cGMP AUDIT PROFORMA

(For GMP compliance inspection)

Part 1:
1.1 General Information

Name of Manufacturer As per DML

Physical Address As visited and verified

Drug Manufacturing license No.

and Validity (Date of application
for DML renewal)
Contact Address Name/designation of the person authorized for
correspondence/communication
Date of inspection
Purpose of inspection 1. Panel Inspection
2. Grant of GMP certificate
3. Re-inspection after non-compliance report
4. Grant of Registration
5. Renewal of Drug Manufacturing Licence.
Name of inspector (s)

Name of Firm‟s Representative Who accompanied and assisted during the course of inspection
(s) accompanying during
inspection

1.2 General Information about the Unit:

A brief of company‟s profile, management, establishment.

1.3 Detail of manufacturing section (s)

Pharmacological Dosage Form Total Number of Remarks (if any)

Category(ies) Registered
products
For Example: Tablet
Non-antibiotic,
Antibiotic,
Psychotropic,
Hormones,
Steroid,
Cephalosporin,
Penicillin etc
Write the Capsule
applicable

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 Continue…as
required

1.4 Brief History of previous inspections:

A brief about previous two years inspections (date of inspection/ Overall cGMP compliance/
Non-Compliance/ improvements).

1.5 Focus of the inspection :

GOOD MANUFACTURING PRACTICES (GMPs) FOR MANUFACTURERS. SCHEDULE B-II UNDER THE DRUGS
(LICENSING, REGISTERING AND ADVERTISING)
RULES 1976, FRAMED UNDER THE DRUGS ACT, 1976

PART-I

GRADING
S. No. CONDITION Remarks
(A,B,C or D)
SECTION-I
1 GENERAL CONDITIONS

Responsibility of licensee for drug’s fitness for use.

SECTION – 2
Quality assurance system
(a) drugs are designed and developed as per requirements of
good manufacturing practices;
(b) production and control operations are clearly specified in a
written form and good manufacturing practices requirements are
adopted and followed;
(c) managerial responsibilities are clearly specified in job
descriptions;
(d) arrangements are made for the manufacture, supply, and use
of the correct starting and packaging materials;
(e) all necessary controls on starting materials, intermediate
products, and bulk products and other in process controls
calibrations and validations are carried out;
(f) the finished products are correctly processed and checked,
according to the defined procedures;
2 (g) finished drugs are not sold or supplied before the authorized
person(s) has certified that each production batch has been produced
and controlled in accordance with the requirements of the good
manufacturing practices and the relevant rules made under the Act
relevant to the production, control and release of drugs as well as of
conditions of registration;
(h) satisfactory arrangements exist to store in appropriate storage
conditions;
(i) Procedure for self inspection and or quality audit exists and
documented;
(j) Written Standard Operating Procedure available according to
which complaints about marketed products are examined, the causes of
quality defects investigated, and appropriate measures taken in respect
of the defective products and to prevent recurrence and that system is
followed.

SECTION – 3
3 Quality control
Quality control department exists which is independent of other
departments and under the authority of a person with the
3.1 required qualifications and experience and with adequate
facilities.
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3.2 Basic requirements.--
(a) During the period of validity of license, adequate facilities,
trained personnel and approved procedures are available for
sampling, inspecting, testing starting materials, packaging materials,
intermediate, bulk, and finished products, and where appropriate for
monitoring environmental conditions for good manufacturing
practices purposes;
(b) Samples of starting materials, packaging materials,
intermediate products, bulk products and finished products are taken by
methods, and personnel approved of by the quality control department.

(c) Testing methods are validated;

(d) Records are made that all the required sampling, inspecting
and testing procedures have actually been carried out and that any
deviation has been fully recorded and investigated;
(e) The finished products contain ingredients complying with the
qualitative and quantitative composition of the product described in the
marketing authorization.
(f) Records are made of the results of inspecting and testing
materials and intermediate, bulk and finished products against
specifications and product assessment.
(g) No batch of product is released for sale prior to certification by
the authorized person(s) that it is in accordance with the
requirement of the rules;
(h) Sufficient samples of starting materials and products are
retained to permit future examination of the product.
(i) All quality control procedures are established, validated and
implemented; the reference standards for substances are evaluated
maintained, and stored; correct labeling of containers of materials and
products is ensured; the stability of the active pharmaceutical
ingredients and products is monitored.

Complaints related to the quality of the product are investigated. All

these operations shall be carried out in accordance with

written procedures.
3.3 Control Procedures:
3.3.1 General.-- All tests and analysis conducted shall be in
accordance with the instructions given in the relevant written test
procedures. The result shall be checked by the supervisor before the
material or product is released or rejected.
3.3.2 Sampling.-- The samples shall:--
(a) be representative of the batches of material from which they
are taken and in accordance with the approved written
procedure;
(b) be taken in a manner so as to avoid contamination or other
adverse effect on quality.
(c) be taken with care to guard against contamination or mix-up. All
sampling equipment that comes into contact with the material shall be
clean.
(d) be taken with equipment which shall be cleaned and, if
necessary, sterilized before and after each use and stored
separately form other laboratory equipment.
3.3.3 Test requirement for starting and packaging materials:
(i) Test before use.-- Before releasing a starting or packaging
material for use, the quality control manager ensure that the materials
have been tested for conformity with specifications for identity,
strength, purity, and other quality parameters.

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 (ii) Identity from each container.-- An identity test shall be
conducted on a sample from each container of starting material.
(iii) Examination of each batch.-- Each batch (lot) of printed
packaging materials shall be examined following receipt.
3.3.4 Test requirement for in-process control:
Records of testing.- In process control records shall be
maintained and form a part of the batch records.
3.3.5 Test requirements for finished products:
(i) Testing each batch.- For each batch of drug product, there shall
be an appropriate laboratory determination of satisfactory
conformity to its finished product specifications prior to release.
(ii) Rejection of failed products.-- Product failing to meet the
established specifications or any other relevant quality criteria may
be revalidated and shall be rejected if they do not qualify revalidation
protocols.
(iii) Reprocessing.- Reprocessing may be performed, if feasible,
but the reprocessed product shall meet all specifications and other
quality criteria prior to its acceptance and release.
3.3.6 Production record and batch review;

(i) Review of Records.- Production and control records shall be

reviewed.
(ii) Retention of Samples.-- Retention samples from each batch of
finished product shall be kept for at least one year after the expiry date.

3.3.7 Stability studies:

(i) The quality control department shall:--
(a) Evaluate the quality and stability of finished pharmaceutical
products and, of starting materials and intermediate products;
and, of starting materials and intermediate products; and

(b) Establish expiry dates and shelf-life specifications on the basis

of stability tests related to storage conditions.
(ii) A written program for ongoing stability determination shall be
developed and implemented to include elements such as:--
(iii) Stability of the finished product shall be evaluated and
documented prior to marketing.
3.4 Self-inspection
3.4.1 General.- The management shall appoint a self inspection team. The
team responsible for self-inspection shall consist of
personnel who can evaluate the implementation of good manufacturing
practices objectively; all recommendations for corrective action shall
be implemented; The procedure for self- inspection shall be
documented and there shall be an effective follow-up program. Self
inspections shall be performed routinely.
3.4.2 Items for self-inspection.- Written instructions for self-inspection
shall be established to provide a minimum and uniform standard
of requirements.
3.4.3 Frequency of self-inspection.- it shall be at least once every year.
3.4.4 Self-inspection report.-- A report shall be made at the completion of
self-inspection which shall include:--
(a) self-inspection results;
(b) evaluation and conclusions; and
(c) recommended corrective actions.
3.5 Quality audit:
3.5.1 Audit by independent specialist.- Quality audit shall be conducted

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 which consists of an examination and assessment of all or part of
a quality system.
3.2.2 Supplier’s audits.- The quality control department shall have
responsibility together with other relevant departments for
approving suppliers.
3.6 Complaints:
3.6.1 Review of complaints.-- All complaints must be carefully
reviewed according to written procedures.
3.6.2 Person authorized.-- A person responsible for handling the
complaints.
3.6.3 Written procedures.-- There shall be written procedures
describing the action to be taken including the need to consider a
recall, in the case of a complaint concerning a possible product defect.

3.6.4 Recording defects and investigation.-- Any complaint concerning

a product defect shall be recorded with all the original details and
thoroughly investigated.
3.6.5 Investigation.-- If a product defect is discovered or suspected in
a batch, consideration shall be given to whether other batches shall be
checked in order to determine whether they are also affected.

3.6.6 Follow-up action.-- Where necessary, appropriate follow-up

section, possibly including product recall, shall be taken after
investigation and evaluation of the complaint.
3.6.7 Recording measures.-- All the decisions and measures taken as
a result of a complaint shall be recorded and referenced to the
corresponding batch records.
3.6.8 Review for recurring problems.--Complaint record shall be
regularly reviewed for any indication of specific or recurring
problems the require attention.
3.7 Product recalls:
3.7.1 System.-- There shall be a system to promptly and effectively
recall from the market the products known or suspected to be
defective.
3.7.2 Authorized person.-- A person responsible for the execution and
coordination of recalls shall be designated.
3.7.3 Written procedure.--There shall be established written
procedures, regularly checked and updated for the organization
of any recall activity.
3.7.4 Recall with promptness.-- All competent authorities to whom a
given product may have been distributed shall be promptly
informed of any intention to recall the product.
3.7.5 Distribution records.-- The distribution records shall be readily
available to the person(s) responsible for recall.
3.7.6 Recording of progress.-- The progress of the recall process shall be
recorded and a final report issued, including a reconciliation
between the delivered and recovered quantities of the products.
3.7.7 Evaluation.-- The effectiveness of the arrangements for recalls
shall be evaluated from time to time.
3.7.8 Storage of recalled drugs.-- An instruction shall be included to
store recalled products in a secure segregated area while their fate is
decided.
SECTION--4
4 Personnel
4.1 General.-- The licensee shall provide:--

(a) sufficient qualified personnel (at least one technical person

for each section) to fulfill all its responsibilities required under
these rules; and

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 (b) organization chart.

4.2 Written duties.-- All responsible staff shall have their specific
duties recorded in written descriptions.
4.3 Good manufacturing practices awareness.-- All personnel shall be
aware of the principles of good manufacturing practices that affect
them and receive initial and continuing training, including hygiene
instructions, relevant to their needs.
4.4 Prohibition of unauthorized persons.-- Steps shall be taken to
prevent unauthorized people from entering production,
storage, and quality control areas and personnel who do not work in
these areas shall not use them as a passageway.
4.5 Duties of head of departments.-- The head of the production
and quality control department may have shared, or jointly
exercised the following responsibilities relating to quality,
namely:
(a) the authorization of written procedures and other
documents, including amendments;

(b) the monitoring and control of the manufacturing

environment;

(c) plant hygiene;

(d) process validation and calibration of analytical apparatus;
(e) training, including the application and principles of quality
assurance;
(f) the approval and monitoring of suppliers of materials;

(g) the approval and monitoring of contract manufacturers;

(h) the designation and monitoring of storage conditions for

materials and products;
(i) the retention of records;
(j) the monitoring of compliance with good manufacturing
practices requirements; and

(k) the inspection, investigation, and taking of samples in order

to monitor factors that may affect product quality.

4.6 Duties of production incharge.-- The head of the production

department may have the following responsibilities, namely:--
(a) to ensure that products are produced and stored according
to the appropriate documentation in order to obtain the
required quality;
(b) to approve the instructions relating to production
operations including the in-process controls, and to ensure their
strict implementation;
(c) to ensure that the production records re evaluated and
signed by a designated person before they are made available to the
quality control department;
(d) to check the maintenance of the department, premises,
and equipment;

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 (e) to ensure that the appropriate process validations and
calibrations of control equipment are performed and recorded and
the reports made available; and

(f) to ensure that the required initial and continuing training of

production personnel is carried out and adapted according to need.

4.7 4.7 Duties of Quality Control Incharge.-- The head of the

quality control department shall have the following
responsibilities, namely:--
(a) to approve or reject starting materials, packaging materials,
and intermediate, bulk, and finished products’

(b) to evaluate batch records’

(c) to ensure that all necessary testing is carried out;
(d) to approve sampling instructions, specifications, test
methods, and other quality control procedures;

(e) to approve and monitor analyses carried out under

contract;
(f) to check the maintenance of the department, premises and
equipment;

(g) to ensure that the appropriate validation, including those of

analytical procedures and calibrations of control equipment are
done; and
(h) to ensure that the required initial and continuing training of
quality control personnel is carried out and adapted according to
need.
4.8 Training:
4.8.1 Written programme.-- The training shall be provided in
accordance with a written program for all the personnel whose duties
require them to work in the production areas, as the case may be, in
the control laboratories (including the technical, maintenance, and
cleaning personnel), and for other personnel whose activities could
affect the quality of the product.

4.8.2 Training appropriate to duties.-- Besides basic training on the

theory and practice of good manufacturing practices, newly
recruited personnel shall receive training appropriate to the duties
assigned to them., continuing training shall also be given, and
its practical effectiveness shall be periodically assessed, training
programs shall be available, approved by the head of either
production or quality control, as appropriate, and training records
shall be kept.
4.8.3 Specific training.-- Personnel working in areas where
contamination is a hazard, such as clean areas or areas
where highly active, toxic, infectious, or sensitizing materials are
handled, shall be given specific training.
4.8.4 Understanding concepts.-- The concept of quality assurance
and all the measures capable of improving its understanding and
implementation shall be fully discussed during the training sessions.

4.8.5 Visitors or untrained personnel discouraged.-- Visitors or

untrained personnel shall be discouraged entry into the
production and quality control areas.
4.9 Personnel hygiene:
4.9.1 Health Examination.-- All personnel prior to and during
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 employment as may be appropriate, shall undergo health
examinations and personnel conducting visual inspections shall
also undergo periodic eye examinations.
4.9.2 Practices in personal hygiene.-- All personnel shall be trained
in the practices of personal hygiene, a high level of personal
hygiene shall be observed by all those concerned with
manufacturing processes, personnel shall be instructed particularly
to wash their hands before entering production areas, and signs to
this effect shall be pasted and instructions observed.

4.9.3 Illness.-- Any person down at any time to have an apparent

illness or open lesions that may adversely affect the quality of
products shall not be allowed to handle starting materials,
packaging materials, in process materials, or drug products until
the condition is no longer judged to be a risk.
4.9.4 Reporting health problems.-- All employees shall be instructed
and encouraged to report to their immediate supervisor any
conditions, relating to plant, equipment, or personnel, that they
consider may adversely affect the products.
4.9.5 Avoiding direct contact with materials.-- Direct contact shall be
avoided between the operator’s hands and starting materials,
primary packaging materials, and intermediate or bulk product.
4.9.6 Appropriate clothing and covering.-- To ensure protection of
the product from contamination, personnel shall war clean body
coverings appropriate to the duties they perform, including
appropriate hair cover, and used clothes, if re- usable, shall be
stored in separate closed containers until properly laundered and,
if necessary, disinfected or sterilized
4.9.7 Foods and drinks prohibited.-- Smoking eating, drinking,
chewing and keeping plants, food, drink, smoking material, and
personal medicine shall not be permitted in production, laboratory,
and storage areas or in any other areas where they might adversely
influence product quality.

SECTION--5
Good practices in manufacturing processing
(Separate format may be used for each manufacturing section)
5.1 5.1 General responsibility of licensee.-- The licensee shall
follow Good Manufacturing Practices in production of drugs
under which it shall be ensured that:--
(a) all manufacturing processes which shall be defined are
systematically reviewed in the light of experience, and shown to be
capable of consistently manufacturing pharmaceutical products of
the required quality that comply with their specifications;

(b) critical steps of manufacturing processes and any

significant change made to the processes are validated;

(c) all necessary facilities are continued to be made available

including:--
(i) appropriately qualified and trained personnel; (ii)
adequate premises and space;
(iii) suitable equipment and services;
(iv) correct materials, containers, and labels; (v)
approved procedures and instructions; (vi)
suitable storage and transport; and
(vii) adequate personnel, laboratories and equipment for in-
process controls under the responsibility of the production
management.

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 (d) instructions and procedures are written in clear and
unambiguous language, specifically applicable to the facilities
provided and followed in letter and spirit;

(e) operators receive training and refresher courses at regular

intervals to carry out procedures correctly, and records of such
training are maintained;

(f) records are made, manually and or by recording instruments,

during manufacture to show that all the steps required by the defined
producers and instructions have in fact been taken and that the
quantity and quality of the product are as expected, and any
significant deviations are fully recorded and investigated;

(g) records covering manufacture and distribution, which

enable the complete history of a batch to be traced, are
retained in a comprehensible and accessible form;

(h) the proper storage and distribution of the products

minimizes any risk to their quality; and

(i) the written system to recall any batch of product from sale or
supply is followed whenever a recall is necessitated.

SECTION-- 6
MATERIALS
6.1 Material, general
6.1.1 Quarantine.-- All incoming materials and finished products shall
be quarantined immediately after receipt or processing,
until they are released for use or distribution
6.1.2 Appropriate storage.-- All materials and products shall be
stored under the appropriate conditions established by the
manufacturer and in an orderly manner to permit batch segregation
and stock rotation by a first-in, first-out rule.
6.2 Starting materials
6.2.1 Purchase.-- The purchase of starting materials is an important
operation that must involve staff who have a particular and
thorough knowledge of the products and suppliers and a
pharmacist with some experience of production may be
preferred.
6.2.2 Purchase from producer or established supplies.-- Staring
materials shall be purchased directly from the producer or only form
established suppliers.
6.2.3 Checking of containers.-- For each consignment, the
containers shall be checked for integrity of package and seal and
for correspondence between the order, the delivery note, and the
supplier’s labels, and, containers shall be cleaned where necessary
and labelled, if required, with the prescribed data.

6.2.4 Damaged container.-- Damage to containers and any other

problem that might adversely affect the quality of a material shall be
recorded and reported to the quality control department and
investigated.
6.2.5 Delivery from different batches.-- If a delivery of material is
made up of different batches, each batch shall be considered as
separate for sampling, testing and release.
6.2.6 Labelling.-- Starting materials in the storage area shall be
appropriately labelled, and labels shall bear at least the
following information, namely:--
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 (a) the designated name of the product and the internal code
reference where applicable;

(b) the batch number(s) given by the supplier and on receipt by

the manufacturer, if any.

(c) where appropriate, the status of the contents such as on

quarantine, on test, released, rejected returned, and recalled, and;

(d) where appropriate an expiry date or a date beyond which

retesting is necessary. When fully computerized storage systems
are used appropriate system shall be developed for the
identification of above referred information.

6.2.7 Identity of contents.-- There shall be appropriate procedures or

measures to ensure the identity of the contents of each container of
staring material, but bulk containers form which samples have been
drawn shall be identified.
6.2.8 Released materials to be used.-- Only starting materials
released by or quality control department and within their self- life
shall be sued.
6.2.9 procedure to ensure that the correct materials are accurately
weighted or measured into clean and properly labelled
containers.
6.2.10 Checking.-- Each dispensed material and its weight or volume shall
be independently checked and the check recorded.
6.2.11 Labelling.-- Materials dispensed for each batch of the final
product shall be kept together and conspicuously labelled as such.

6.3 Packaging materials

6.3.1 Purchase.-- The purchase, handling and control of primary and
printed packaging materials shall be as for starting materials.
6.3.2 Printed materials.-- Particular attention shall be paid to printed
packaging materials which shall be stored in secure conditions so as
to exclude the possibility of unauthorized access, cut labels, and
other loose printed materials shall be stored and transported in
separate closed containers so as to avoid mix- ups and packaging
materials shall be used for use only by designated personnel
following an approved and documented procedure.

6.3.3 Reference numbers.-- Each delivery or batch of printed or

primary packaging material shall be given a specific reference
number or identification mark.
6.3.4 Obsolete materials.-- Outdated or obsolete primary packaging
material or printed packaging material shall be destroyed and its
disposal be recorded.
6.3.5 Checking before delivery.-- All products and packaging
materials to be used shall be checked on delivery to the
packaging department for quantity, identity, and conformity with
the packaging instructions.
6.4 Intermediate and bulk products

6.4.1 Storage.-- Intermediate and bulk products shall be kept under

appropriate conditions.
6.4.2 Handling.-- Intermediate and bulk products purchased as such
shall be handled on receipt as though they were starting
materials.
6.5 Finished pharmaceutical products
6.5.1 Quarantine.-- Finished pharmaceutical products shall be held

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 in quarantine until their final release, and thereafter they shall
be stored as usable stock under conditions established by the
manufacturer.
6.5.2 Release.-- The evaluation of finished products and the
documentation necessary for release of a product for sale, as per
requirement of these rules, shall be followed.
6.6 Rejected and recovered materials
6.6.1 Storage and disposal.-- Rejected materials and products shall
be clearly marked as such and stored separately in restricted areas,
and they shall either be returned to the suppliers, or, where
appropriate, reprocessed or destroyed and then action shall be
approved by authorized personnel and recorded.
6.6.2 Reprocessing.-- The reprocessing of rejected products shall
be exceptional, it is permitted only if the quality of the final product
is not affect, if the specifications are met, and if it is done in
accordance with a defined and authorized procedure after evaluation
of the risks involved and record shall be kept of the reprocessing
and a reprocessed batch shall be given a new batch number.

6.6.3 batch recovery.-- The introduction of all or part of earlier

batches, conforming to the required quality, into a batch of the same
product at a defined stage of manufacture shall be authorized
beforehand, this recovery shall be carried out in accordance with a
defined procedure after evaluation of the risks involved including
any possible effect on shelf-life and the recovery shall be recorded.

6.6.4 Additional testing of reprocessed materials.-- The need for

additional testing of any finished product that has been reprocessed,
or into which a recovered product has been incorporated, shall
be considered by the quality control department.

6.7 Recalled and returned products

6.7.1 Recalled products.-- Recalled products shall be identified,
clearly marked as such and stored separately in a secure area until a
decision is taken on their fate.
6.7.2 Returned goods.-- Products returned from the market shall be
destroyed unless it is certain that their quality is satisfactory, they
may be considered for resale, relabelling, or bulking with a
subsequent batch only after they have been critically assessed by the
quality control department in accordance with a written procedure.
The nature of the product, any special storage conditions, it
requires, its condition and history, and the time elapsed since it
was issued shall all be taken into account in this assessment, where
any doubt arises over the quality of the product, it shall not be
considered suitable for reissue or re-use, although basic chemical
reprocessing to recover the active ingredient may be possible, and
any action taken shall be appropriately recorded.

6.8 Reagents and culture media

6.8.1 All reagents and culture media shall be recorded upon receipt or
preparation.
6.8.2 Reagents made up in the laboratory shall be prepared
according to written procedures and appropriately labelled, the label
shall indicate the concentration, standardization factor, shelf-life, the
date when re-standardization is due, and the storage conditions and
the label shall be signed and dated by the person preparing the
reagent.
6.8.3 Both positive and negative controls shall be applied to verify
the stability of culture media and the size of the inoculum used in
positive controls shall be appropriate to the sensitivity
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 required.
6.9 Reference standards
6.9.1 Testing of prepared reference standard.-- Reference
standards may be available in the form of official reference
standards and reference standards prepared by the producer shall be
tested, released, and then stored in the same way as official
standards, and they shall be kept under the responsibility of a
designated person in a secured area.
6.9.2 Use.-- Official reference standards shall be used only for the
purpose described in the appropriate testing method submitted for
registration purposes.
6.9.3 Working standards.-- Secondary or working standards may be
established by the application of appropriate tests and checks at
regular intervals to ensure standardization, and all in-house
reference standards shall be based on official reference standards,
when available
6.9.4 Storage.-- All reference standards shall be stored and used in
a manner that will not adversely affect their quality
6.10 Waster materials
6.10.1 Storage.-- Provision shall be made for the proper and safe
storage of waste materials awaiting disposal, and toxic
substances and flammable materials shall be stored in suitably
designed and separate enclosed cupboards.
6.10.2 Disposal.-- Waste material shall not be allowed to accumulate,
and it shall be collected in suitable receptacles for removal to
collection points outside the buildings and disposed of safely and in
a sanitary manner at regular and frequent intervals.
6.10.3 Effluent Control.-- There shall be a effluent control system.
6.11 Miscellaneous
Rodenticides, insecticides, fumigating agents and sanitizing
materials shall not be permitted to contaminate equipment, starting
materials, packaging, materials, in-process materials, or finished
products.
SECTION – 7
7.1 Processing operations
7.1.1 General.-- Production operations must follow clearly defined
procedures with the objective of obtaining products of the
requisite quality.
7.1.2 Material handling.-- All handling of materials and products such
as receipt and quarantine, sampling, storage, labelling
dispensing, processing, packaging, and distribution shall be done in
accordance with written procedures or instructions and, where
necessary, recorded.
7.1.3 Avoiding deviation.-- Any deviation from instructions or
procedures shall be avoided as far as possible and if deviations
occur, they shall be approved in writing by a designated person, with
the involvement of the quality control department.

7.1.4 Yield checks.-- Check on yields and re-conciliation of

quantities shall be carried out as necessary to ensure that yields are
within acceptable limits.
7.1.5 Avoiding mix-ups.-- Operations on different products shall not
be carried out simultaneously or consecutively in the same room
unless there is no risk of mix-up or cross-contamination.
7.1.6 Labelling.-- At all times during processing, all materials, bulk
containers, major items of equipment, and where appropriate the
rooms used shall be labelled or otherwise identified with an
indication of the product or material being processed and its
strengths, where applicable, and the batch number, and where

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 applicable this indication shall also mention the stage of
production.
7.1.7 Un-authorized entry prohibited.-- Access to the production
premises shall be restricted to authorized personnel.
7.1.8 In-process controls.-- In process controls are mostly performed
within the production are and they shall not carry any risk for
the quality of the product.
7.2 Prevention of cross-contamination and bacterial contamination
in production.
7.2.1 Precautions against dust.-- When dry materials and products
are used in production, special precautions shall be taken to prevent
the generation and dissemination of dust. This applies particularly to
the handling of highly active or sensitizing materials.

7.2.2 Measures against contamination.-- Contamination of a starting

material or of a product by another material or product shall
also be avoided and similarly, cross-examination shall be avoided
by appropriate technical or organizational measures, as may be
necessary by production segregated areas,
namely:--
(a) conducting production in segregated areas;
(b) providing appropriate airlock, pressure differentials and
dust extraction;
(c) minimizing the risk of contamination caused by re-
circulation or re-entry of untreated or insufficiently treated air;

(d) wearing and keeping protective clothing in areas where products

with special risk of cross-contamination re processed;
(e) using, cleaning and decontamination procedures of known
effectiveness, as in-effective cleaning of equipment is a
common source of cross-contamination;
(f) encourage using a ‘closed system" of production;
(g) testing for residues where necessary;
(h) using cleanliness status labels on equipment, showing the
name of the previous product.
7.2.3 Cross-contamination checks.-- Measures to prevent cross-
contamination and their effectiveness shall be checked
periodically according toe standard operation procedures.
7.2.4 Microbiological monitoring.-- Production areas where
susceptible products are processed shall undergo periodic
microbiological monitoring and the bio-burden shall be kept within
the specified limits.
7.3 Processing operations, intermediate and bulk products
7.3.1 Pre-processing cleanliness checks.-- Before any processing
operation is started, steps shall be taken to ensure that the work area
and equipment are clean and free from any starting materials,
products, product residues, labels, or documents not required for
the current operation.
7.3.2 2 In-process controls.-- Necessary in-process controls and
environmental controls shall be carried out and recorded.
7.3.3 Defective equipment.-- Means shall be instituted for indicating
failures of equipment or of services, such as water or gas, to
equipment. Defective equipment shall be withdrawn from use until
the defect has been rectified.
7.3.4 Cleaning containers.-- Containers for filling shall be cleaned
before filing and attention shall be given to avoiding and removing
any contaminants such as glass fragments and metal particles.
Production equipment shall be cleaned
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 according to detailed written procedures and stored only under
clean and dry conditions.
7.3.5 Yield deviations.-- Any significant deviation from expected
yield shall be recorded and investigated.
7.3.6 Product pipelines.-- Checks shall be carried out to ensure that
pipelines and other pieces of equipment used for the
transportation of products from one are to another are
connected in a correct manner.
7.3.7 Water pipes.-- Pipes used for conveying distilled or deionized
water and, where appropriate, other water-pipes shall be sanitized
according to written procedures that detail the action and limits for
microbiological contamination and the measures to be taken.

7.3.8 Equipment calibration.-- Measuring, weighing, recording

control equipment and instruments shall be serviced and
calibrated at pre-specified intervals and records maintained. To
ensure satisfactory functioning instruments shall be checked
daily or prior to use for performing analytical tests and the date of
calibration and the date when re-calibration is due
shall be clearly indicated.
7.3.9 Repair and maintenance.-- Repair and maintenance
operations shall present any hazard to the quality of the
products.
7.4 Packaging operations
7.4.1 Avoiding mix-ups.-- When the program for packaging
operations is being set up particular attention shall be given to
minimizing the risk of cross-contamination, mix-up, or
substitutions, and different products shall not be packaged in close
proximity unless there is physical segregation or the use of
electronic surveillance.
7.4.2 Pre-packaging checks.-- 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, or documents previously used and not
required for the current operation, and the line clearance shall be
performed according to an appropriate checklist and recorded.

7.4.3 Labelling of packaging line.-- The name and batch number of

the product being handled shall be displayed at each
packaging station or line.
7.4.4 Process continuity.-- Normally, filling and sealing shall be
followed as quickly as possible by labeling and if labelling is
delayed, appropriate procedures shall be applied to ensure that no
mix-up or mis-labelling can occur.
7.4.5 5 Printing operation checks.-- The correct performance of any
printing, mode numbers or expiry dates, done separately or in the
course of the packaging shall be checked and recorded, and attention
shall be paid to printing by hand which shall be re-checked at
regular intervals.
7.4.6 Label verification.-- Special care shall be taken when cut
labels are used and when over-printing is carried out off-line and in
hand-packaging operations, roll-feed labels are normally
preferable to cut labels in helping to avoid mix-up. On-line
verification of all labels by automated electronic means can be
helpful in preventing mix-up, but checks shall be made to ensure
that electronic code readers, label counters, or similar devices are
operating correctly.
7.4.7 Fast colour printing on labels.--Printed and embossed
information on packaging materials shall be distinct and
resistant to fading or erasing.
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7.4.8 One-line packaging checks.-- On-line control of the product
during packaging shall include at least check on:-- (a)
the general appearance of the packages;
(b) whether the packages are complete;
(c) whether the correct products and packaging materials are used;
(d) whether any over-printing is correct;
(e) the correct functioning of line monitors; and
(f) samples taken from the packaging line shall not be returned
unless inspection is done in close the packaging proximity of line.

7.4.9 Product re-introduction on packaging line.-- Products that have

been involved in an un-usual event during packaging shall be re-
introduced into the process only after special inspection,
investigation, and approval by authorized personnel and a
detailed record shall be kept of this operation.
7.4.10 Discrepancies to be investigated.-- Any significant or un-usual
discrepancy observed during reconciliation of the amount of bulk
product and printed packaging materials and the number of units
produced shall be investigated and satisfactorily accounted for
before release
7.4.11 Destruction of un-used packaging materials.-- Upon
completion of a packaging operation, un-used batch-coded
packaging materials shall be destroyed and the destruction recorded,
and a documented procedure shall be followed if encoded printed
materials are returned to stock.
SECTION—8
8 Sanitation and hygiene
General.-- A high level of sanitation and hygiene shall be practiced
in every aspect of the manufacture of drug products, the scope of
sanitation and hygiene covers personnel, premises, equipment and
apparatus, production materials and containers, product for cleaning
and disinfection, and anything that could become a source of
contamination to the product, and potential sources of
contamination shall be eliminated through an integrated
comprehensive program of sanitation and hygiene (For sanitation
and hygiene please also refer to Section 5 of Schedule B and
Section 4.9 of Schedule B-II).
SECTION—9
9 Validation
9.1 General.-- Validation studies shall be conducted in accordance
with pre-defined protocols. A written report summarizing recorded
results and conclusions shall be prepared and stored. Processes and
procedures shall be established on the basis of a validation study
and undergo periodic re-validation to ensure that they remain
capable of achieving the intended results, and particular attention
shall be accorded to the validation of processing, testing and
cleaning procedures.
9.2 Process Validation to be performed as per written procedures
9.2.1 Validation of critical processes.-- Critical processes shall be
validated, prospectively or retrospectively.
9.2.2 Validation of new master formula.-- When any new master
formula or method of preparation is adopted, steps shall be taken to
demonstrate its stability for routine processing, and, the defined
process, using the materials and equipment specified, shall be
shown to yield a product consistently of the required quality.

9.2.3 Validation of equipment and materials.-- Significant

amendments to the manufacturing process, including any
change in equipment or materials that may affect product
16 / 37
 quality and or the re-productibility of the process shall be
validated.
SECTION – 10
10 Documents
10.1.1 Maintenance of documents.-- Documents, as required under these
rules, shall be meticulously maintained and regularly
reviewed and kept up to date, and when a document has been
revised, a system shall exist to prevent inadvertent use of the
superseded version.
10.1.2 Records of action.-- Records shall be made or completed
when any action is taken and in such a way that all significant
activities, concerning the manufacture of pharmaceutical products
are traceable. The batch record shall be retained for at least one year
after the expiry date of the finished product.
10.1.3 Documentation systems.--Data may be recorded by electronic
data processing systems or by photographic or other reliable means.
Master formulate and detailed standard operating procedures relating
to the system in use shall be available and the accuracy of the
records shall be checked and if documentation is handled by
electronic data-processing method, only authorized persons shall
be able to enter or modify data in the computer, and there shall be
a record of changes, and deletions, access shall be restricted by
passwords or their means and the entry of critical data shall be
independently checked and data shall also be readily
available.

10.1.4 Staus identification.-- Labels applied to containers, equipment,

or premises shall be unambiguous and in the company’s agreed
format. The labels of different colours may also be used in
addition to the working to indicate the status such as
"quarantined," "accepted," "rejected," or "clear."
10.1.5 Product labelling.-- All finished products shall be labelled in
accordance with the Drugs (Labelling and Packing) Rules
1986.
10.1.6 Reference standards identification.-- For reference standards,
the label or accompanying documents shall indicate concentration,
date of manufacture, expiry, date, and storage conditions, where
appropriate.
10.1.7 Specification approvals. -- Each specification, shall be
approved and maintained by the quality control unit.
10.1.8 Revision of specification.-- Periodic revisions of the specifications
may be necessary to comply with new editions
of the national pharmacopoeia or other official compendia or the
Drugs (Specifications) Rules 1978.
10.1.9 Packaging material specification.-- Packaging material shall
conform to specifications, with emphasis placed on the
compatibility of the material with the drug product it contains.
10.1.10 Starting material re-assay.-- Documents describing testing
procedures shall state the required frequency for re-assaying each
starting material, as determined by its stability.
10.2 Specifications for Intermediate and bulk products
Specifications for intermediate and bulk products shall be available
if these are purchased or dispatched, of if data obtained from
intermediate products are used in the evaluation of the finished
product, and the specifications shall be similar to specifications for
starting materials or for finished products.
10.3 Batch processing records
10.3.1 General.-- A batch processing record shall be kept for each
batch processed based on the relevant parts of the currently
approved master formula and the method of preparation of
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 such records shall be designed to avoid transcription errors.
10.3.2 Checking work station.-- Before any processing begins, a
check shall be made that the equipment and work station are clear of
previous products, documents, or materials not required for the
planned process, and that the equipment is clean and suitable for use,
and this check shall be recorded.
10.3.3 Recording process operation.-- During processing, the
following information shall be recorded at the time each action is
taken, and after completion the record shall be dated and signed by
the person responsible for the processing operations, namely:-
(a) the name of the product;
(b) the number of the batch being manufactured; (c) date
and times of commencement of significant intermediate
stages and of completion of production; (d) the name of
person responsible for each stage of production;
(e) the initials of the operator(s) of different significant steps of
production and, where appropriate, of the person(s) who
checked each of these operations (e.g. weighing);
(f) the batch number and or analytical control number and the
quantity of each starting material actually weighed including the
batch number and amount of any recovered or reprocessed material
added;
(g) any relevant processing operation or event and the major
equipment used;
(h) the in-process controls performed, the initials of the
person(s) carrying them out, and the results obtained;
(i) the amount of product obtained at different and pertinent stages
of manufacture (yield), together with comments or explanation for
significant deviations from the expected yield; and
(j) notes on special problems including details, with signed
authorization for any deviation from the master formula.

10.4 Batch packaging records

10.4.1 General.-- A batch packaging record shall be kept for each
batch or part batch processed based on the relevant parts of the
packaging instructions, and the method of preparing such records
shall be designed to avoid transcription errors.
10.4.2 Pre-packing line checks.-- Before any packaging operation
beings, checks shall be made that the equipment and work station
are clear of previous products, documents or materials not required
for the planned packaging operations, and that equipment is clean
and suitable for use. There checks shall be recorded.

10.4.3 Recording of packaging operation.-- The following information

shall be recorded at the time each action is taken, and the date and
the person responsible shall be clearly identified by signature or
electronic password, namely:--
(a) the name of the product, the batch number, and the quantity of
bulk product to be packed, as well as the batch number and the
planned quantity of finished product obtained, the quantity actually
obtained, and the reconciliation;
(b) the date(s) and time(s) of the packaging operations; (c)
the name of the responsible person carrying out the
packaging operation;
(d) the initials of the operators of the different significant steps; (e)
the checks made for identity and conformity with the packaging
instructions, including the results of in-process controls;

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 (f) details of the packaging operations carried out, including
reference to equipment and the packaging lines used, and, when
necessary, the instructions for keeping the product un- packed or a
record or returning product that has not been packaged to the
storage area.
(g) whenever possible, samples of the printed packaging
materials used, including specimens bearing the batch
number, expiry date, and any additional overprinting;
(h) notes on any special problems, including details of any
deviation from the packaging instructions, with written
authorization by an appropriate person; and
(i) the quantities and reference number or identification of all
printed packaging materials and bulk product issued, used,
destroyed, or returned to stock and the quantities of product
obtained to permit and adequate reconciliation.

10.4.4 Recording batch numbers.-- Batch-number allocation shall be

immediately recorded in a logbook, and the record shall include
date of allocation, product identity, and size of batch.
10.4.5 Analytical records.-- Analysis records shall include at least the
following namely:--
(a) the name of the material or product and, where applicable,
dosage form;
(b) the batch number and, where appropriate, the
manufacturer and/or supplier;
(c) references to the relevant specifications and testing
procedures;
(d) test results, including observations and calculations, and
reference to any specifications (limits);
(e) dates of testing;
(f) the initials of the persons who performed the testing;
(g) the initials of the persons who verified the testing and the
calculations, where appropriate; and
(h) a clear statement of release or rejection (or other status
decision) and the dated signature of the designated responsible
person.

10.4.6 Finished product release procedure.-- Written release and

rejection procedures shall be available for materials and
products, and in particular for the release for sale of the
finished product by an authorized person.
10.4.7 Recording batch distribution.-- Records shall be maintained of the
distribution of each batch of a product in order to facilitate
the recall of the batch if necessary.
10.4.8 Standard operating procedures.-- Standard operating
procedures and associated records of actions taken or, where
appropriate, conclusions reached shall be available at the premises
for:--
(a) equipment assembly and validation; (b)
analytical apparatus and calibration;
(c) maintenance, cleaning, and sanitization;
(d) personnel matters including qualification, training, clothing, and
hygiene;
(e) environmental monitoring;
(f) pest control;
(g) complaints;
(h) recalls; and
(i) status.

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10.4.9 Equipment logbooks.-- Logbooks shall be kept with major and
critical equipment as identified by the licensee and shall record,
as appropriate, any validations, calibrations, maintenance, cleaning,
or repair operations including dates and the identity of the people
who carried out these operations.
10.4.10 Equipment utilization record.-- The use of major and critical
equipment and the areas where products have been
processed shall be appropriately recorded in chronological order.

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 PART-II
ADDITIONAL CONDITIONS FOR MANUFACTURE OF STERILE
PRODUCTS
In addition to the general conditions for manufacture of drugs by
way of formulation as described in Part-II of this Schedule, the
following additional conditions shall be followed for the manufacture
of sterile products.

SECTION—I
1 General
1.1 The production of sterile preparations shall be carried out in
clean areas, entry to which shall be through airlocks for personnel
and/or for goods. Clean areas shall be maintained to an appropriate
standard of cleanliness and supplied with air that has passed through
filters of an appropriate efficiency.

1.2 The various operations of component preparation (such as

containers and closures) product preparation, filling, and
sterilization shall be carried out in separate areas within the clean
area.

1.3 Clean areas for the production of sterile products are classified
according to the required characteristics of the air, in grades A, B, C
and D

1.4 Area Grade.-- Area grades must be selected by the

manufacturer on the basis of validation runs (e.g. sterile media fills.

2 Manufacture of sterile preparations

2.1 Manufacturing Operations Classifications are here divided into
three categories:
(a) Terminally sterilized product.-- Those in which the
preparation is sealed in its final container and terminally
sterilized;
(b) Products sterilized by filtration.-- The preparation is sterilized by
filtration;?
(c) Products manufactured under aseptic conditions.-- Those in
which the preparation can be sterilized neither by filtration nor
terminally and consequently must be produced from sterile starting
materials in an aseptic way.
2.2 Terminally sterilized products.-- Solutions shall generally be prepared
in a grade C environment in order to give how microbial and
particulate counts, suitable for immediate filtration and sterilization.
Solution preparation could be allowed in a
grade D environment if additional measures are taken to
minimize contamination, such as the use of closed vessels. For
parenteral, filing shall be done in a laminar-airflow workstation
(grade A) in a grade C environment. The preparation of other sterile
products, e.g., ointments, creams, suspensions and emulsions, and
filling of containers shall generally be done in a grade C environment
before terminal sterilization.
2.3 Products sterilized by filtration.-- The handling of starting
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 materials and the preparation of solutions shall be done in a
grade C environment. These activities could be allowed in a grade D
environment if additional measures are taken to minimize
contamination, such as the use of closed vessels prior to filtration.
After sterile filtration, the product must be handled and dispensed into
containers under aseptic conditions in a grade A or B area with a grade
B or C background, respectively.
2.4 Products manufactured under aseptic conditions.-- The handling
of starting materials and all further processing shall be done in a grade
A or B area with a grade B or C background respectively.
3. Personnel
3.1 General.-- Only the minimum number of personnel required shall
be present in clean areas, and it is particularly, important
during aseptic processes. Inspections and control shall be
conducted from outside the areas as far as possible.
3.2 Personnel training.-- All personnel, including those concerned
with cleaning and maintenance, employed in such areas shall receive
regular training for disciplines relevant to the correct manufacture of
sterile products, including reference to hygiene and to the basic
elements of microbiology. When outside staff who have not received
such training (e.g. building or maintenance contractors), need to be
brought in, particular care shall be taken over their supervision.

3.3 Entry restricted.-- Staff who have been engaged in the

processing of animal tissue materials or of cultures of microorganisms
other than those used in the current manufacturing process shall not
enter sterile-product areas unless rigorous and clearly defined
decontamination procedures have been followed.

3.4 Hygiene and cleanliness.-- High standards of personal hygiene

and cleanliness are essential and personnel involved in the
manufacture of sterile preparations shall be instructed to report
apparent illness or open lesion. Periodic health checks for such
conditions are desirable, and actions to be taken about personnel who
could be introducing undue microbiological hazard shall be decided
by a designated competent person.
3.5 Use of protective garments.-- Outdoor clothing shall not be
brought into the clean areas, personnel entering the changing rooms
shall already be clad in standard factory protective garments and
changing and washing shall follow a written procedure.

3.6 Clothing requirements.-- The clothing and its quality shall be

appropriate for the process in such a way so as to protect the
product from contamination.
3.7 Protective garments in grade B room.-- For every worker in a
grade B room, clean sterilized protective garments shall be provided
at each work session, or at least once a day if monitoring results
justify it, the gloves shall be regularly dis- infected during
operations, masks and gloves shall be changed at least at every
working session, and the use of disposable clothing may be followed
when possible.
3.8 Washing of clothing.-- Clothing used in clean areas shall be
washed or cleaned in such a way that it does not gather additional
particulate contaminants that can later be shed. Separate laundry
facilities for such clothing are desirable. If fibers are damaged by
inappropriate cleaning or sterilization there may be an increased risk
of shedding particles. Washing and sterilization operations shall
follow standard operating procedures.

3.9 Prohibitions.-- Wrist-watches and jewellery shall not be worn in

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 clean areas, and cosmetics that can shed particles shall not be
used, clothing shall be appropriate to the air grade of the area where
the personnel will be working, and the description of clothing
required for each grade is given below:
Grade D:-- The hair and, where appropriate, beard shall be covered,
protective clothing and appropriate shoes or long shoes shall be worn,
and appropriate measures shall be taken to avoid any contamination
coming from outside the clean area.

Grade C:-- The hair and, where appropriate, beard shall be covered,
a single or two-piece trouser suit, gathered at the wrists and with a
high neck and appropriate shoes or overshoes, shall be worn, and
the clothing shall shed virtually no fibers or particulate matter.

Grade B:-- Headgear shall totally enclose the hair and where
appropriate, beard; it shall be tucked into the neck of the suit, a face
mask shall be worn to prevent the shedding of droplets’ sterilized
non-powdered rubber or plastic gloves and sterilized or disinfected
footwear shall be worn; trouser-bottoms shall be
tucked inside the footwear and garment sleeves into the gloves, and
the protective clothing shall shed virtually no fibers or particulate
matter and shall retain particles shed by the body.

SECTION—2
4. Maintenance of clean area
4.1 General.-- Each manufacturing operation requires an
appropriate air cleanliness level in order to minimize the risks of
particulate or microbial contamination of the product or
materials being handled.
4.2 Airlock system.-- The entry to the sterile production areas shall be
through airlocks for personal and/or for materials. Airlocks
doors shall not be opened simultaneously, and an interlocking
system and a visual and/or audible warning system where
appropriate shall be operated to prevent the opening of more
than one door at a time.
4.3 Air supply system.-- A filtered air supply system of appropriate
efficiency, shall maintain a positive pressure relative to
surrounding area under all operational conditions and flush the area
effectively. Moreover particular attention shall be paid to the
protection of the zone of greatest risk that is, the immediate
environment to which the product and the cleaned components in
contact with it are exposed, and the various
recommendations regarding air supplies and pressure
differentials may need to be modified if it becomes necessary to
contain materials such as pathogenic, highly toxic, radioactive, or live
viral or bacterial materials. Decontamination facilities and the
treatment of air leaving a clean area may be necessary for some
operations.
4.4 Maintenance of equipment.-- When equipment maintenance is
carried out within the clean area, clean instruments and tools
shall be used, and the area shall be cleaned and dis-infected, where
appropriate, before processing recommences if the required standards
of cleanliness and/or asepsis have not been maintained during the
maintenance work.
4.5 Water supply.-- Water treatment plants shall not be operated beyond
their designed capacity and water shall be produced,
stored and distributed in a manner that prevents microbial growth
for example by constant circulation at 90C or at temperature validated
to keep microbial count of water within the limit.

23 / 37
 SECTION—3
5. Equipment maintenance
5.1 Documentation.-- All equipment, including sterilizers, air-
filtration systems, and water-treatment systems including still, shall
be subject to planned maintenance, validation and monitoring, and its
approved use, following maintenance work, shall be documented.

SECTION—4
6.1 Procedure.-- The sanitation of clean areas is particularly
important, they shall be cleaned frequently and thoroughly in
accordance with a written progress approved by the quality
control department, where disinfectants are used, more than one
type shall be employed with periodic alterations, the monitoring shall
be regularly undertaken in order to detect the emergence of resistant
strains of microorganisms, and in view of its limited effectiveness,
ultraviolet light shall not be used as a substitute for chemical
disinfection.
6.2 Use of disinfectants and detergents.-- Disinfectants and
detergents shall be monitored for microbial contamination. Dilutions
shall be kept in previously cleaned containers and shall not be
stored for long periods unless sterilized, and partly emptied containers
shall not be topped up.
6.3 Fumigation.-- Fumigation of clean areas may be useful reducing
microbiological contamination in inaccessible places, if required.
6.4 Monitoring of clean areas.-- Clean areas shall be monitored at
planned intervals during operations by means of microbial counts
of air and surfaces, where aseptic operations are performed,
monitoring shall be frequent to ensure that the environment is within
specifications, the results of monitoring shall be considered when
batches are assessed for approval, air particulate quality shall also be
evaluated on a regular basis, and additional monitoring is sometimes
desirable even when there are no production operations such as after
validation of systems, cleaning and fumigation.

SECTION—5
7. Processing
7.1 Precautions against contamination.-- Precautions to minimize
contamination shall be taken during all processing stages
including the stages before sterilization.
7.2 Preparations of live organisms.-- Preparations containing live
microbiological organisms shall not be made or containers filled in
areas used for the processing of other pharmaceutical products except
for validation purposes, however, vaccines of dead organisms or of
bacterial extracts may be dispensed into containers after validated
inactivation and validated cleaning procedures in the same premises
as other sterile pharmaceutical products.

24 / 37
7.3 Simulation of aseptic operations validation.-- The use of nutrient
media that support microbial growth in trials to simulate aseptic
operations, sterile media fills and broth fills, is a valuable part of
overall validation of an aseptic process, and such trials shall have the
following characteristics, namely:--

(a) they shall simulate as closely as possible actual operations, taking

into account such factors as complexity of operations, number of
personnel working, and length of time;

(b) the medium or media selected shall be capable of growing a wide-

spectrum of microorganisms, including those that would be expected
to be found in the filling environment; and

(c) they shall include a sufficient number of units of production to give

a high degree of assurance that low levels of
contamination, if present would be detected.
7.4 Monitoring water supply sources.-- Water sources, water-
treatment equipment and treated water shall be monitored regularly
for chemicals, biological contamination and contamination with
endotoxins to ensure that the water complies with the specifications
appropriate to its use. records shall be maintained of the results of the
monitoring and of any action.
7.5 Activities in clean areas kept minimum.-- Activities in clean
areas, especially when aseptic operations are in progress, shall be
kept to a minimum and the movement of personnel shall be
controlled and methodical to avoid excessive shedding of particles
and organisms due to over-vigorous activity, and the ambient
temperature and humidity shall, not be uncomfortably high because
of the nature of the garments worn.
7.6 Care of staring materials.-- Micro-biological contamination
(bioburden) of starting materials shall be minimal which shall be
monitored before sterilizations, and specifications shall include
requirements for microbiological quality when the need for this has
been indicated by monitoring.
7.7 Care against fibres.-- The presence of containers and materials
liable to generate fibers shall be minimized in clean areas and
avoided completely whole aseptic work is in progress.
7.8 Care after final cleaning of materials.-- Components, bulk-
product containers and equipment shall be handled after the final
cleaning process in such a way that they are not recontaminated,
and the stage of processing of component, bulk-product
containers, and equipment shall be properly identified.

7.9 Interval between operations to be minimal.-- The interval

between the washing and drying and the sterilization of components,
bulk-product container and equipment, as well as between
sterilization and use, shall be as short as possible and subject to a
time-limit appropriate to the validated storage conditions, similarly
the time between the start of the preparation of solution and its
sterilization or filtration through a bacteria-retaining filter shall be as
short as possible, and maximum permissible time shall be set for
each product that
takes into account its composition and the prescribed method of
storage.
7.10 Sterilization of gases used.-- Any gas that is used to purge a
solution or blanket a product shall pass through a sterilization
filter.
7.11 Bioburden to be minimal.-- The microbiological contamination of
products (bioburden) shall be minimal prior to sterilization, there

25 / 37
 shall be working limit on contamination immediately before
sterilization that is related to the efficiency of the method to be used
and the risk of pyrogens, all solutions in particular large- volume
parenteral, shall be passed through a micro-organism retaining filter,
if possible immediately before the filling process, and when aqueous
solutions are held in sealed vessels, any pressure-release outlets shall
be protected such as by hydrophobic microbial air filters.

7.12 Asepsis of articles in clean areas.-- Components, bulk-product

containers equipment and any other articles required in a clean area,
where aseptic work is in progress, shall be sterilized and, wherever
possible, passed into the area through double-ended sterilizers sealed
into the wall, and other procedures that achieved the same end of not
introducing contamination, such as triple wrapping, may be
acceptable in some circumstances.
7.13 New processes to be validated.-- The efficacy of any new
processing procedure shall be validated and the validation shall be
repeated at regular intervals thereafter or when any significant change
is made in the process of equipment.
SECTION—6
8 Sterilization
8.1 General.-- Sterilization can be achieved by moist or dry heat, by
ethylenoxide or other suitable gaseous sterilizing agent, by filtration
with subsequent aseptic filing of sterile final containers, or by
irradiation with ionizing radiation but not with ultraviolet radiation
unless the process is thoroughly validated each
method has its particular applications and limitations, and where
possible and practicable heat sterilization is the method of choice.

8.2 Validation.-- All sterilization processes must be validated and

particular attention shall be given when the adopted sterilization
method is not in accordance with prarmacopoeial or other national
standards or when it is used for a preparation that is not a simple
aqueous or oily solution.
8.3 Suitability of process.-- Before any sterilization process is adopted,
its suitability for the product and its efficacy in achieving the desired
sterilization conditions in all parts of each type of load to be
processed shall be demonstrated and this
work shall be repeated at scheduled intervals, at least annually,
and whenever significant modifications have been made to the
equipment, and records shall be kept of the results.
8.4 Care for biological indicators.-- Biological indicators shall be
considered only as an additional method for monitoring the
sterilization, and if they are used, strict precautions shall be taken to
avoid transferring microbial contaminations from them.
8.5 Sterilized not sterilized product differentiation.-- There shall be a
clean means of differentiating products that have not been
sterilized from those that have and each basket, try, or other carrier
of products or components shall be clearly labelled with
the name of the material, its batch number and an indication of
whether or not it has been sterilized, and indicators such as autoclave
tape may be used, where appropriate, to indicate
whether or not a batch, or sub-batch, has passed through a
sterilization process, but they do not give a reliable indication that
the lot is, in fact, sterilize.
9 Sterilization by heat
9.1 Recording sterilization cycle.-- Each heat sterilization cycle shall
be recorded by appropriate equipment with suitable accuracy
and precision such as time and temperature chart with a suitably large
scale, the temperature shall be recorded from a probe at

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 the coolest part of the load or loaded chamber having been
determined during the validation. The temperature shall preferably, be
checked against a second independent temperature probe located at the
same position, the chart, or a photocopy of it, shall form part of the
batch record, and chemical or biological indicators may also be used
but shall not take the place of physical controls.

9.2 Sufficient time allowed to reach required temperature.--

Sufficient time must be allowed for the whole of the load to reach
the required temperature before measurement of the sterilizing time
is started and this time must be determined for each type of load to
be processed.
9.3 Precautions during cooling.-- After the high-temperature phase
of a heat sterilization cycle, precautions shall be taken against
contamination of a sterilized load during cooling, and any
cooling fluid or gas in contact with the product shall be sterilizer,
unless it can be shown that any leaking container would not be
approved for use.
10 Sterilization by moist heat
10.1 General.-- Sterilization by moist heat is suitable only for water-
wettable materials and aqueous solutions, both temperature and
pressure shall be used to monitor the process, the temperature recorder
shall normally be independent of the temperature regulator and there
shall be an independent temperature
indicator, the reading from which is 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, and there shall be regular leak test on the chamber when a
vacuum phase is part of the cycle.
10.2 Wrapping materials.-- The items to be sterilized, other than
products in sealed containers, shall be wrapped in a material
that allows removal of air and penetration of steam but prevents
recontamination after sterilization and all parts of the load shall be in
contact with water or saturated steam at the required
temperature for the required time.
10.3 Care shall be taken to ensure that steam used for sterilization is of
suitable quality and does not contain additives at a level that
could cause contamination of the product or equipment.
11. Sterilization by dry heat
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, if air is supplied,
it shall be passed through a microorganism-retaining filter, and where
this process of sterilization by dry heat is also intended to remove
pyogens, challenge tests using endotoxins would be required as part of
the validation.
12. Sterilization by radiation
12.1 General.-- Radiation sterilization is used mainly for the
sterilization on heat-sensitive materials, and products, many
pharmaceutical products and some packaging materials are radiation-
sensitive, so this method is permissible only when the absence of
deleterious effect on the product has been confirmed experimentally,
and ultraviolet irradiation is not acceptable method for terminal
sterilization.
12.2 Outside contractor.-- If radiation sterilization is carried out by an
outside contractor, the manufacturer has the responsibility of ensuring
that the requirements of section 12.1 are met and that the sterilization
process is validated and the responsibilities of the radiation plant
operator, such as the right does, shall also be

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 specified.
12.3 Measurement of radiation.-- During the sterilization procedure
the radiation dose shall be measured and for this purpose,
dosimeters that are independent of dose rate shall be used giving a
quantitative measurement of the dose received by the product itself,
dosimeters shall be inserted in the load in sufficient number and
close enough together to ensure that there is always a dosimeter on
the chamber; where plastic dosimeters are used, they shall be used
within the time-limit of their calibration, dosimeter absorbance shall
be read within a short period after exposure to radiation. Biological
indicators may be used only as an additional control. Radiation-
sensitive
colour discs may be used to differentiate between packages that have
been subjected to irradiation and those that have not; they are not
indicators of successful sterilization. The information obtained shall
constitute part of the batch record, and the total radiation dose shall be
administered within a predetermined time span.

12.4 Validation.-- Validation procedures shall ensure that

consideration is even to the effect of variations in the density of the
packages.
12.5 Handling procedures.-- Handling procedures shall prevent any
mix-up between irradiated and non-irradiated materials. Each
package shall carry a radiation-sensitive indicator to show whether
or not it has been subjected to radiation treatment.
13. Sterilization by ethylene oxide
13.1 General.-- Various gases and fumigants may be used for
sterilizations, ethylene oxide shall be used only when no other
method is practicable. During process validation it shall be shown
that the gas has no damaging effect on the product and that the
conditions and time allowed for degassing are such as to reduce any
residual gas and re-action products to defined acceptable limits for
the type of product or material, and these limits shall be incorporated
into the specifications.
13.2 Ensure contact between gas and microbial cells.-- Direct contact
between gas and microbial cells is essential, precautions shall
be taken to avoid the presence of organisms likely to be enclosed in
material such as crystals or dried protein, and the
nature and quantity of packaging materials can significantly
affect the process.
13.3 Equilibrium with humidity and temperature.-- Before exposure to
the gas, materials shall be brought into equilibrium with the humidity
and temperature required by the process. The time required for this
shall be balanced against the opposing need to minimize the time
before sterilization.
13.4 Monitoring each cycle.-- Each sterilization cycle shall be
monitored with suitable biological indicators, using the
appropriate number of test pieces distributed throughout the
load, and the information so obtained shall form part of the batch
record.
13.5 Biological indicators.-- Biological indicators shall be stored and
used according to the manufacturer’s instructions and their
performance checked by positive controls.
13.6 Record maintenance.-- For each serialization cycle, records
shall be made of the time taken to complete the cycle of the pressure,
temperature, and humidity within the chamber during the process
and of the gas concentration, the pressure and temperature shall be
recorded throughout the cycle on a chart and the records shall form
part of the batch record.
13.7 Validation.-- After sterilization, the load shall be stored in a

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 controlled manner under ventilated conditions to allow residual
gas and re-action products to fall to the defined level, and this
process shall be validated.
14. Filtration of pharmaceutical products that cannot be sterilized in the final container.
14.1 General.-- Whenever possible, products shall be sterilized in the final
container preferably by heat sterilization. Certain solutions
and liquids that cannot sterilized in the final container can be filtered
through a sterile filter of nominal pore size 0.22um or less, or with a
least equivalent microorganism-retaining properties into a previously
sterilized container, such filters can remove bacteria and moulds, but
not all viruses or
mycoplasmas.
14.2 Using double filter layer.-- Owing to the potential additional risks
of the filtration method as compared with other sterilization
processes, a double filter layer or second filtration via a further
sterilized microorganism-retaining filter immediately prior to filling
may be advisable and the final sterile filtration shall be carried out
as close as possible to the filling point.
14.3 Eliminate fibres.-- Filters that shed fibres shall not be used and
the use of asbestos-containing filters shall be absolutely
excluded.
14.4 Checking integrity of filters.-- The integrity of the filter shall be
checked by an appropriate method such as a bubble point test
immediately after each use, it may also be useful to test the filter in
this way before use, the time taken to filer a known volume of bulk
solution and the pressure difference to be used across the filter shall be
determined during validation and any significant differences from this
shall be noted and investigated. Results of these checks shall be
recorded in the batch record.
14.5 Frequency of use of filter.-- The same filter shall not be used for
more than one working day unless such use has been validated.
14.6 Filter safety.-- The filter shall not affect the product by removal of
ingredients from it or by release of substances into it.
15. Finishing of sterile products
15.1 General.-- Containers shall be closed by appropriately validated
methods, and samples shall be checked for integrity according to
appropriate procedures.
15.2 Use of vacuum.-- Containers sealed under vacuum shall be
sampled and the samples tested for maintenance of that vacuum after
an appropriate pre-determined period.
15.3 Inspection of containers.-- Filled containers of parenteral products
shall be inspected individually, when inspection is done
visually it shall be done under suitable and controlled conditions of
illumination and background, operators doing the inspection shall pass
regular eyesight checks, with spectacles if worm, and be allowed
frequent breaks from inspection, and where other methods of
inspection are used, the process shall be validated
and the performance of the equipment checked at intervals.
SECTION—7
16. Quality control
16.1 Sterility testing.-- Samples taken for sterility testing shall be
representative of the whole of the batch but shall, in particular,
include samples taken from parts of the batch considered to be most
at risk of contamination, such as:-- (a) for products
that have been filled aseptically, samples shall include containers
filled at the beginning and end of the batch and after any
significant interruption of work; and

(b) for products that have been heat sterilized in their final containers,
and samples can be taken from any part of the load.
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16.2 Sterility test as the last measures.-- The sterility test applied to
the finished product shall be regarded only as the last in a series of
control measures by which sterility is assured and can be interpreted
only in conjunction with the environmental and batch processing
records.
16.3 Monitoring endotoxins.-- For injectable products, consideration
shall be given to monitoring the water and the intermediate and
finished product for endotoxins, using an established pharmacopoeial
method that has been validated for each type of product, for large-
volume infusion solutions, such monitoring of water or intermediates
shall always be done, in addition to any tests required by the marketing
authorization on the finished product, and when a sample fails a test,
the cause of failure shall be investigated and remedial action taken
where necessary.

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 SCHEDULE B-III
[See rule 20 (b)]
PARTICULARS TO BE SHOWN IN MANUFACTURING
RECORDS
A. Substances Parenteral preparation in general: Remarks
1. Serial Number.
2. Name of the drug.
3, Batch Size,
4. Batch number.
5. Date of commencement of manufacture and date when
manufacture was completed,
6. Name of all ingredients, quantities required for the batch size,
quantities actually used. (All weighing and measurements shall be
checked initiated b¥ the competent person in the section).
7. Control reference numbers in respect of raw materials used in
formulation.
8. Date of mixing in case of dry products, e.g., powder, powder
mixture for capsule products, etc.
9. Date of granulation wherever applicable.
10. Weight of granules.
11. Date of compression in case of tablets/date of filling in case of
capsules.
12. Dates of coating wherever applicable.
13. Records of test to be carried out in case of tablets as under
(a) Average weight every thirty minutes.
(b) Disintegration time as often as practicable.
14. Records of readings taken to check weight variation in case of
capsules,
15. Reference to Analytical Report number stating whether of
standard quality or otherwise.
16, Records on the disposal of rejected batches and batches with-
drawn from the market.
17, Actual production and packing particulars indicating the size and
quantity of finished packings,
18. Date of release of finished packings for distribution or sale,
19. in case of Hypodermic tablets and ophthalmic preparations which
are required to be manufactured under aseptic conditions, records shall
be maintained indicating the precautions taken during the process of
manufacture to ensure that aseptic conditions are maintained,
20. Signature of the expert staff responsible for the manufacture,

B. Parenteral preparation:

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1. Serial Number,
2. Name of the drug,
3. Batch Size,
4. Batch number (if bulk lot is divided into various batches and processed
separately, a batch number distinctly different from that of the bulk lot
should be assigned to each of the processed batch),
5. Date of commencement of manufacture and date of completion.
6. Name of all ingredients, quantities required for the lot size, quantities
actually used. (All weighings and measurements shall be checked and
initialled by the competent person in the section).
7. Control reference numbers in respect of raw materials used.
8. PH of the solution wherever applicable.
9. Date and methods of filtration.
10. Sterility test reference on bulk batch wherever applicable. (If bulk lot is
divided into various batches and processed separately, a batch number
distinctly different from that of the bulk lot should be assigned to each of the
processed batch.
11. Date of filling.
12. Records of tests employed :--
(a) To ensure that sealed ampules are leak-proof, (b)
To check the presence of foreign particles.
(c) For pyrogens wherever applicable.
13. Records of sterilisation in case of parenteral preparation which are
heat sterilised including particulars of time temperature and pressure
employed.
14. Number and size of containers filled and number rejected.
15, Reference to Analytical Report numbers stating whether of
standard quality or otherwise.
16. Records of the disposal of rejected batch and batches with-drawn from
the market.
17. Actual production and packing particulars.
18. Date of release finished packings for distribution or sale.
19. Particulars regarding the precautions taken during manufacture to ensure
that aseptic conditions are maintained.
20. Control reference numbers in respect of the lot of glass
containers used for filling.
21. Signature of the expert staff responsible for manufacture.

II. RECORDS OF RAW MATERIALS

Records in respect of each raw material shall be maintained indicating the
quantity received, control reference numbers, the quantities issued from
time to time, the names and batch Nos. of the products for the manufacture
of which the quantities have been issued and the particulars relating to the
proper disposal of the stocks.

III. PARTICULARS TO BE RECORDED IN THE ANALYTICAL RECORDS

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A. Tablets and capsules:
1. Analytical report number.
2. Name of the sample.
3. Date of receipt of sample,
4. Batch number.
5. Protocols of tests applied:
(a) Description.
(b) Identification.
(c) Uniformity of weight.
(d) Uniformity of diameter (if applicable).
(e) Disintegration test (time in minutes). (f)
Any other tests.
(g) Results of assay.
6. Signature of the Analyst.
7. Opinion and signature of the approved Analyst.
B. Parenteral Preparations

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 1. Analytical report number.
2. Name of the sample.
3. Batch number.
4, Date of receipt of sample.
5. Number of containers filled.
6. Number of container packed
7. Protocols of tests applied
(a) Clarity,
(b) PH wherever applicable
(c) Identification.
(d) Volume in container,
(e) Sterility--(/) Bulk sample wherever applicable (ii) container sample. (f)
Pyrogen test, wherever applicable.
(g) Toxicity test, wherever applicable. (h)
Any other teats.(i) Results of assay.
8. Signature of the Analyst.
9, Opinion and signature of the approved Analyst
Pyrogen Tests:-
1. Test Report number.
2. Name of the sample.
3. Batch number.
4. Number of rabbits used.
5. Weight of each rabbit.
6. Normal temperature of each rabbit.
7. Mean initial temperature of each rabbit,
8. Dose and volume of solution injected into each rabbit and time of
injection.
9. Temperature of each rabbit noted at suitable intervals,
10. Maximum temperature.
11. Response.
12. Summed response,
13. Signature of the Analyst,
14. Opinion and signature of the approved Analyst
Toxicity Test:
1. Test Report number.
2. Name of the Sample
3, Batch number
4. Number of mice used and weight of each mouse, Strength and
volume of the drug injected,
6, Date of injection,
7. Results and remarks,
8. Signature of Analyst,
9. Opinion and signature of the approved Analyst.

C. For other drugs:

1.Analytical report number
2. Name of the sample
3. Batch number.
4, Date of receipt of sample
5. Protocols of tests applied:
(a) Description.
(b) Identification. (c)
Any other tests (d).
Results of assay.
6. Signature of the Analyst.
7. Opinion and signature of the approved Analyst.

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D. Raw materials:
1. Serial number
2. Name of the material
3. Name of the manufacturer/supplier.
4. Quantity received.
5. Invoice/Challan number and date.
6. Protocols of tests applied.

E. Container, packing material, etc.:

1. Serial number.
2. Name of the item.
3. Name of the manufacturer/supplier.
4. Quantity received.
5. Invoice/Challan number and date.
6, Results of tests applied.
Note: Particulars regarding various tests applied shall be maintained and
necessary reference to these records shall be entered serial No.
6 wherever necessary.
7. Remarks.
8. Signature of the examiner.

Manufacturer’s A B C D
over all rating Good Fair Poor Non-compliance
Compliance l Compliance Compliance
Consequences Needs Needs active Needs active Stoppage of
improvements improvements improvements and production and
stoppage of cancellation of
production License

Recommendations / desired action:

Names and signatures of Names and signatures of Production /

Inspectors / Panel QC Incharge / Plant Manager

Note:
i. The format provides guidance to the Inspectors for reporting, so that no mandatory parameters are
left unreported.
ii. Adequate space may be provided for reporting as may be needed, by using soft copy.
iii. Mark “N.A.” against the parameter which is Not Applicable, with reasons thereof.
iv. Take in to consideration non compliance to the „Critical Parameters‟ which may endanger public
health and report accordingly.
Annex-I
Detailed list of Machinery/ Equipment

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S. No. Name Validation/ Calibration status Capacity/ shift Section

Annex-II
Detailed list of Management and technical staff

S.No. Name Designation Qualification Experience Section

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37 / 37