CURRENT GOOD MANUFACTURING PRACTICES
NOTIFIED ON MAY 15, 1998 UNDER DRUGS ACT 1976 AND
DRUGS (LICENSING, REGISTERING AND ADVERTISING) RULES 1976.
AS PREVIOUSLY PUBLISHED BY:
MINISTRY OF HEALTH, (NOW DEFUNCT)
GOVERNMENT OF PAKISTAN
Islamabad, the 15th May 1998
S.R.O. 470(I)/98, - In exercise of the powers conferred by section 43 of the
Drugs Act, 1976(XXXI of 1976), the Federal Government of Pakistan to direct that
the following further amendments shall be made in the Drugs (Licensing, shall be
made in the Drugs (Licensing , Registering and Advertising) Rules , 1976, the
same having been previously published as required by sub-section (3) of the said
section, namely :-
In the aforesaid Rules-
I. For rule 2 the following shall be substituted, namely :-
2. Definitions In these rules, unless there is anything repugnant in the subject
(a) “active pharmaceutical ingredient” means a substance pharmacologically
active compound (ingredient);
(b) “airlock” means an enclose space with two or more doors, which is interposed
between two or more rooms of differing classes of cleanliness for the purpose of
controlling the airflow between those rooms when they need to be entered and an
airlock is designed for and used by either people or goods;
(c) “authorized person responsible for the release of batches of product for
(d) “basic manufacture” means manufacturer of a drug from basic raw material to
a product which is ready for use as a staring material for the formulation of a
finished drug or for repacking and such manufacture may involve chemical ,
bio-chemical, photochemical, microbial or such other processes or a combination
of any of such processes;
(e) “batch (or lot)” means a defined quantity of starting material, packaging
material, or finished product processed in a single process or series of
processes so that it could be expected to be homogeneous, in the case of
continuous manufacture the batch must correspond to complete to be homogeneous,
in the case of continuous manufacture the batch must correspond to a defined
fraction of the production , characterized by its intended homogeneity, and to
complete certain stages of manufacture it may sometimes be necessary to divide a
batch into a number of sub-batches, which are later brought to form a final
(f) “batch number (or lot number)” means a distinctive combination of numbers
and or letters which specifically identifies a batch on the labels , the batch
to be trace and revived.
(g) “batch numbering system” means a standard operating procedure describing the
details of the batch numbering;
(h) “batch records” means all documents associated with the manufacture of a
batch of bulk product or finished product showing a history of each batch of
product and of all circumstances pertinent to the quality of the final product;
(i) “biological agents” means micro-organisms, including genetically engineered
microorganisms, cell cultured and endoparasites, whether pathogenic or not ;
(j) “biological agents” means micro-organisms, including genetically engineered
micro organisms, cell culture and end parasites, including final packing;
(k) “calibration” means the set of operations that established, under specified
conditions, the relationship between values indicated by an instruments or
meaning system for especially weighing, recording, and controlling, or the
values relationship between values indicated by an instrument or measuring
system for especially weighing, recording, and controlling, or the values
represented by a material measure, and the corresponding known values of a
reference standard and the limits for acceptance of the results;
(l) “Clean area” means an area with defined environments control of particulate
and microbial contamination, constructed and used in such a way as to reduce and
or eliminate introduction, generation, and retention of contaminants within the
(m) “compounding” means scientific combination of two or more ingredients with a
view to make a finished;
(n) “consignment or delivery” means the quantity of starting material, or of a
drug product, made by one manufacturer and supplied at one time in response to a
particular request or order, a consignment may comprise one or more packages or
containers and may include material belonging to more than one batch;
(o) “critical process” means a process that may cause variation in the quality
of the pharmaceutical product;
(p) “cross-contamination” means of a starting material, intermediate product, or
finished product with another starting martial or drug during production;
(q) “finished product” means a product that has undergone al stags of
production, including packaging in its final container and labeling;
(r) “Form” means a form set forth in Schedule A;
(s) “formulation” means all operations involved in converting a drug into a
final pharmaceutical dosage form ready for use as a finished drug including
compounding, processing, formulating, filling, packing, finishing, labeling, and
other like processes;
(t) “good manufacturing practices for pharmaceutical products” means part of
quality assurance which:-
(u) “half-finished product” means any material or mixture of materials that has
to undergo further manufacture;
(v) “in-process control” means checks performed during production in order to
monitor and if necessary to adjust the process to ensure that the product
conforms to its specifications and control of the environment or equipment may
also be regarded as a part of in-process control;
(w) “intermediate product” means partly processed material that must undergo
further manufacturing steps before it becomes a bulk product;
(x) “large-volume parenteral” means sterile solutions intended for parenteral
application with a volume of more than 100 ml one container of the finished
(y) “manufacturer” means all operations of production , quality control,
release, storage and the related controls;
(z) “manufacturer” means a company that carries out at least one step of
(aa) “manufacturer authorization” means a document, issued by the Drug
Registration Board set up under the Drugs Act, 1976, as a certificate of drug
(ab)“master formula” means a document or set of documents specifying the
starting materials with their quantities and the packaging materials , together
with a description of the procedures and precautions required to produce a
specified quantity of a finished product as well as the processing instructions,
including the in-process controls;
(ac) “master record” means a documents or set of documents that as a basis for
the batch documentation (blank batch record);
(ad) “new drug” means drug that has not been commonly sold or distributed to the
public in Pakistan and is introduced for the first time;
(ae) “Ordinance” means the Drug s Ordinance, 1976(IV of 1976)
(af) “Packing” means all operations, including filling and labeling which a
bulk drug has to undergo in order to become a finished product;
Note : Sterile filling would not normally be regarded as part of packaging,
the bulk product being the filled , but not the finally packaged, primary
(ag) “Packing material” means any a material, including printed material,
employed in the packing of a pharmaceutical product, excluding any outer
packaging used for transportation or shipment and packaging material are
referred to as primary or secondary according to whether or not they are
intended to be in direct contact with the product;
(ah) “Pharmaceutical product” means any drug intended for human use or
veterinary use presented in its finished dosage form or as a starting material
for use in such a dosage form;
(ai) “Processing instruction or procedures” means as defined include (ab) of
(aj) “production” means all operations involved in the preparation of a
(ak) “Purity” means the degree to which other chemical or biological entities
are present in any substance;
(al) “quality assurance” means the totality of the arrangements made with the
object of ensuring that pharmaceutical products are of the quality required for
their intended use and so incorporates good manufacturing practices , Quality
Control and other factors including design and development and good laboratory
(am) “quality control” means the part of good manufacturing practices concerted
with sampling, specifications, and necessary and relevant tests are actually
carried out and that materials are not released for use, nor finished products
released procedures which ensure that the necessary and relevant tests are
actually carried out and that materials are not released for use , nor finished
products released for sale or supply until their quality has been judged to be
satisfactory and it is involved in all decision concerning the quality of the
(an) “quarantine” means status of starting or packing materials, intermediates,
or bulk or finished products isolated physically or by other effective means
while a decisions concerning the quality of the product;
(ao) “ reconciliation” means a comparison, making due allowance for normal
variation between the amount of product or used and the amount actually produced
or used and the amount actually produced or used;
(ap) “recovering or blending” means the introduction of all or part of previous
batches or of redistilled solvents and similar prints of the requires quality
into and the batch at defined stage of manufacture;
(aq) “repacking “ means all operations involved in the transfer of a drug from a
larger container or packing into smaller xontanes or pickings including filling,
packing and labeling with a view to make it ready for retail sale or wholesale,
but does not includes any compounding , or processing with a view to formulate
it in any dosage form;
“Retail Sale” means a sale other than wholesale.
(as)”reprocessing” means the reworking of all or part of a barh of product of an
unacceptable quality from a refined sage of production so that its quality may
be rendered acceptable by one or more additional operators;
(at)“returned product” means finished product sent back to the manufacturer or
(au) “schedule” means schedule to these rules:
(av) “semi-basic manufacture means manufacture from an intermediate substance of
a drug to be used as starting material for the formulation of a finished drug or
to be used for repacking;
(aw) “specification” means the requirements with which the products or materials
udder or obtained during manufacture must confirm as specified in the Drugs
(Specification) Rules, 1978;
(ax) “standard operating procedure” means an authorized written procedure
including instructions for performing operations not necessarily specific to a
given product or material but of amore general nature such as control sampling
and inspection, and certain standard operating procedures may be used to
supplement specific master batch production documentation;
(ay) “Starting material” means any substance used in the production of
pharmaceutical product but excluding packing materials;
(az) “system” means a regulated pattern of interacting activities and techniques
which are united to form an organized whole;
(ba) “validation” means the documents fact of proving that any procedure
process, equipment, material, activity or system works correctly and actually
leads to the expected results ; and
(bb) “wholesale” means sale to a person who purchases for the purpose of selling
again and includes sale to a hospital or dispensary, or to medical, educational
or research institute.
11. In rule 16:-
A. in clause(a) for the Schedule B the following shall be substituted, namely:-
1. Location and Surroundings
2. Building Layout And Its Pre-Approval
3. Building Design And Construction (General)
3.3 Protection Against Insects etc
4. Storage Area
4.6 Rejected Material
4.7 Special Material
4.8 Packaging Material
4.9 Weighing Area
5. Production Department
5.1 General Facilities
5.2 Dedicated Facilities for Production
5.3 General Requirements for Production
(vi) Environmental Controls
6. Ancillary Area
6.1 Rest Rooms
6.2 Changing Rooms
6.4 Animal House
EQUIPMENT FOR PRODUCTION
2.7 Cleaning Equipment
2.8 Defective Equipment
QUALITY CONTROL DEPARTMENT
(iii) Written Procedures
CONTITIONS FOR GRANT OF A LICENSE TO MANUFACTURE DRUGS BY WAY OF FORMUATION
1. Location and surroundings.
1.1 Location : The premises shall be located preferably in an industrial area
and in any case not in any congested residential or commercial area.
1.2 Surroundings : Premises shall be situated in an environment that, when
considered together with measures to protect the manufacturing processes,
presents minimum risk of causing any contamination of materials or products. It
shall be away from filthy surroundings and shall not be adjacent to an open
sewerage, drain, public lavatory or any factory which products. It shall be away
from filthy surroundings and shall be adjacent to an open sewerage, drain,
public lavatory or any factory which products a disagreeable or obnoxious odor
or fumes or large quantities of soot, dust or smoke which may contaminate the
drugs being manufactured or adversely affect their quality. Existing units shall
keep the surroundings under their control to be clean.
1.3 Size: The size of the plot shall be less than 2000 square yards.
2. Building layout and its pre-approval .The building shall be of adequate size
and suitable design and construction in view of the need for drugs to be
manufactured and to suit the operations to be carries out. The site and layout
plan of building shall be not approval from the central Licensing Board or
person authorized by it in this behalf before starting construction of the
building and any minor subsequent change in the layout plan will be communicated
as and when made with a revised updated layout plan at the time of renewal of
Drug Manufacturing License.
3. Building, design and construction (General) .
3.1 General : The layout and design shall aim at minimization the risk of
errors, facilitate good sanitation and permit effective cleaning and maintained
in order to avoid cross contamination , build-up of dust or dirt, and in general
, any adverse effect on the quality of products.
3.2 Services: Electrical supply, lighting, temperature and humidity controls and
ventilation shall be appropriate and such that they do not adversely effect,
directly or indirectly either the pharmaceutical products during their
manufacture and storage, or the accurate functioning of equipment.
4.2 Specifications & Testing Procedures
(i) Reference Books
(ii) Testing Procedures
4.3 Specifications for Starting and Packing Materials
4.4 Specifications For Starting and Packaging Materials
4.5 Mater Formula
4.6 Packing Instructions
4.7 Standard Operating Procedures (SOPs) and Records
4.8 S.O. Ps for Testing
4.9 S.O.Ps for Sanitation
4.10 S.O.Ps Miscellaneous
4.12 Batch Processing records
SANITAON AND HYGIENE
3.4 Surfaces : In arrears where raw materials, in-process materials or drugs are
exposed, the following general condition shall apply to the extent necessary
prevent contamination, namely :-
(i) floors, walls, and ceilings/permit easy cleaning, brick , cement blocks, and
other porous materials are sealed;
(ii) floors, walls, ceilings, and other surfaces are hard, smooth, and free of
sharp corners where extraneous material can collect;
(iii) joints are sealed between walls, ceilings and floors;
(iv) pipes, light fittings, ventilation points and other services do not create
surfaces that can not be cleaned; and
(v) screened and trapped floor drains are provided if required.
4. Storage areas.
4.1 Capacity: Storage area shall be properly defined of sufficient capacity to
allow orderly storage of virus categories of materials and products in
quarantine, and released, rejected, returned ,or recalled products.
4.2 Design: Storage areas shall be designed or adapted to ensue good storage
conditions. In particular, they shall be clean and dry , suitably lit and
maintained within acceptable temperature limits which should be commensurate
with storage requirements of the drugs. Where special storage conditions are
required (e.g., controlled temperature and humidity) these shall be provided,
checked, and monitored.
4.3 Bays: Receiving and dispatch bays shall protect materials and products from
the weather, Reception areas shall be designed and equipped to allow containers
of incoming materials to be cleaned if necessary before storage.
4.4 Quarantine: Well defined quarantine area shall be provided for the incoming
materials, in process materials and finished drugs. Where quarantine status is
ensured by storage in separate areas, these areas shall be clearly marked and
their access restricted to authorized personnel. Any system replacing the
physician quarantine shall be given equivalent security.
4.5 Sampling: These shall normally be a separate sampling area for starting
materials. If sampling is to be performed in the storage area, it shall be
provided for the storage of rejected, recalled, or returned materials, or
4.6 Rejected Materials: Segregation in a separate area shall be provided for the
storage of rejected, recalled, or returned materials or products.
4.7 Special Materials : Highly active materials, narcotics, other dangerous
drugs, and substances presenting special risks of abuse , fire or explosion
shall be stored in safe an secure areas.
4.8 Packaging Materials : Printed packing materials are considered critical to
the conformity of the pharmaceutical product to its labeling, and special
attention shall paid to safe and secure storage of these materials .
4.9 Weighing Area : The weighing of starting materials on the basis of
estimation of yield shall be carried out in separate weighing areas designed for
that use with provisions for dust control. Separate provisions shall be made for
materials posing high risks of contamination, like steroids and antibiotics
5. Production Department.
5.1 General Facilities : A Production Department shall be provide which shall
have all necessary facilities including:-
(i) adequate number of appropriately qualified and trained technical personnel;
(ii) adequate and properly planned areas;
(iii) suitable equipment, instruments and containers for manufacture including
their validation where necessary;
(iv) Clearly defined manufacturing processes shown to be capable of consistently
manufacturing pharmaceutical products of the required quality and complying with
(v) validated critical steps of manufacturing processes;
(vi) Procedure and instructions for working approval by the Quality Control
(vii) suitable storage places for in process materials;
(viii) adequate number of technically trained and skilled personnel and
equipment for in-process controls;
(ix) skilled operations trained to carry out procedures correctly, the record of
training should be available; and
(x) appropriate air handling system to avoid contamination and cross
5.2 Dedicated facilities for production.
Dedicated and self-contained facilities for the production of particular drugs
shall be provide in addition to the general facilities such as highly sanitizing
materials (e.g., penicillin) or biological preparations (e.g., love
microorganisms) or cytotoxic substances or radiopharmaceutical or veterinary
immunological preparations or sterile products or for that matter such other
highly active pharmaceutical products, antibiotics, hormones as may be
identifies by the Central Licensing Board at any stage in order to minimize the
risk of a serious medical hazard due to cross contamination. Veterinary products
containing ingredients similar to those used for human health and of the same
quality can be manufactured in the same premises use for manufactured of
pharmaceutical products, however, simultaneously human drugs shall not be
manufactured. Non-pharmaceutical products, technical poisons, such as pesticides
shall not be manufactured. Non-Pharmaceutical products , however ,
simultaneously human drugs shall not be manufactured in the same premises
already use for the manufacture of pharmaceutical products. In exceptional cases
of emergency, the principle of campaign working in the same facilities may be
allowed by the Central Licensing Board provided that specific precautions are
taken and the necessary validations are made.
5.3 General requirements for production areas.
(i) Layout: The production area shall be laid out in such a way as to allow the
production to take place in areas connected in a logical order corresponding to
the sequence of the operations and to the requisite cleanliness levels.
(ii) Adequacy : The adequacy of the working and in process storage space shall
permit the orderly and logical placement of equipment and materials so as to
minimize the risk of confusion between different pharmaceutical products or
their components, to avoid cross contamination, and to minimize the risk of
omission error or working application of any of the manufacturing or control
(iii) Surfaces : Starting and primary packaging materials and intermediate or
bulk products are exposed to the environment, interior surfaces (walls, floors,
and ceilings) shall be smooth and free from cracks and open joints shall not
shed particulate matter, and shall permit easy effective cleaning and , if
(iv) Services : Pipe work, light fittings, ventilation points and other services
shall be designed and sided to avoid the creation of recesses that are difficult
to clean. As far as possible, for maintenance purposes, they shall be accessible
from outside the manufacturing areas.
(v) Drains : Drains shall be of adequate size and equipped to prevent back-flow.
Open. Channels shall be avoided.
(vi) Environmental Controls : Production areas shall be effectively ventilated,
with air-control facilities (including control of temperature and, where
necessary, humidity and filtration ) appropriate to the products handled to the
operations undertaken, and to the external environment. These areas shall be
regulatory monitored during production and non-production periods to ensure
compliance with design specifications.
(vi) Packaging : Area (s) for the packing of pharmaceutical products shall be
specifically designed and laid out so as to avoid mix-ups or cross
(vii) Light :Production areas shall be well lit, particularly where visual
on-line controls are carried out.
6. Ancillary areas.
6.1 Rest rooms : Rest and refreshment rooms shall be separate from other areas.
6.2 Changing rooms : Facilities shall be provided for changing and storing
clothes and for washing and toilet purposes which shall be easily accessible and
appropriate for the number of users. Toilets shall not communicate directly with
production or storage areas.
6.3 Workshop : Maintenance workshop shall perfectly be separated from production
areas. Whenever parts and tools are stored in the production area, they shall be
kept in rooms or lockers reserved for that use.
6.4 Animal houses :Animal houses shall be well isolated from other areas, with
separate entrance (animal access) and air-handing facilities.
SECTION – 2
EQUIPMENT FOR PRODUCTION
2.1 General: The all necessary equipment shall be provided which
shall be so designed, constructed, located installed and maintained as to suit
the operation to be carried out, and the layout and design of equipment must aim
to minimize the risk of errors and permit effective cleaning and maintenance in
order to avoid cross-contamination, build-up of dust or dirt, and, in general,
any adverse effect on the quality of products.
2.2 Layout: The equipment shall be so laid that: -
(a) Permits it to function in accordance with its intended use. Parts in
contact with raw material, in-process materials, or drugs are accessible to
cleaning or are removable;
(b) Permits cleaning of adjacent areas and does not interfere with other
processing operations, and it also minimizes circulation of personnel and
optimizes flow of material;
(c) Prevents the contamination of drugs by other drugs, by dust, and by foreign
material such as rust, lubricant, and particles coming from the equipment; and
(d) The base of immovable equipment is adequately sealed along points of contact
with their floor.
2.3 Construction: The equipment shall be so constructed that it does not add
extraneous material to the drug and for that;
(a) the surfaces that come in contact with raw materials, in-process materials,
or drugs are smooth and are made of material that is non-toxic, corrosion
resistant, non-reactive to the drug being manufactured, and capable of with
standing repeated cleaning or sanitizing;
(b) The design is such that the possibility of a lubricant or other maintenance
material contaminating the drug is minimum;
(c) wooden equipment and equipment made of material that is prone to shed
particles or to harbor bacteria do not come in contact or contaminate raw
material, in- process materials, or drugs; and
(d) Chain drives and transmission gears are enclosed or properly covered.
2.4 Pining: All service piping and devices shall be clearly labeled to
indicate the contents and, where applicable, the direction of flow and special
attention is paid to the provision of non-interchangeable connection or adopter
for dangerous gases and liquids.
2.5 Tanks: Tanks used in processing liquids and ointments are equipped with
fittings that can be dismantled and cleaned and are provided with appropriate
2.6 Filters: Filter assemblies are designed for easy dismantling.
2.7 Cleaning equipment: Washing and cleaning equipment shall be provided
which shall not be a source of contamination.
2.8 Defective equipment: Defective equipment shall, if possible, be removed
form production and quality control areas, at least, be clearly labeled as
SECTION – 3
QUALITY CONTROL DEPARTMENT
3.1 General: The Quality Control Department shall be independent with
adequate number of trained personnel and under the authority of a person who
shall be a full time employee.
3.2 Laboratories: Adequate laboratory facilities shall be provided with
necessary equipment and instrument, glassware, chemicals, reagents etc. suited
to testing procedures of drugs to be manufactured.
3.3 Area: The quality control laboratories shall have adequate areas which
shall : -
(i) Be separated from production areas, and the areas where biological,
microbiological or radioisotope test methods are employed shall be separated
from each other;
(ii) Be designed to suit the operations to be carried out in them and
sufficient space shall be given to avoid mix-ups and cross-contamination;
(iii) be so designed so that it takes into account the suitability of
construction materials, fume prevention and ventilation and separate air
handling units and other requirements shall be provided for biological,
microbiological, sterility testing and radioisotope laboratories;
(iv) have separate room for highly sensitive instruments to protect these
against electrical interference, vibrations, contact with excessive moisture and
other external factors or where there is need to isolate the instrument; and
(v) Have appropriate facilities to store samples and records.
3.4 Facilities: The quality control laboratory shall have;
(i) Satisfactory equipment required for test and analysis of drugs intended
to be manufactured, protocols for test and analysis of drugs to be manufactured
including their validation where necessary;
(ii) have adequate other facilities and approved procedures for sampling,
inspecting and testing starting materials, packaging materials, intermediate,
bulk, and finished products, and where applicable for monitoring environmental
conditions for good manufacturing practice purposes;
(iii) Written procedures specifically: -
(a) Validation of methods of manufacture and quality control testing;
(b) Validation of equipment and instruments and cleaning procedures;
(c) Stability testing of the active pharmaceutical substances and the
finished drugs; and
(d) Determining the shelf life of both raw materials and finished drugs.
(vi) Validations studies conducted for important equipment or instruments,
methods of manufacture and quality control and cleaning procedures in accordance
with predefined protocols. A written report summarizing results and conclusions
shall be available.
(vii) Separate facilities for the bulk storage of volatile and inflammable
SECTION – 4
4.1 General: The documents shall: -
(i) be designed and prepared, complying with the relevant parts of the drug
(ii) be approved, signed, and dated by appropriate authorized persons and
shall not be changed without authorization.
(iii) have unambiguous contents and shall clearly state the title, nature, and
purpose, and they shall be laid out in an orderly fashion and be easy to check,
reproduced documents shall be clear and legible.
4.2 Specifications and Testing Procedures: Following document shall be
(i) Reference Bodies: Pharmacopoeias, reference standards, reference spectra,
and other reference materials, where necessary.
(ii) Testing Procedures: Validated testing procedures in the context of
available facilities and equipment.
(iii) Specifications: Appropriately authorized and dated specifications,
including tests on identity, content, purity, and quality, for starting and
packaging material and finished products; and where appropriate, for
intermediate or bulk products. Specifications for water, solvents, and reagents
(e.g. acids and bases) used in production shall also be included.
4.3 Specifications for Starting and Packaging Materials: Specifications for
starting and primary or printed packaging materials shall include, if
(i) the designated name (if applicable, the International Non-proprietary
Name) and internal code reference;
(ii) the reference, if any, to a pharmacopoeia monograph;
(iii) qualitative and quantitative requirements with acceptance limits; and
(iv) packaging material shall conform to specifications, with emphasis placed
on the compatibility of the material with the drug product it contains.
4.4 Specifications for Finished Products:
Specification for finished products shall include: -
(i) the designated name of the product and the code reference where
(ii) the designated name(s) of the active ingredient(s) (if applicable, the
International Non-proprietary Name)
(iii) the label claim or the reference to the formula.
(iv) a description of the dosage form;
(v) directions for sampling and testing or a reference to procedures;
(vi) the qualitative and quantitative requirements with acceptance limits;
(vii) the storage conditions and precautions where applicable; and
(viii) the shelf – life.
4.5 Master formula: A formally authorized master formula shall exist for each
product and batch size to be manufactured, which shall include;
(i) the name of the product, with a product reference code relating to its
(ii) a description of the dosage form, strength of the product, and batch
(iii) a list of all starting materials to be used (If applicable, with the
International Non-proprietary Name), with the amount of each described, using
the designated name and a reference that is unique to that material (mention
shall be made of any substance that may disappear in the course of processing)
and a reference number that may disappear in the course of processing) and a
reference number or code number to its quality control testing.
(iv) a statement of the expected final yield with the acceptance limits, and of
relevant intermediate yields where applicable;
(v) a statement of the processing location and the principal equipment to be
(vi) detailed step-wise processing instructions (e.g. checks on materials,
pretreatment, sequence for adding materials, mixing times, temperatures);
(vii) the instructions for any in-process controls with their limits;
(viii) where necessary, the requirements for storage of the products, including
the container, the labeling, and any special storage conditions; and
(ix) any special precautions to be observed.
4.6 Packaging Instructions: Formally authorized packaging instructions shall
exist for each product, pack size, and type which shall normally include, or
made reference to
(i) the name of the product;
(ii) a description of its pharmaceutical for, strength and method of application
(iii) the pack size expressed in terms of the number, weight, or volume of the
product in the final container;
(iv) a complete list of all the packaging materials required for a standard
batch size, including quantities, sizes, and types, with the code or reference
number relating to the specifications for each packaging materials;
(v) where appropriate, an example or reproduction of the relevant printed
packaging materials and specimens, indicating where the batch number and expiry
date of the product have been marked;
(vi) special precautions to be observed, including a careful examination of the
packaging area and equipment in order to ascertain the line clearance before
(vii) a description of the packaging operations, including any significant
subsidiary operations, and equipment to be used; and
(viii) details of in-process controls with instructions for sampling and
4.7 Standard Operating Procedures and Records. There shall be standard
operating procedures for : -
(i) the receipt of each delivery of starting material and primary and printed
(ii) the international labeling, quarantine, and storage of starting materials,
packaging materials, and other materials, as appropriate;
(iii) each instrument and piece of equipment. These shall be placed in close
proximity to the equipment;
(iv) sampling, which specify the person(s) authorized to take samples, and the
sampling instructions shall included;
(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 amount of sample to be taken;
(e) instructions for any required sub-division of the samples;
(f) the type of sample container to be used, and whether they are for aseptic
sampling or for normal sampling; and
(g) any specific precautions to be observed, especially in regard to the
sampling of sterile or noxious material;
(v) describing the details of the batch (lot) numbering system, with the
objective of ensuring that each batch of intermediate, bulk, or finished product
is identified with a specific batch number;
(vi) for batch numbering that are applied to the processing stage and to the
respective packaging stage shall be related to each other;
(vii) for batch numbering shall assure that the same batch numbers will not be
repeatedly used; this applies also to reprocessing.
4.8 There shall be written procedures for testing materials and products at
different stage of manufacture, describing the methods and equipment to be used.
The tests performed shall be recorded and shall include: -
(a) name of the material or drug and, where applicable, dosage form;
(b) batch number and, where appropriate, the manufacturer and /or supplier;
(c) references to the relevant specifications and testing procedures;
(d) test results, including observations and calculations, and reference to any
(e) dates of testing;
(f) initials of the persons who performed the testing;
(g) initials of the persons who verified the testing and the calculations. Where
(h) a clear statement of release or rejection and the dated signature of the
designated responsible person.
4.9 There shall be written procedures assigning responsibility for sanitation
and describing in sufficient detail the cleaning schedules, methods, equipment,
and materials to be used and facilities to be cleared and such written
procedures shall be followed.
4.10 Written standard operating procedures and the associated records of actions
taken shall be available, for: -
(a) equipment assembly and validation;
(b) analytical apparatus and calibration;
(c) maintenance, cleaning and sanitization;
(d) personnel matters including qualifications, training, clothing, hygiene;
(e) environmental monitoring;
(f) pest control;
4.11.1 Labels firmly affixed or security attached to containers, equipment or
working areas shall be clear and unambiguous and shall indicate the status like
“quarantined” “accepted” “rejected” “clean”, etc.
4.11.2 All finished drugs shall be labeled in accordance with the approval of
Registration Board and with at least the following information: -
a) the name of the drug;
b) a list of the active ingredients, showing the amount of each present, and a
statement of the net contents, e.g. number of dosage units, weight or volume;
c) the batch number assigned by the manufacturer;
d) the expiry date;
e) any special storage conditions or handling precautions that my be necessary;
f) direction for use, and warnings and precautions that may be necessary; and
g) the name and address of the manufacturer or the company or the person
responsible for placing the drug on the market.
4.11.3 The label or accompanying document of reference standards shall
indicate concentration, date of manufacture, expiry date, date the closure is
first opened and storage conditions, where appropriate.
4.12 Batch Processing Records:
4.12.1 A Batch Processing Record shall be maintained for each batch
processed. It shall be based on the relevant portions of the approved Master
Formula and Processing Instructions.
4.12.2 Before starting any processing a check shall be performed and recorded
that the equipment and work station are clear of previous products, documents or
materials not required for the planned process, and that equipment is clean and
suitable for use.
4.12.3 During processing, the following information shall be recorded and, after
completion, the record shall be dated and signed in agreement by the person
responsible for the processing operations:
a) the name of the drug;
b) the number of the batch being manufactured;
c) dates and time of commencement of significant intermediate stage 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.g.
e) the batch number and / or analytical control number as well as the quantities
of each starting material actually weighed (including the batch number and
amount of any recovered or reprocessed material added);
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 drug obtained at different stages of manufacture (yield)
explaining any significant deviations fro the expected yield;
i) notes on special problems including details, with signed authorization, for
nay deviation from the Master Formula.
SECTION – 5
SANITATION AND HYGIENE
5.1 Sanitation: A written sanitation program
shall be available which will include instructions on the sanitary production of
drugs and the handling of materials used in the production of drugs and, in
particular, indicating the following cleaning procedures for the premised and
the equipment used in the production of drug, namely: -
(i) cleaning requirements applicable to all production areas of the plant,
with emphasis on manufacturing areas that require special attention;
(ii) cleaning requirements applicable to processing equipment;
(iii) cleaning intervals;
(iv) cleaning materials, their concentration, and the equipment to bused;
(v) responsibilities of outside contractors, if any;
(vi) disposal procedures for waste material and debris;
(vii) pest control measures;
(viii) precautions required to prevent contamination of a drug when
rodenticides, insecticides, and fumigation agents are used;
(ix) microbial and environmental monitoring procedures and limits in areas where
susceptible products are manufactured; and
(x) the personnel responsible for carrying out cleaning procedures.
5.2.1 Minimum requirements of health, hygienic behavior and clothing for
personnel shall be available in writing in order to ensure the clean and
sanitary production of the drug.
5.2.2 No person who is affected with or is a carrier of a disease in a
communicable for, or has an open lesion on any exposed surface of the body shall
be employed for areas where a drug during any stage of its production is
5.2.3 Minimum requirements of health shall be available in in writing and shall
provide for : -
(j) pre-employment medical examination;
(ii) assessment of an employee’s health prior to return to his place of
employment following illness involving a communicable disease;
(iii) action to be taken in the event of a positive diagnosis or a case
suspected of being hazardous to consumers of the products; and
(iv) routine supervisory check system of employees.
5.2.4 The hygiene program shall clearly define clothing requirements and
hygiene procedures for company personnel and visitors including the following :
(i) Where a potential for the contamination of a raw material, in-process
material, or drug exists, individuals shall wear clean clothing and protective
(ii) Eating, smoking, or any unhygienic practice shall not be permitted in
(iii) Requirements concerning personal hygiene, with emphasis on hand hygiene.
(iv) Requirements concerning cosmetics and jewelry worn by employees.
B in clause (c), in sub-clause (i) : -
(a) for the words “ twelve months” the words “three years” shall be substituted;
(b) for the word “drug” the words “type of drugs to be manufactured” shall be
C in clause (e), for the words “sufficient experience in testing of drugs”
the words “three years experience in testing of types of drugs intended to be
manufactured” shall be substituted;
III. in rule 20, in clause (a), for the “Schedule B II” the following new
Schedule B II shall be substituted, namely : -
GOOD MANUFACTURING PRACTICES (GMPS) FOR LICENSE TO
MANUFACTURE BY WAY OF FROMULATION
PART – I
SECTION – I
1 Responsibility of licensee for drugs fitness for use
SECTION – 2
2. Quality assurance system
SECTION – 3
3. Quality control
3.1 Quality Control Department
3.2 Basic requirements
3.3 Control procedures.
3.3.3 Test requirement for starting and packaging materials
3.3.4 Test requirement for in-process controls
3.3.5 Test Requirement for Finished Products
3.3.6 Production record/batch review
3.3.7 Stability studies
3.4 Self inspection
3.4.2 Items for self inspection
3.4.3 Self inspection team
3.4.4 Frequency of self inspection
3.4.5 Self inspection report
3.5 Quality Audit
3.5.1 Audit by independent specialist
3.5.2 Supplier’s audits
3.6.1 Review of complaints
3.6.2 Person authorized
3.6.3 Written procedures
3.6.4 Recording defects and investigation
3.6.6 Follow-up action
3.6.7 Recording measures
3.6.8 Review for Reviewing Problem
3.7 Product recalls
3.7.2 Authorized person
3.7.3 Written procedures
3.7.4 Recall with promptness
3.7.5 Distribution records
3.7.6 Recording and progress
3.7.8 Storage of recalled drugs
3.7.9 All concerned to be informed
SECTION – 4
4.2 Written duties
4.3 GMP awareness
4.4 Prohibition of unauthorized person
4.5 Duties of Heads of Departments
4.6 Duties of Production Incharges
4.7 Duties of Quality Control Incharges
4.8.1 Written programme
4.8.2 Training appropriate to duties
4.8.3 Specific training
4.8.4 Understanding concepts
4.8.5 Visitor and untrained personnel discouraged
4.9 Personal hygiene
4.9.1 Health examination
4.9.2 Practices in personal hygiene
4.9.4 Reporting health problems
4.9.5 Avoiding direct contact with materials
4.9.6 Appropriate clothing and covering
4.9.7 Foods and drinks prohibited
SECTION – 5
GOOD PRACTICES IN MANUFACTURING PROCESSING
5.1 General responsibility of licensee
SECTION – 6
6.1 Material general
6.1.2 Appropriate storage
6.2 Starting materials
6.2.2 Purchase from producer or established supplier
6.2.3 Checking of containers
6.2.4 Damaged container
6.2.5 Delivery from different batches
6.2.7 Identity of contents
6.2.8 Released materials to be used
6.2.9 Correct dispensing
6.3 Packaging materials
6.3.2 Printed materials
6.3.3 Reference numbers
6.3.4 Obsolete materials
6.3.5 Checking before delivery
6.4 Intermediate and bulk products
6.5 Finished pharmaceutical products
6.6 Rejected and recovered materials
6.6.1 Storage and disposal
6.6.3 Batch recovers
6.6.4 Additional testing of reprocessed material
6.7 Recalled and returned products
6.7.1 Recalled products
6.7.2 Returned goods
6.8 Reagents and culture media
6.9 Reference standards
6.9.1 Testing prepared reference standard
6.9.3 Working standards
6.10 Waste materials
SECTION – 7
7.1 Processing operations
7.1.2 Material handling
7.1.3 Avoiding deviation
7.1.4 Yield checks
7.1.5 Avoiding mix-ups
7.1.7 Unauthorized entry prohibited
7.1.8 In price controls
7.2 Prevention of cross-contamination and bacterial
Contamination in production
7.2.1 Precautions against dust
7.2.2 Measures against contamination
7.2.3 Cross contamination checks
7.2.4 Microbiological monitory
7.3 Processing operations intermediate and bulk
7.3.1 Pre-Processing cleanliness checks
7.3.2 In-process controls
7.3.3 Defective equipment
7.3.4 Cleaning containers
7.3.5 Yield deviations
7.3.6 Product pipelines
7.3.7 Water pipes
7.3.8 Equipment calibration
7.3.9 Repair or maintenance
7.4 Packaging operations
7.4.1 Avoiding mix-ups
7.4.2 Pre-packaging checks
7.4.3 Labeling packaging line
7.4.4 Process continuity
7.4.5 Printing operation checks
7.4.6 Label verification
7.4.7 Resistant printing on labels
7.4.8 On-line packaging checks
7.4.9 Product re-introduction on packaging line
7.4.10 Discrepancies to be investigated
7.4.11 Destruction of un-used packaging materials
SECTION – 8
Sanitation and hygiene
SECTION – 9
9.2 Process validation
9.2.1 Validation of critical processes
9.2.2 Validation of new master formula
9.2.3 Validation of equipment or materials
SECTION – 10
10.1.1 Maintenance of documents
10.1.2 Recording actions
10.1.3 Documentation system
10.1.4 Status identification
10.1.5 Product labeling
10.1.6 Reference standards identification
10.1.7 Specification approvals
10.1.8 Revision of specification
10.1.9 Packaging material specification
10.1.10 Starting material re-assay
10.2 Specification for intermediate and bulk products
10.3 Batch processing records
10.3.2 Checking work station
10.3.3 Recording process operation
10.4 Batch packaging records
10.4.2 Pre-packaging line checks
10.4.3 Recording packaging Operation
10.4.4 Recording packaging batch numbers
10.4.5 Analytical records
10.4.6 Finished product release procedure
10.4.7 Recording batch distribution
10.4.8 Standard operating procedures
10.4.9 Equipment logbooks
10.4.10 Equipment utilization records
PART – II
ADDITIONAL CONDITIONS FRO MANUFACTURE OF
1.1 Air Classification System for manufacture of sterile products
Manufacture of sterile preparations
2.1 manufacturing operations
2.2 Terminally sterilized products
2.3 Products sterilized by filtration
2.4 Products manufactured under aseptic conditions
3.2 Personnel training
3.3 Entry restricted
3.4 Hygiene and cleanliness
3.5 Use of protective garments
3.6 Clothing requirements
3.7 Protective garments in grade B room
3.8 Washing of clothing
SECTION – 2
4 Maintenance of clean area
4.2 Airlock system
4.3 Air supply system
4.4 Maintenance of equipment
4.5 Water supply
SECTION – 3
5 Equipment maintenance
SECTION – 4
6.2 Use of disinfectants and detergents
6.4 Monitoring of clean areas
SECTION – 5
7.1 Precautions against contamination
7.2 Preparation of live organisms
7.3 Simulation of aseptic operations validation
7.4 Monitoring water supply sources
7.5 Activities in clean areas kept minimum
7.6 Care of stating materials
7.7 Care against fibers
7.8 Care after final cleaning of materials
7.9 Interval between operations to be minimal
7.10 Sterilization of gases used
7.11 Disburden to be minimal
7.12 Asepsis of articles in clean areas
7.13 New processes to be validated
SECTION – 6
8.3 Suitability of process
8.4 Care for biological indicates
8.5 Sterilized non-sterilized products
9 Sterilization by heat
9.1 Recording sterilization cycle
9.2 Sufficient time allowed to reach required temperature
9.3 Precautions drugging cooling
10 Sterilization by moist heat
10.2 Wrapping materials
11 Sterilization by dry heat
12 Sterilization by radiation
12.2 Outside contractor
12.3 Measurement of radiation
12.5 Handling procedures
13 Sterilization by ethylene oxide
13.2 Ensure contact between gas and microbial cells
13.3 Equilibrium with humidity and temperature
13.4 Monitoring each cycle
13.5 Biological indicators
13.6 Record maintenance
14 Filtration of pharmaceutical products that can not
Be sterilized in the final container
14.2 Using double filter layer
14.3 Eliminate fibers
14.4 Checking integrity of filters
14.5 Frequency of use of filter
14.6 Filter safety
15 Finishing of sterile products
15.2 Use of vacuum
15.3 Inspection of containers
16 Quality control
16.1 Sterility testing
16.2 Sterility test as the last measures
16.3 Monitoring end toxin
GOOD MANUFACTURING PRACTICES (GMPS) FOR LICENSE TO
MANUFACTURE BY WAY OF FROMULATION
PART – I
SECTION – 1
1. Responsibility of licensee for drug’s fitness for use.
The licensee shall assume the responsibility for the quality of
the furs manufactured by it to ensure that they are fit for their intended use,
comply with the requirements of the Ordinance and rules made there under and do
not place patients at risk due to inadequate safety, quality or efficacy. To
achieve the quality objective reliably, there shall be a comprehensively
designed and correctly implemented system of quality assurance incorporating
good manufacturing practices nod quality control. It shall be fully documented
and its effectiveness monitored. All parts of the quality assurance system shall
be adequately staff with competent personnel and shall have suitable and
sufficient premises, equipment, and facilities.
SECTION – 2
2. Quality assurance system.
The licensee shall have a system of quality assurance appropriate to the
manufacture of drugs which shall ensure that: -
(a) drugs are designed and developed in a way that takes into account the
requirements of good manufacturing practices and other associated codes as may
be notified form time to time;
(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 description;
(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
(f) the finished products are correctly processed and checked, according to the
(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 Ordinance 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) there is a procedure for self inspection and or quality audit at appropriate
intervals that regularly reviews the effectiveness and applicability of the
quality assurance system and that such a procedure is followed; and
(j) a system exist in the form of written Standard Operating Procedures
according to which complaints about marketed products are examined, the causes
of quality defects investigated, and appropriate measure taken in respect of the
defective products and to prevent recurrence and that system is followed.
SECTION – 3
3. Quality control.
3.1. Quality control department: The licensee shall maintain and satisfactory
run its quality control department which is independent of other departments and
under the authority of a person with the required qualifications and experience
and with adequate facilities to ensure that all the quality control arrangements
are effectively and reliably carried out.
3.2. Basic requirements: The basic requirements to be met for quality control
shall be as follows: -
(a) During the period of validity of license, adequate facilities, trained
personnel and approved procedures are available for sampling, inspecting, and
testing stating materials, packaging materials, and 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) Test methods are validated;
(d) Records are made manually and or by recording instruments demonstrating 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
authorization, the ingredients shall be of the required purity, in their proper
container, and correctly labeled;
(f) Record are made of the results of inspecting and testing materials and
intermediate, buck, and finished precuts against specification and product
documentation and an assessment of deviations from specified procedures;
(g) No batch of product is released for sale prior to certification by the
authorized person(s) that it is in accordance with the requirements of the
(h) Sufficient samples of starting materials and products are retained to permit
future examination of the product if necessary and the retained product is kept
in its final pack unless the pack is exceptionally large; and
(i) All quality control procedures are established, validated and implemented;
the reference standard for substances are evaluated, maintained, and stored,
correct labeling of containers of materials and product is ensured; the
stability of the active pharmaceutical ingredients and products is monitored,
complaints related to the quality of the product are investigated and
environmental monitoring is conducted. All these operations shall be carried out
in accordance with written procedures and where necessary, recorded, provided
that the Central Licensing Board may allow other arrangements if it is
considered so necessary for an effective quality control system of the licensee.
3.3 Control Procedures.
3.3.1 General: All tests and analysis 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 approved written procedure;
(b) be taken in a manner so as to avoid contamination or other adverse effects
on quality, and the containers that have been sampled shall be marked
accordingly and carefully resealed after sampling;
(c) be taken with care to guard against contamination or mix-up of, or by, the
material being sampled, all sampling equipment that comes into contact with the
material shall be clean, and some particularly hazardous or potent materials may
require special precautions;
(d) be taken with equipment which shall be cleaned and, if necessary, sterilized
before and after each use and stored separately from other laboratory equipment;
(e) bear a label indication: -
(i) the name of the sampled material;
(ii) the batch or lot number;
(iii) identify the container from which the sample has been taken
(iv) the signature of the person who has taken the sample; and
(v) the date of sampling.
3.3.3 Testing requirement for starting and packaging materials.
(i) Test before use: Before releasing a starting or packaging material for use,
the quality control manager shall ensure that the materials have been tested for
conformity with specifications for identity, strength, purity, and other quality
(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 controls.
Records of testing: In-process control records shall be maintained and form a
par------ 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: Products 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 and any
divergence or failure of a batch to meet its specifications shall be thoroughly
investigated, the investigation shall, if necessary, extend to other batches of
the same product and other products that may have been associated with the
specific failure or discrepancy, and a written record of the investigation shall
be made and shall include the conculsio0n and details of follow-up action.
(ii) Retention of Samples: Retention samples from each batch of finished
product shall be kept for at least one year after the expiry date. Finished
products shall usually be kept in their final packaging and stored under the
recommended conditions. If exceptionally large packages are produced, smaller
samples might be stored in appropriate container. Samples of active starting
materials shall be retained for five years. Other starting materials (other than
solvents, gases, and water) shall be retained for minimum of two years if their
stability allows; Retention samples of materials and products shall be of a size
sufficient to permit at least tow full re-examinations.
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
(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: -
(a) a complete description of the drug involved in the study;
(b) the complete testing parameters and methods describing all tests for
potency, purity, and physical characteristics and documented evidence that these
test indicate stability.
(c) Provision for the inclusion of a sufficient number of batches;
(d) The testing of each drug;
(e) Provision for special storage conditions;
(f) Provision for adequate sample retention; and
(g) A summary of all the data generated, including the evaluation and the
conclusions of the study.
(iii) Stability of the finished product shall be evaluated and documented prior
to marketing and following and significant changes in the processes, equipment,
primary packaging materials, etc.
3.4.1 General: The licensee shall conduct repeated self inspection with a
view to evaluate its own compliance with good manufacturing practices in all
aspects of production and quality control; The self inspection program shall be
designed to detect any shortcomings in the implementation of good manufacturing
practices and to recommend the necessary corrective actions; Self inspections
shall be performed routinely, and may be, in addition, performed on special
occasions, e.g. in the case of product recalls or repeated rejections or when an
inspection by the Central Licensing Board is required; 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.
3.4.2 Items for self inspection: Written instructions for self inspection shall
be established to provide a minimum and uniform standard of requirements and
shall include questionnaires on good manufacturing practices requirements
covering at least the following items, namely;
(b) premises including personnel facilities;
(c) maintenance of buildings and equipment;
(d) storage of starting materials and finished products;
(f) production and in-process controls;
(g) quality control;
(i) sanitation and hygiene;
(j) validation and verification programs;
(k) calibration of instruments or measurement systems;
(l) recall procedures;
(m) complaints management;
(n) labels control; and
(o) results of previous self-inspections and any corrective steps taken.
3.4.3 Self-inspection team: Management shall appoint a self-inspection team of
members from inside or outside the company who are expert in the field of
inspection and familiar with good manufacturing practices.
3.4.4 Frequency of self-inspection: The frequency at which self-inspections are
conducted may depend on company requirements but it shall be at least once every
3.4.5 Self-inspection report: A report shall be made at the completion of
self-inspection which shall include: -
(a) self-inspection results;
(b) evaluation and conclusion; and
(c) recommended corrective actions.
3.4.6 Follow-up actions: The company management shall evaluate both the
self-inspection report and the corrective actions as are necessary.
3.5 Quality audit:
3.5.1 Audit by independent specialist: It may be useful to supplement
self-inspection with a quality audit which consists of an examination and
assessment of all or part of a quality system with the specific purpose of
improving it; a quality audit is usually conducted by outside or independent
specialists or a tem a designated by the management for this purpose; such
audits may also be extended to suppliers and contractors.
3.5.2 Supplier’s audits: The quality control department shall have
responsibility together with other relevant departments for approving suppliers
who can reliably supply starting and packaging materials that meet established
3.6.1 Review of complaints: All complaints and other information concerning
potentially defective products must be carefully reviewed according to written
3.6.2 Person authorized: A person responsible for handling the complaints and
deciding the measures to be taken shall be designated, together with sufficient
supporting staff to assist him and if this person is different from the
authorized person, the latter shall be made aware of any complaint,
investigation, or recall.
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; The person responsible for quality control shall normally be
involved in the study of such problems.
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; in particular, other batches that
may contain reprocessed product from the defective batch shall be investigated.
3.6.6 Follow up action: Where necessary, appropriate follow-up action, possibly
including product recall, shall be taken after investigation and evaluation of
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 record.
3.6.8 Review for recurring problems: Complaint record shall be regularly
reviewed for any indication of specific or recurring problems that require
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, as well as sufficient staff to handle all
aspects of the recalls with the appropriate degree of urgency; this person shall
normally be independent of the sales and marketing organization; if this person
is different from the authorized person the latter shall be jade aware of any
3.7.3 Written procedures: There shall be established written procedures,
regularly checked and updated for the organization of any recall activity.
Recall operations shall be capable of being initiated promptly at least down to
the level of the health institutions and all sale channels including whole sale
and where possible retail sale and a public notice if required.
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 because it is, or was suspected of being, defective.
3.7.5 Distribution records: The distribution records shall be readily available
to the person(s) responsible for recalls, and they shall contain sufficient
information on wholesalers and directly supplied customers(including, for
exported products, those who have received samples for clinical tests and
medical samples) to permit and effective 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 decide.
3.7.9 All concerned to be informed: The Central Licensing and Registration
Boards and other concerned government authorities shall be immediately informed
if it is intended to recall product(s) or if a product has been recalled.
Effective system shall be maintained to inform the doctors, pharmacists and
public of the recalled products.
SECTION - 4
4.1 General: The licensee shall provide: -
(a) sufficient qualified personnel to fulfill all its responsibilities required
under these rules; and
(b) organization chart.
4.2 Written duties: All responsible staff shall have their specific duties
recorded in written descriptions and adequate authority to carry out their
responsibilities. There shall be no gaps or unexplained overlaps in the
responsibilities of personnel concerned with the application of good
manufacturing practices. Individual responsibilities shall be clearly understood
by the individuals concerned;
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
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
4.5 Duties of heads of departments: The heads of the production and quality
control departments may have shared, or jointly exercised the following
responsibilities relating to quality, namely: -
(a) the authorization of written procedures and other documents, including
(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
(i) the retention of records;
(j) the monitoring of compliance with good manufacturing practices requirements;
(k) the inspection, investigation, and taking of samples in order to monitor
factors that may affect product quality.
4.6 Duties of production in charge: 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 are evaluated and signed by a
designated person before they are made available to the quality control
(d) to check the maintenance of the department, premises, and equipment;
(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.
4.8.1 Written programmed: The training shall be provided in accordance with a
written program for all the personnel whose duties required 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
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
4.9 Personal hygiene:
4.9.1 Health examination: All personnel, prior to and during 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 productions areas,
and signs to this effect shall be pasted and instructions observed.
4.9.3 Illnesses: Any person shown 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 judge to be a risk.
4.9.4 Reporting health problem: 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 clothings and covering: To ensure protection of the product
form contamination, personnel shall wear clean body coverings appropriate to the
duties they perform, including appropriate hair covering, 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 medicines 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.
5.1 General responsibility of licensee: The licensee shall follow Good
Manufacturing Practices in production of drugs under which it shall be ensured
(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
(b) critical steps of manufacturing processes and any significant changes 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 of in-process controls
under the responsibility of the production management.
(d) instructions and procedures are written in clear and unambiguous language,
specifically applicable to the facilities provided and followed in letter and
(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 procedures 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
(g) records covering manufacture and distribution, which enable the complete
history of a batch to be traced, are retained in a comprehensible and accessible
(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
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 product 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.
6.2.1 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
6.2.2 Purchase from producer or established suppliers: Starting materials shall
be purchased directly from the producer or only from 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 labeled, 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 materials 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 Labeling: Starting materials in the storage area shall be appropriately
labeled, and labels shall bear at least the following information, namely: -
(a) the designated name of the product and the internal code reference where
(b) the batch number(s) given by the supplier and on receipt by the manufacture,
(c) where appropriate, the status of the contents such as on quarantine, on
test, released, rejected, returned, and recalled; and,
(d) where appropriate, and 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 starting material, and
bulk containers from which samples have been drawn shall be identified.
6.2.8 Released materials to be used: Only starting materials released by the
quality control department and with in their shelf-life shall be used.
6.2.9 Correct dispensing: Starting materials shall be dispensed only by
designated persons, following a written procedure to ensure that the correct
materials are accurately weighed or measured in to clean and properly labeled
6.2.10 Checking: Each dispensed material and its weight or volume shall be
independently checked and the check recorded.
6.2.11 Labeling: Materials dispensed for each batch of the final product shall
be kept together and conspicuously labeled 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 printed materials shall
be stored and transported in separate closed containers so as to avoid mix-ups
and packaging materials shall be issued 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
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 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 affected, 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
6.6.3 Batch recovery: The introduction of all or part of earlier batches,
conforming to the required quality, in to 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
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
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 if
requires, its condition and history, and the time elapsed since it was issued
shall 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 medial shall be recorded upon receipt or
6.8.2 Reagents made up in the laboratory shall be prepared according to written
procedures and appropriately labeled, 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
suitability of culture media, and the size of the inoculum used in positive
controls shall be appropriate to the sensitivity 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 purposed
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 a 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 Waste 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 ---------------
shall be stored in suitably designed and separate enclosed cupboat---------
6.10.2 Disposal: Waste material shall not be allowed to accumulate, and
-----------collected in suitable receptacles for removal to collection points
--------------- buildings and disposed of safely and in a sanitary manner at
regular and -------------intervals.
6.10.3 Effluent Control: There shall be a effluent control system.
6.11 Miscellaneous: Rodenticides, insecticides, fumigating agents, and
sanitizing-----shall not be permitted to contaminate equipment, starting
materials, packaging-------in-process materials, or finished products.
SECTION – 7
7.1 Processing operations:
7.1.1 General: Productions 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, labeling, 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
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 Labeling: At all times during processing, all materials, bulk containers,
major items of equipment, and where appropriate the rooms used shall be labeled
or otherwise identified with an indication of the product or material being
processed and its strength, where applicable, and the batch number, and where
applicable this indication shall also mention the stage of production.
7.1.7 Unauthorized entry prohibited: Access to the production premises shall be
restricted to authorized personnel.
7.1.8 Inprocess controls: In-process controls are mostly performed within the
production area and they shall not carry any risk for the quality of the
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-contamination 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 are 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
7.2.3 Cross contamination checks: Measures to prevent cross-contamination and
their effectiveness shall be checked periodically according to standard
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 and 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 Inprocess 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
filling and attention shall be given to avoiding and removing any contaminants
such as glass fragments and metal particles. Production equipment shall be
cleaned according to detailed written procedures and stored only under clean and
7.3.5 Yield deviations: Any significant deviation from the 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 form one
area to another are connected in a correct manner.
7.3.7 Water pipes: Pipes used for conveying distilled or deionizer 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 interclass and
records maintained. To ensures 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 not
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-ups, or substitutions, and different products shall not be
packaged in close proximity unless there is physical segregation or these of
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 Labeling 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 labeling is delayed, appropriate
procedures shall be applied to ensure that no mix-up or mislabeling can occur.
7.4.5 Printing operation checks: The correct performance of any printing, code
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 rechecked at regular intervals.
7.4.6 Label verification: Special care shall be taken when cut labels are used
and when overprinting 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 operation 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 .
7.4.8 On-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 overprinting is correct;
(e) the correct functioning of line monitors and
(f) sample 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 unusual 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 unusual 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, unused 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 hygiene
covers personnel, premises, equipment and apparatus, production materials and
containers, products 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 and integrated comprehensive program
of sanitation and hygiene. (For sanitation and hygiene please also refer to
Section 59 Schedule B-I and Section 4.9 of Schedule.
SECTION – 9
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 suitability for
routine processing, and, the defined process, using the materials and equipment
specified, shall be shown to yield a product consistently of the required
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 quality and or the re-producibility of the process shall be
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 on 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 formulae 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 methods, only authorized persons shall be able to
enter or modify data in the computer, and there shall be a record of changes and
deletion; access shall be restricted by passwords or other means and the entry
of critical data shall be independently checked and data shall also be readily
10.1.4 Status identification: Labels applied to containers, equipment, or
premises shall be unambiguous and in the company’s agreed format. the labels of
different colors to indicate the status such as “quarantined”, “accepted”,
“rejected”, or “clear” may also be used in addition to the wording.
10.1.5 Product labeling: All finished products shall be labeled in accordance
with the Drug (Labeling and Packing) Rules 1986
10.1.6 Reference standard 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 specifications 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 edition 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
specification, 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:
Specification for intermediate and bulk products shall be available if these are
purchased or dispatched, or 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 such records shall be designed to avoid transcription
10.3.2 Checking work station: Before any processing beings, a check shall be
made that the equipment and work station are clear of previous products,
documents, or materials not required for the planed 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 time of commencement of significant intermediate stages, and of
completion of production;
(d) the name of the 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
(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 result obtained;
(i) the amount of product obtained at different and pertinent stage of
manufacture (yield,) together with comments or explanations for significant
deviations from the expected yield; and
(j) notes on special problems including details, with signed authorization for
nay 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 instruction, and
the method of preparing such records shall be designed to avoid transcription
10.4.2 Pre-packaging line check: Before any packaging operation beings, checks
shall be made that the equipment and work station are clear of previous
products, document s or material not required for the planned packaging
operations, and that equipment is clean and suitable for use. These checks shall
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
(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 operator s of the different significant steps;
(e) the checks made for identity and conformity with the packaging instruction,
including the results of in-process controls;
(f) details of the packaging operations carried out, including references to
equipment and the packaging lines used, and, when necessary, the instructions
for keeping the product un-packed or a record of 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
(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 an adequate
10.4.4 Recording batch numbers: Batch-number allocation shall be immediately
recorded in a logbook, and the record shall included 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
(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,
(h) a clear statement of release or rejection (or other status decision) and the
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;
(h) recalls; and
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.
PART – II
ADDITIONAL CONDITIONS FOR MANUFACTURE
OF STERILE PRODUCTS.
In additional to the general conditions 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 – 1
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 ark in grades A,B,C, and D as given in
Air classification system for manufacture of sterile products
Maximum number of Maximum number
particles permitted per m3 of viable micro-organisms
permitted per m3
Grade 0.05µm >5µm
A 3500 none less than 1
B 3500 none 5
C 350 000 2 000 100
D 3 500 000 20 000 500
• Laminar-airflow systems shall provide a homogeneous air speed about
0.30±20%m/s for vertical flow and about 0.45±20%m/s for horizontal flow but
precise air speeds will depend on the type of equipment.
• In order to reach the B, C, and D air grades, the number of air changes shall
generally be higher than 20 per hour in a room with a good airflow pattern and
appropriate HEPA (high efficiency particulate air) filters.
• Low values for contaminants are reliable only when a large number of air
samples are taken.
• The guidance given for the maximum permitted number of particles corresponds
approximately to the United States Federal Standard 209E as follows: Class 100
(grades A and B), Class 10 000 (grade C), and Class 100 000 (Grade D).
It may not always be possible to demonstrate conformity with particular air
standards at the point of fill when filling is in progress, owing to the
generation of particles or droplets from the product itself.
1.4 Area Grades: Area grades must be selected by the manufacturer on the
basis of validation runs e.g., sterile media fills as identified below.
2. Manufacture of sterile preparations
2.1 Manufacturing Operations Classifications are here divided into three
(a) Terminally sterilized products: those in which the preparation is sealed in
its final container and terminally sterilized;
(b) Products sterilized 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
grade C environment in order to give low microbial and particulate counts,
suitable for immediate filtration and sterilization. Solution preparation could
be allowed in a grad D environment if additional measures are taken to minimize
contamination, such as the use closed vessels. For parenteral, filling shall be
done in a laminar-airflow workstation (grade A) in grade C environment. The
preparation of other sterile products, e.g., ointments, creams, suspensions, and
emulsion, 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 materials and
the preparation of solutions shall be done in 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.
3.1 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
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
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
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
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 goes 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 where 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 jewelry shall not be worn in 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
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 Section 1.3 gives the
minimum air grades required for different manufacturing operations. The
particulate and microbiological conditions as prescribed shall be maintained in
the zone immediately surrounding the product whenever the product is exposed to
the environment. These conditions shall also be achieved throughout the
background environment if no personnel are present in the processing area and if
the standards fall for any reason it shall be possible to recover the conditions
after a short “clean-up” period. The utilization of absolute-barrier technology
and automated systems to minimize human interventions in processing areas can
produce significant advantages in ensuring the sterility of manufactured
products, and when such techniques are used the recommendations relating to air
quality an monitoring, still apply, with appropriate interpretations of the
terms “workstation” and environment.
4.2 Airlock system: The entry to the sterile production areas shall be through
airlocks for personal and/or for materials. Airlock 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. More over particular
attention shall be paid to the protection of the zone of great 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 become 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 manner
that prevents microbial growth for example by constant circulation at 90ºC or at
temperature validated to keep microbial count of water within the limit.
SECTION – 3
5. Equipment maintenance:
5.1 Documentation: All equipment, including sterilizers, air-filtration systems,
and water-treatment systems including stills, shall be subject to planed
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 program
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
microorganism, 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 hall be kept in previously
cleaned container 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 for 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 surface,
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
7.1 Precautions against contamination: Precautions to minimized contamination
shall be taken during all processing stages including the stage before
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.
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
Note:- It is recommended that at least 3000 units of production be included in
each broth-fill trial. The target shall be zero growth and anything above 0.1%
of units contaminated shall be considered unacceptable. Any contamination shall
be investigated. Broth fills shall be repeated at regular intervals, and
whenever a significant alteration in the product, premises, equipment or process
warrants revalidation. Care shall be taken that validations do not harm the
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 starting materials: Micro-biological contamination (bioburden) of
starting materials shall be minimal which shall be monitored before
sterilization, and specifications shall included requirements for
microbiological quality when the need for this has been indicated by monitoring.
7.7 Care against fibers: The presence of containers and materials liable to
generate fibers shall be minimized in clean areas and avoided completely while
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 components,
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 containers, 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 on
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 shall be a 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 processes, and where aqueous
solutions are held in sealed vessels, any pressure-release outlets shall be
protected such as by hydrophobic microbial air filter.
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
achieve 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 or equipment.
SECTION – 6
8.1 General: Sterilization can be achieved by moist or dry heat, by ethylene
oxide or other suitable gaseous sterilizing agent, by filtration with subsequent
aseptic filling 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 pharmacopoeial 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
sterilizing 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 and additional method for monitoring the sterilization, and if they are
used, strict precautions shall be taken to avoid transferring microbial
contamination from them.
8.5 Sterilized not sterilized product differentiation: There shall be a clear
means of differentiating products that have not been sterilized from those that
have and each basket, tray, or other carrier of products or components shall be
clearly labeled 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 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 sterilized, 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 steri8lization 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 tests 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 pyrogens, 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 of
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
12.2 Outside contractor: If radiation sterilizations 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 dose, shall also be 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 dosimeter in the
chamber: where plastic dosimeters are used, they shall be used within the
time-limit of their calibration, 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 given
to the effect of variations in the density to 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
13 Sterilization by ethylene oxide:
13.1 General: Various gases and fumigants may be used for sterilization,
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
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
13.6 Record maintenance: For each sterilization 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 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
14.1 General: Whenever possible, products shall be sterilized in the final
container preferably by heat sterilization. Certain solutions and liquids that
cannot be sterilized in the final container can be filtered through a sterile
filter of nominal pore size 0.22um or less, or with at least equivalent
microorganism-retaining properties into a previously sterilized container, such
filter 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
14.3 Eliminate fibres: Filters that shed fibers 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 filter 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
same shall be checked for integrity according to appropriate procedures.
15.2 Use of vacuum: Containers sealed under vacuum shall be
sampled and the same tested for maintenance of that vacuum after and appropriate
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
worn, 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 form any part of the load.
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 and 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 test required
by the marketing authorization on the finished product, and when a sample fails
a test, the causes of failure shall be investigated and remedial action taken
Saving: This Schedule B-II shall come into force with effect form the date as
may be notified by the Federal Government and till such time Schedule B-II as
already provided in the Rules shall remain in-force.
After rule 20 the following new rule shall be inserted, namely: -
“20A. Contract Manufacture. Manufacture or analysis on contract is permissible
on behalf of a licensee or of a pharmaceutical company whose products are
registered for import in Pakistan for sale subject to the conditions laid down
in Schedule G”, as a special case and for genuine reasons as approved by the
1. Contract production and analysis:
1.1 Contract of manufacture shall be undertaken only by a manufacturer who holds
a valid drug manufacturing license, and the contract acceptor shall/have
adequate facilities, knowledge, experience and competent personnel to
satisfactorily carry out the work ordered by the contract giver.
1.2 General: Contract production and analysis shall be correctly defined, agreed
and controlled in order to avoid misunderstandings that could result in a drug
or work or analysis of unsatisfactory quality. A written contract between the
contract giver and the contract acceptor shall clearly establish the duties of
each party and state the way in which the authorized person shall exercise his
full responsibility in releasing each batch of product for sale or issuing the
certificate of analysis, and a copy of such a contract shall be supplied to the
Central Licensing Board also.
1.3 All arrangements for contract manufacture and analysis, including any
proposed changes in technical or other arrangements, shall be in accordance with
the registration of the drug concerned.
1.4 There shall be a written contract covering the manufacture and or analysis
arranged under contract and any technical arrangements made in connection with
1.5 The contract shall permit the contract giver to audit the facilities of the
1.6 In the case of contract analysis, the final approval for release must be
given by the authorized person(s).
2. Contract Giver
2.1 The contract giver shall be responsible for assessing the competence of the
contract acceptor in successfully carrying out the work or tests required and
for ensuring by means of the contract that the principles of good manufacturing
practices are followed.
2.2 The contract giver shall provide the contract acceptor with all the
information necessary to carry out the contracted operations correctly in
accordance with the registration and any other legal requirement’s and the
contract giver shall ensure that the contract acceptor is fully aware of any
problem associated with the product, work, or tests that might pose a hazard to
premises, equipment, personnel, other material or other products.
2.3 The contract giver shall ensure that all processed products and material
delivered by the contract acceptor to comply with their specifications or that
the product has been released by the authorized person(s)
3. Contract acceptor:
3.1 The contract acceptor shall not pass to a third party any of the work
entrusted to him or her under the contract without the written consent of the
contract giver and prior evaluation and approval by the arrangements of the
Central Licensing Board, and arrangements made between the contract acceptor and
any third party shall ensure that the manufacturing and analytical information
is made available in the same way as between the original contract giver and
3.2 The contract acceptor shall refrain from any activity that may adversely
affect the quality of the product manufactured and or analyzed for the contract
4. The contract:
4.1 A contract shall be drawn up between the contract giver and the contract
acceptor that specifies their respective responsibilities relating to the
manufacture and control of the product, and technical aspects of the contract
shall be drawn up by competent persons suitably knowledgeable in pharmaceutical
technology, analysis, and good manufacturing practices. All arrangements for
production and analysis must be in accordance with the registration and agreed
by both parties.
4.2 The contract shall specify the way in which the authorized person releasing
the batch for sale ensures that each batch has been manufactured in, and checked
for, compliance with the requirements of the marketing authorization.
4.3 The contract shall describe clearly who is responsible for purchasing,
testing, and releasing material and for undertaking production and quality
controls, including in process controls, and who has responsibility for sampling
and analysis, and in the case of contract analysis, the contract shall state
whether or not the contract acceptor shall take samples at the premises of the
4.4 Manufacturing, analytical distribution records and reference samples shall
be kept by, or be available to, the contract giver, and any records relevant to
assessing the quality of a product in the event of complaints or a suspected
defect shall be accessible and specified in the defect or recall procedures of
the contract giver.
4.5 The contract shall describe the handling of stating material intermediate
and bulk products and finished products if they are rejected and it shall also
describe the processing of information if the contract analysis shows that the
tested product must be rejected.