routinely checked against
the chart-recorder during the sterilization period. For sterilizers fitted with a drain at the
bottom of the chamber, it may also be necessary to record the temperature at this position
throughout the sterilization period. There shall be frequent leak tests done on the chamber
during the vacuum phase of the cycle.

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

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

cycle until it has been filled and sealed.

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

10.9. Completion/finalisation of sterile products.-

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

10.9.2. Containers shall be closed by appropriately validated methods.

Containers closed by fusion e.g. glass or plastic ampoules shall be subjected to 100%
integrity testing. Samples of other containers shall be checked for integrity according to
appropriate procedures.
 10.9.3 Containers sealed under vacuum shall be tested for required vacuum
conditions.

10.9.4 Filled containers parenteral products shall be inspected individually for

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

11. Product Containers and Closures.

11.1 All containers and closures intended for use shall comply with the
pharmacopoeial and other specified requirements. Suitable 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 validated for the
absence of particulate matter generated over a period of the shelf life of the product and
shall be 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 tuber 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) Results 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.
(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 printed packaging and testing.
(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 trail 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 Parenterals in glass containers and/or plastic
containers,

(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 install automatic (with all operations)
Form–Fill-Seal machines having one continuous operation.

PART I-B

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL SOLID DOSAGE

FORMS (TABLETS AND CAPSULES)

Note: - The General 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, mutates
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 professes shall be provided. Filters shall be installed to retain dust and
protect the factory and local environment.

1.3. Special care shall be taken to protect against subsequent contamination

of the product by particles of metal or wood. The use of metal detector is recommended.
Wooden equipment should be avoided. Screens, sieves, punches and dies shall be
examined for wear and tear or for breakage before and after each use.

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

1.5. Where the facilities are designed to provide special environmental

conditions of pressure differentials between rooms, these conditions shall be regularly
monitored and any specification results brought to the immediate attention of the
Production and quality Assurance Department which shall be immediately attended to.

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

2.1. Unless operated as a closed system, mixing, sifting and blending

equipments shall be fitted with dust extractors.

2.2. Residues from sieving operations shall be examined periodically for

evidence of the presence of unwanted materials.

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

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

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

3. Compressions (Tablets)

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

3.2. Suitable physical,, procedural and labeling arrangements shall be made

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

3.3. Accurate and calibrated weighting equipment shall be readily available

and used for in-process monitoring of tablet weight variation. Procedures used shall be
capable of detecting out-of-limits tablets.

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

compression points in a compression machine, sufficient individual tablets
shall be examined at fixed intervals to ensure that a tablet from each
compression station or from each compression point has been inspected
for suitable pharmacopoeial parameters like ‘appearance’, ‘weight
variation’, ‘disintegration’, ‘hardness’, ‘friability’ and ‘thickness’. The
results shall be recorded as part of the batch documentation.

3.5. Tablets shall be de-dusted, preferably by automatic device and shall be

monitored for the presence of foreign materials besides any other defects.
 3.6. Tablets shall be collected into clean, labeled containers.

3.7. Rejected or discarded tablets shall be isolated in identified containers and

their quality recorded in the Batch Manufacturing Record.

3.8 In-process control shall be employed to ensure that the products remain
within specification. During compression, samples of tablets shall be taken at regular
intervals of not greater than 30 minutes to ensure that they are being produced in
compliance with specified in-process specification. The tablets shall also be periodically
checked for additional parameters such as ‘appearance’, ‘weight variation’,
‘disintegration’, ‘hardness’, ‘friability’ and ‘thickness’ and contamination by lubricating
oil.

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 ‘drug 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 ‘rogue’ tablets, capsules or foils
from packaging operation are removed f\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.

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 I-C
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, mutates mutandis, for the manufacture
of (Syrups, Elixirs, Emulsions and Suspensions). In addition to these requirement, 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 fly proof by use of ‘fly catcher’ and/or ‘air curtain’.

1.3. Drainage shall be of adequate size and have adequate traps, without open
channels and 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.

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.)

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 systems, a flushing shall be
done to ensure that the sanitizing agent has been effectively removed.

3. Manufacturing

3.1. Manufacturing personnel shall wear non-fiber shedding clothing to

prevent contamination of the product.

3.2. Materials likely to shed fiber like gunny bags, or wooden pallets shall not
be carried into the area where products or cleaned-containers are exposed.

3.3. Care shall be taken to maintain the 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 validated.

PART I-D
SPECIFIC REQUIREMENTS FOR MANUFACTURE OF TOPICAL PRODUCTS i.e.
EXTERNAL PREPARATIONS (CREAMS, OINTMENTS, PASTES, MULSIONS,
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, mutates 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, following Specific Requirements shall
also be followed, namely: -

1. The entrance to the area where topical products are manufactured should 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. The area shall be ventilated.
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. No rags or dusters shall be used in the process of cleaning or drying the process
equipment or accessories used.
6. Water used in compounding shall be Purified Water IP.
7. Powders, 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 I-E
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, mutates 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 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.

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 area 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 1.5mm 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 labeling machines
shall be provided in the department.

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

7. Manufacture.-

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

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, there 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, labeling 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 I-F
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, mutates 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 Part-I, General note, 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 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 mutates 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 the 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.

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,

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 equipments are recommended for the manufacture of ‘External
preparations’ i.e. Ointments, Emulsion, Lotions, Solutions, Pastes, Creams, Dusting
powders and such identical products used for external applications whichever is
applicable, namely :-

(1) Mixing and storage tanks (stainless steel),

(2) Jacketted Kettle (steam, gas or electrically heated),
(3) Mixer (electrically operated)
(4) Planetary mixer
(5) A colloid mill or a suitable emulsifier.
(6) A triple roller mill or an ointment mill.

(7) Liquid filling equipment (electrically operated).

(8) Jar or tube filling equipment (electrically operated)

Area. - (1) A minmum area of thirty square meters for basic installation of 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. Oral Liquid Preparations. -

The following equipments are commended for the manufacture of oral/internal

use preparations i.e. Syrups, Elixirs, Emulsions and suspensions, whichever is applicable,
namely: -

(1) Mixing and storage tanks (stainless steel),

(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 deioniser
(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.

3. Tablets

The Tableting section shall be free from dust and floating particles and may be
air-conditioned. For this purpose, each tablet machine shall be isolated into cubicles and
connected to a vacuum dust collector or an exhaust system. 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.
(4) Granulator
(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.
(5) Dissolution test apparatus
(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 (whereever 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 (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.

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.

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.

3.4. The manufacture of effervescent and soluble/dispersible 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 (electrically operated).
(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.

(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 (preferably semi automatic or automatic filling machines).
(3) Capsules counters (wherever applicable)
(4) Weighing balance.
(5) Disintegration test apparatus.
(6) Capsule polishing equipment.

Separate equipment and, filling and packaging area 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.

(6)Surgical Dressing

The following equipment is recommended for the manufacture of Surgical

Dressings other than Absorbent Cotton Wool, namely:-

(1) Rolling machine

(2) Trimming machine
(3) Cutting equipment.
(4) Folding and pressing machine for 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.

(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.

Area. - A minimum area of twenty square meters is recommended to allow for

the basic installation.
 (iii) In the case of Pessaries manufactured by granulation and compression, the
requirements as indicated under “Item 3 of Tablet”, shall be provided.

9. Inhalers and Vitralle

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 meters 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

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 line (Nitrogen, Oxygen, Carbon dioxide) wherever required.
(3) Stainless steel benches / stools

(d) 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.

(e) 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)

(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 are 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.

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) Packing 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.

(f) 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.

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

(h) Quarantine area, - Adequate number of platforms/racks with storage system.

(i) Visual inspection area, - Visual inspection unit (with conveyor belt and
composite

(j) 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 of an Ancillary area of one hundred and fifty square meters 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.]

*SCHEDUE M-I
[See Rule 85-E (2)]

1. Requirements of factory premises for manufacture of Homoeopathic

preparations. -
(a) Location and surroundings. - The factory shall be situated in a place which shall
not be adjacent to an open sewage drain, public lavatory or any factory which
produces a disagreeable or obnoxious odour or fumes or large quantities of soot,
dust or smoke. The factory shall be located in a sanitary place, remove from filthy
surroundings.
(b) Buildings. - The part of the building used for manufacturing shall not be used for
a sleeping place and no sleeping place adjoining to it shall communicate
therewith except through open air or through an intervening open space. The
walls of the room in which manufacturing operations are carried out shall, upto a
height of six feet from the floor, be smooth, waterproof and shall be capable of
being kept clean. The flooring shall be smooth, even and washable and shall be
such as not to permit retention or accumulation of dust. There shall be no chinks
or crevices in the walls or floor.

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

(d) Water Supply. - The water used in manufacture shall be pure and drinkable
quality, free from pathogenic microorganisms.

(e) Disposal of waste. - There should be adequate arrangement for disposal of

wastewater and other residues from the laboratory.

(f) The rooms should be airy and clean and the temperature of the room should be
moderately comfortable.
(g) Health, Clothing and Sanitary requirement of the Staff. - All workers shall be
free from contagious or obnoxious disease. Their clothing shall consist of a white
or coloured uniform suitable to the nature of the work and the climate, and shall
be clean. Adequate facilities for personal cleanliness, such as clean towels, soap
and hand scrubbing brushes, shall be provided separately for each sex. The
workers shall be required to wash and change into clean footwear before entering
the rooms where the manufacturing operations are carried on. Workers shall be
required to wear either a clean cap or a suitable headgear so as to avoid any
possibility of contamination by air or perspiration.
________________________________________________________________________
___* Ins. by G.O.I Notification G.S.R. No. 507(E) dt 12-06-1987 w.e.f. 12.06.1987

(h) Medical services. - The manufacturer shall provide adequate facilities for First
Aid, Medical inspection of workers at the time of employment and periodically
check-up thereafter at least once a year.

(i) Working benches. - Working benches shall be provided for carrying out
operations such as filling, labeling, packing etc. such benches shall be fitted
with smooth, impervious tops capable of being washed.

(j) Container management. - Where operations involving use of containers such

as bottles, phials and jars are conducted, there shall be adequate arrangements
separated from potentisation chamber for washing, cleaning and drying such
containers, with suitable equipment for the purpose. Wherever these are
attended manually adequate precaution of perfection in respect of cleanliness
and avoidance of pollutants shall be taken.

2. Requirements of Plant and Equipment. -

(a) Mother tinctures. External tinctures and Mother solution section. - The
following plant and equipment shall be provided namely: -
(i) Disintegrator
(ii) Sieved Separator
(iii) Balances and fluid measures
(iv) Chopping boards and knives.
(v) Macerators with lids.
(vi) Percolators with lids and regulated discharge.
(vii) Moisture determination apparatus or other suitable arrangement.
(viii) Filtering arrangement
(ix) Mixing vessels and suitable non-metallic storage containers.
(x) Portable stirrers.
(xi) Water still
Note: - (1) As for as possible metal contacts may be avoided once the drug is
processed.
(2) An area of 55 sq. meters is recommended for basic installations.

(3) Adequate separate storage facility should be provided for raw material
quarantine, storage and bonded room for alcohol were applicable.

(4) Separate and suitable storage facility should be provided for fresh herbs
and odorous raw materials.

(5) Adequate laboratory facility shall be provided for testing of raw material
and finished products,
 (b) Potentisation Section. - (1) the following arrangements are recommended
for container for closure preparation section namely: -
(i) Washing tanks with suitable brushing arrangement manual or mechanical.
(ii) Purified Water rinsing tank
(iii) Closure macerating or washing tanks.
(iv) Drying chambers.
An area of 20 sq. meters is recommended for basic installation.

(2) The following arrangements are recommended for potency preparation

section, namely: -
(i) Working tables with washable top.
(ii) Facilities for separate storage of different grades of back potencies.
(iii) Suitable measuring devices for discharge of drug and diluent in
potentisation vial,
(iv) Potentiser with counter or suitable manual arrangement.
Note: - (1) Different droppers shall be used for different drugs potencies.

(2) All measuring devices shall be of metric system and be made of glass
and shall be free from metallic contents.

(3) It is desired that glass droppers etc. intended for re-use after cleaning
should be sterilized by autoclave or heating in a hot air oven.

(4) Plastics, rubber tubes, bulks etc. coming in contact with tinctures or
back potencies should not be re-used for other tincture and potencies.

(5) Method of potentisation will be adopted as specified in Homoeopathic

Pharmacopoeia of India Vol. I (3) Triturating, Tableting and Pill/Globules section -

(3) The following arrangement are recommended: -

(i) Triturating machine for suitable device
(ii) Disintegrator
(iii) Mass Mixer
(iv) Granulator
(v) Oven
(vi) Tableting punches or machines
(vii) Kettle (Steam/gas/electrically heated) for preparation solution.
(viii) Dryers
(ix) Sieved separator, tablet counters and balances.

Note: - Tablet section shall be free from dust and floating particles. An area of 55
sq. meters is recommended for basis installations

(4) Ointments and lotion section.

The following arrangements are recommended namely: -

 (i) Mixing tank
(ii) Kettle (Steam, gas or electrically heated).
(iii) Suitable powder mixer
(iv) Ointment mill
(v) Filling equipment or arrangement.
An area of 20 sq. meters is recommended for basic installation.

(5) Syrups and tonics: -

The following arrangements are recommended namely:-

(i) Mixing and storage tank

(ii) Potable mixer
(iii) Filtering equipment
(iv) Water still / Deioniser
(vi) Filling and sealing equipment.
An area of 20 sq. meters is recommended for basic installations.

(6) Ophthalmic Preparations:

The following equipment is recommended for manufacture under aseptic

conditions of Eye-Ointments, Eye-Drops, Eye-lotion and other
preparations for external use, namely: -

(i) Hot air even electrically heated with thermostatic control.

(ii) Colloid mill or ointment mill.
(iii) Kettle (gas or electrically heated) with suitable mixing
arrangement.
(iv) Tube filling equipment.
(v) Mixing and storage tanks of stainless steel or of other suitable
material.
(vi) Sintered glass funnel, Seitz filter or filter candle.
(vii) Liquid filling equipment
(viii) Autoclaves

Adequate precaution should be taken to ensure that the finished product is sterile.
An area of 20 Sq. meters is recommended for basic installations.

(7) Adequate arrangements for space and equipment should made for labeling
and packing.

*[SCHEDULE M-II
[See Rule 139]
 REQUIREMENT OF FACTORY PREMISESFOR MANUFACTURE
OF COSMETICS.

1. GENERAL REQUIREMENTS

(A) Location and surroundings. - The factory shall be located in a sanitary place and
hygienic conditions shall be maintained in the premises. Premises shall not be used
for residence or be interconnected with residential area. It shall be well ventilated and
clean.

(B) Buildings. - The buildings used for the factory shall be constructed so as to permit
production under hygienic conditions and not to permit entry of insects, rodents,
files, etc.
The walls of the room in which manufacturing operations are carried out, shall up to
a height of six feet from the floor, be smooth, waterproof and capable of being kept
clean. The flooring shall be smooth, even and washable and shall be such as not to
permit retention or accumulation of dust.

(C) Water supply: - The water used in manufacture shall be of potable quality.

(D) Disposal of water. - Suitable arrangements shall be made for disposal of wastewater.

(E) Health, clothing and sanitary requirements of the staff. - All workers shall be free
from contagious or infectious diseases. They shall be provided with clean uniforms,
masks, headgears, and gloves wherever required. Washing facilities shall also be
provided.

(F) Medical Services. - Adequate facilities for first aid shall be provided.

* Ins. by G.O.I. Notification No. GSR 723(E) dt 11-8-1992.

(G) Working benches shall be provided for carrying out operations such as filling,
labeling, packing, etc. such benches shall be fitted with smooth, impervious tops
capable of being washed.

(H) Adequate facilities shall be provided for washing and drying of glass containers if the
same are to be used for packing the product.

II. REQUIREMENTS OF PLANT AND EQUIPMENT

The following equipment, area and other requirements are recommended for the
manufacture of: -
A. Powders. - Face powder, cake make-up, compacts, face packs, masks and rouges,
etc.

1. Equipment.

(a) Powder mixer of suitable type provided with a dust collector.

(b) Perfume and colour blender.
(c) Sifter with sieves of suitable mesh size.
(d) Ball mill or suitable grinder.
(e) Trays and scoops (stainless steel).
(f) Filling and sealing equipment provided with dust extractor.
(g) For compacts: -
(i) a separate mixer, (ii) compact pressing machine.
(h) Weighing and measuring devices
(i) Storage tanks.

An area of 15 square meters is recommended. The section is to be provided with adequate

exhaust fans.

B. Creams, lotions, emulsions, pastes, cleansing milks, shampoos, pomade,

brilliantine, shaving creams and hair-oils etc.

(a) Mixing and storage tanks of suitable materials.

(b) Heating kettle – steam, gas or electrically heated.
(c) Suitable agitator.
(d) Colloidal mill or homogeniser (wherever necessary)
(e) Triple roller mill (wherever necessary).
(f) Filling and sealing equipment.
(g) Weighing and measuring devices.
An area of 25 square meters is recommended.

C. Nail Polishes and Nail lacquers.

1. Equipment:
(a) A suitable mixer.
(b) Storage tanks.
(c) Filling machine – hand operated or power driven.
(d) Weighing and Measuring devices.
An area of 15 square meters is recommended. The section shall be provided with
flameproof exhaust system.

2. Premises: - The following are the special requirements related to Nail

Polishes and Nail Lacquers: -

(a) It shall be suited in an industrial area.

 (b) It shall be separate from other cosmetic-manufacturing areas by metal/brick
partition up to ceiling.
(c) Floors, walls, ceiling and doors shall be fireproof.
(d) Smoking, cooking and dwelling shall not be permitted and no naked flame
shall be brought in the premises.
(e) All electrical writing and connections shall be concealed and main electric
switch shall be outside the manufacturing area.
(f) All equipment, furniture and light fittings in the section shall be flameproof.
(g) Fire extinguisher like foam and dry powder and sufficient number of buckets
containing sand shall be provided.
(h) All doors of the section shall open outwards.

3. Storage. - All explosive solvents and ingredients shall be stored in metal

cupboards or in a separate enclosed area.

4. Manufacture:

(a) Manufacture of lacquer shall not be undertaken unless the above conditions
are complied with.
(b) Workers shall be asked to wear shoes with rubber soles in the section.

5. Other requirements: - No objection certificate from the local Fire Brigade

Authorities shall be furnished.

D. Lipsticks and Lip-gloss, etc.

1. Equipment

(a) Vertical mixer

(b) Jacketted kettle – steam, gas or electrically heated.
(c) Mixing vessel (stainless steel)
(d) Triple roller mill/Ball mill.
(e) Moulds with refrigeration facility.
(f) Weighing and measuring devices.
An area of 15 square meters is recommended.

E. Depilatories.
1. Equipment:

(a) Mixing tanks.

(b) Mixer
(c) Triple roller mill or homogeniser (where necessary).
(d) Filling and sealing equipment
(e) Weighing and measuring devices.
(f) Moulds (where necessary)
An area of 10 square meters is recommended.
F. Preparations used for Eyes: - Such preparations shall be manufactured under
strict hygienic conditions to ensure that these are safe for use.

1. Eyebrows, Eyelashes, Eyeliners, etc.

1 Equipment:

(a) Mixing tanks.

(b) A suitable mixer.
(c) Homogeniser (where necessary)
(d) Filling and sealing equipment.
(e) Weighing and measuring devices.
An area of 10 square meters is recommended.

2. Kajal and Surma

1. Equipment:

(a) Base sterilizer

(b) Powder sterilizer (dry heat oven).

(c) Stainless steel tanks.
(d) A suitable Mixer
(e) Stainless steel sieves
(f) Filling and sealing arrangements.
(g) Weighing and measuring devices.
(h) Homogeniser (where necessary)
(i) Pestle and Mortar (for Surma)
An area of 10 square meters with a separate area of 5 square meters for base
sterilization is recommended.
Other requirements for 1 and 2

(a) False ceiling shall be provided wherever required.

(b) Manufacturing area shall be made fly proof. An airlock or an air curtain shall
be provided.
(c) Base used for Kajal shall be sterilized by heating the base at 150 degree C for
required time in a separate enclosed area.
(d) The vegetable carbon black powder shall be sterilized in a drying oven at 120
degree C for required time.
(e) All utensils used for manufacture shall be of stainless steel and shall be
washed with detergent water, antiseptic liquid and again with distilled water.
(f) Containers employed for ‘Kajal’ shall be cleaned properly with bactericidal
solution and dried.
(g) Workers shall put on clean overalls and use hand gloves wherever necessary.

G. Aerosol.
 1. Equipment: -

(a) Air-compressor (wherever necessary).

(b) Mixing tanks.
(c) Suitable propellant filling and crimping equipments.
(d) Liquid filling unit.
(e) Leak testing equipment.
(f) Fire extinguisher (wherever necessary)
(g) Suitable filtration equipment.
(h) Weighing and measuring devices.
An area of 15 square meters is recommended.
2. Other requirements: - No objection certificate from the Local Fire Brigade
Authorities shall be furnished.

H. Alcoholic Fragrance Solutions.

Equipment: -

(a) Mixing tanks with stirrer

(b) Filtering equipment.
(c) Filling and sealing equipment.
(d) Weighing and measuring devices.
An area of 15 square meters is recommended.

I. Hair Dyes.
Equipment:
(a) Stainless steel tanks.
(b) Mixer.
(c) Filling Unit
(d) Weighing and measuring devices.
(e) Masks, gloves and goggles.
An area of 15 square meters with proper exhaust is recommended.

J. Tooth powders and toothpastes, etc.

1. Tooth-powder in General.
Equipment:

(a) Weighing and measuring devices.

(b) Dry mixer (powder blender)
(c) Stainless steel sieves
(d) Powder filling and sealing equipments.
An area of 15 square meters with proper exhaust is recommended.

2. Toothpastes.
 Equipment:

(a) Weighing and measuring devices.

(b) Kettle – steam, gas or electrically heated (where necessary)
(c) Planetory mixer with de-aerator system.
(d) Stainless steel tanks.
(e) Tube filling equipment.
(f) Crimping machine.
An additional area of 15 square meters with proper exhaust is recommended.
3. Tooth-powder (Black)
Equipment:
(a) Weighing and measuring devices.
(b) Dry mixer powder blender.
(c) Stainless steel sieves.
(d) Powder filling arrangements.
An area of 15 square meters with proper exhaust is recommended. Areas for
manufacturing “Black” and “White” tooth powders should be separate.

K. Toilet Soaps.
Equipment: -
(a) Kettles/pans for saponification.
(b) Boiler or any other suitable heating arrangement.
(c) Suitable stirring arrangement.
(d) Storage tanks or trays
(e) Driers.
(f) Amalgamator/chipping machine.
(g) Mixer
(h) Triple roller mill.
(i) Granulator
(j) Plodder
(k) Cutter
(l) Pressing, stamping and embossing machine
(m) Weighing and measuring devices.
A minimum area of 100 square meters is recommended for the small-scale
manufacture of toilet soaps.
The areas recommended above are for basic manufacturing of different categories
of cosmetics. In addition to that separate adequate space for storage of raw materials,
finished products, packing materials shall be provided in factory premises.1 [* * *]

Note No. I. The above requirements of the Schedule are made subject to modification
at the direction of the Licensing Authority, if he is of the opinion that having regard to the
nature and extent of the manufacturing operations it is necessary to relax or alter them in
the circumstances of a particular case.

Note No. II. The above requirements do not include requirements of machinery,
equipments and premises required for preparation of containers and closers of different
categories of cosmetics. The Licensing Authority shall have the discretion to examine the
suitability and adequacy of the machinery, equipments and premises for the purpose of
taking into consideration of the requirements of the licence.

Note No. III. Schedule M-II specifies equipments and space required for certain
categories of cosmetics only. There are other cosmetics items, viz. Attars, perfumes, etc.,
which are not covered in the above categories. The Licensing Authority shall, in respect
of such items or
________________________________________________________________________
___ The words ‘A testing laboratory shall also be provided’ were omitted by
G.O.I.Notification No.G.S.R.285 (E) dt 16.07.1996.

categories of cosmetics have the discretion to examine the adequacy of factory premises,
space, plant and machinery and other requisites having regard to the nature and extent of
the manufacturing operations involved and direct the licensee to carry on necessary
modification in them.

Note No. IV. **[Areas for formulations meant for external use and areas for
formulations meant for internal use shall be separately provided to avoid mix-up even
though they are from the same category of formulations]

***[SCHEDULE M-III
[See Rule 76]
REQUIREMENTS OF FACTORY PREMISES FOR MANUFACTURE OF
MEDICAL DEVICES

1. GENERAL REQUIREMENTS

1.1.1. Location and surroundings. - The factory building(s) shall be located in a

sanitary place and hygienic conditions shall be maintained in the premises. Premises shall
be not used for residence or be interconnected with residence. It shall be well ventilated
and clean.

1.1.2. Buildings. - The buildings used for the factory shall be constructed so as
to permit production under hygienic conditions and not to permit entry of insets, rodents,
flies etc.
 The walls of the rooms in which manufacturing operations are carried out, shall
be up to a height of six feet from the floor, be smooth, water proof and capable of being
kept clean. The floor shall be smooth, even and washable and shall be such as not to
permit retention or accumulation of dust.

1.1.3. Water supply. - The water used in manufacture shall be of potable quality.

1.1.4. Disposal of waste. - Suitable arrangements shall be made for disposal of

wastewater.

1.1.5. Health, Clothing and Sanitation of workers. - All workers shall be free
from contagious or infectious diseases. They shall be provided with clean uniforms,
masks, headgears and gloves wherever required. Washing facilities shall also be
provided.

________________________________________________________________________
_
**

*** Ins. by GOI Notification No. G.S.R. 109(E), w.e.f. 22.2.1994.

1.1.6. Medical Services. - Adequate facilities for first-aid shall be provided.

1.1.7. Workbenches shall be provided for carrying out operations such as

moulding, assembling, labeling, packing etc. such benches shall be fitted with smooth
impervious tops capable of being washed.

1.1.8. Adequate facilities shall be provided wherever required for cleaning,

washing, drying of different containers of devices.

1.1.9. The premises shall be kept under controlled conditions of temperature and
humidity so as to prevent any deterioration in the properties of materials and products due
to storage and process conditions.

2. Requirements for Manufacture of Medical Devices.- The process of manufacture

of medical devices shall be conducted at the licensed premises, wherever required, and
shall be divided into the following separate operations/Sections:-

1) Moulding (wherever manufacture of medical devices is to start from granules).

2) Assembling (include cutting, washing and drying, sealing, packing, labeling, etc.)
3) Raw Materials.
4) Storage Area.
5) Washing, drying and sealing area (wherever required).
6) Sterilization.
7) Testing facilities.
 The following equipments and space are recommended for the basic manufacture
of different categories of medical devices. -

A. STERILE DISPOSABLE PERFUSION AND BLOOD COLLECTION SETS.

(1) Moulding:
(a) Injection Moulding Machine.
(b) Extruder Machine.
(c) PVC Resin compounding Machine.

(2) Assembling:

(a) Hand Pressing Machine for filter fixing a Drip Chamber.

(b) Bag Sealing Machine.
(c) Compressor Machine.
(d) Leak Testing Bench
(e) PVC Tube Cutting Machine.
(f) Tube Winding Machine (wherever necessary).
(g) Welding Machine (wherever necessary)
An area of 30 square meters for Moulding and 15 square meters for Assembling
are recommended for basic installation. The assembling area shall be air-conditioned
provided with HEPA filters. The moulding section shall, if necessary, have proper
exhaust system.

Note: - An additional area of 20 square meters is recommended for any extra

category.

B. STERILE DISPOSABLE HYPODERMIC SYRINGES.

(1) Moulding: -
(a) Granulator
(b) Injection Moulding Machine.
(c) Weighing devices.
(2) Assembling:
(a) Blister Pack Machine.
(b) Vacuum Dust Cleaner
(c) Rubber-tip Washing Machine
(d) Foil stamping or screen printing equipment.
An area of 30 square meters for moulding and 15 square metres for assembling
are recommended for basic installation. The assembling area shall be air-conditioned
provided with HEPA Filters. The moulding section, shall, if necessary, have proper
exhaust system.

Note: - An additional area of 20 square meters is recommended for any extra

category.
 C. STERILE DISPOSABLE HYPRODERMIC NEEDLES.

(1) Moulding:
(a) Needle grinding and leveling machine.
(b) Electro Polishing Machine.
(c) Cutting Machine
(d) Injection Moulding Machine.
(e) Needle Pointing Deburrine Machine
(f) Air-compressor.
(2) Assembling:
(a) Needle cleaning Machine with Magnetic Separator.
(b) Blister Packing Machine.
(c) Needle Inspection Unit.
An area of 30 square meters for Moulding and 15 square meters for Assembling
are recommended for basic installation. The assembling area shall be air-conditioned
provided with HEPA filters. The molding section shall, if necessary, have proper exhaust
system.

Note: - An additional area of 20 square meters is recommended for any extra

category.
3. Raw Materials. - The licensee shall keep an inventory of all raw materials to
be used at any stage of manufacture of devices and shall maintain records as per Schedule
U. All such raw materials shall be identified and assigned control reference umber. They
shall be conspicuously labeled indicating the name of the material, control reference
number, name of the manufacturer and be specially labeled “Under Test” or “ Approved”
or “Rejected”. The under test, approved or rejected materials shall appropriately be
segregated. These shall be tested for compliance with required standards of quality.

A minimum area of 10 Square meters shall be provided for storage of raw

materials.

4. Storage Area. - The licensee shall provide separate storage facilities for
quarantine and sterilized products.

An area not less than 10 square metre shall be provided for each of them.

5. Washing, drying and sealing area. - The licensee shall provide wherever
required adequate equipments like water distillation still, deionizer, washing machine.
Dying Oven with trays for washing, drying and sealing of medical device.

An area not less than 10 square metre shall be provided.

 6. Sterilization. - The licensee shall provide requisite equipments with required
controls and recording device for sterilization of medical devices by Ethylene Oxide Gas
in his own premises or may make arrangements with some Institution approved by the
Licensing authority for sterilization. The products sterilized in this manner shall be
monitored to assure acceptable levels of residual gas and its degradation products. An
area of 10 square meters is recommended for basic installation of such facility.
Provided that the above equipment may not be required in case the licensee opts
for sterilization of medical devices by Ionising Radiation.

7. Testing Facilities. - The licensee shall provide testing laboratory for

carrying out Chemical and Physio-Chemical testing of medical devices and of raw
materials used in its own premises:

Provided that the Licensing Authority shall permit the licensee in the initial stage
to carry out testing of Sterility, Pyrogens, Toxicity on their products from the approved
testing institutions but after one renewal period of licensee shall provide testing facilities
of all such tests in their own premises.

8. Records. - The licensee shall maintain records of different manufacturing

activities with regard to each stage of manufacture in-process control, assembling,
packing, batch records for the quantity of devices manufactured from each lot of blended
granules, duration of work, hourly quantum of production in respect of each item as well
as record of each sterilizing cycle of the gaseous method employed.

Note: - The above requirements of machinery, equipments, space, qualifications

are made subject to the modification at the discretion of the Licensing Authority, if he is
of the opinion that having regard to the nature and extent of the manufacturing operations
it is necessary to relax or alter them in the circumstances of a particular case.]