The manufacturer should have an updated organization chart. Personnel duties and responsibilities should be clearly explained to them and recorded as written job descriptions or by other suitable means. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice.
This involves the basic concept of IPO system i.e. input output process. Here Input is people who need to acquire knowledge, skill and attitude Process is learning that takes place with in the system Output is trained persons. Analyze the system in order to completely understand it and then describe the goals u wish to achieve in order to correct any short coming or faults with in the system Design a method or model to achieve your goals Develop the model into a product (In training this product is called courseware) Implement the courseware Evaluate the courseware and audit trail throughout the four phases and in the field to ensure it is heading in the right direction and achieving the desired results.
Gmp final 97 03
P. Raja Abhilash, M.pharm., (Ph.D.),
H.O.D., Department of Pharmaceutical Analysis,
S.V.S. School of Pharmacy
Essentials of GMP
GMP STANDS FOR…
• Good Manufacturing Practices
• Good Management Principles
• Give More Production
• Get More Profit
What is GMP ?
• GMP is that part of Quality assurance which ensures that
the products are consistently manufactured and controlled
to the Quality standards appropriate to their intended use.
• "GMP" - A set of principles and procedures which, when
followed by manufacturers for therapeutic goods, helps
ensure that the products manufactured will have the
It is the sum total of the organized
arrangements with the objective of
ensuring that products will be of the
quality required for their intended
Is that part of Quality Assurance
aimed at ensuring that products are
consistently manufactured to a
quality appropriate to their intended
Is that part of GMP concerned with
sampling, specification & testing,
documentation & release
procedures which ensure that the
necessary & relevant tests are
performed & the product is released
for use only after ascertaining it’s
• A basic tenet of GMP is that quality cannot be tested
into a batch of product but must be built into each
batch of product during all stages of the
• It is designed to minimize the risks involved in any
pharmaceutical production that cannot be eliminated
through testing the final product.
• Quality of a medicinal product is measured by it’s
fitness for purpose . Safety, purity and efficacy are not
separable from Quality but part of it.
• Quality = PURITY X SAFETY X EFFICACY
Some of the main risks are…
– Unexpected contamination of products, causing
damage to health or even death ( PURITY).
– Incorrect labels on containers, which could mean that
patients receive the wrong medicine (SAFETY).
– Insufficient or too much active ingredient, resulting in
ineffective treatment or adverse effects ( EFFICACY).
Why GMP is important…
• GMP helps boost pharmaceutical export opportunities.
• Most countries will only accept import and sale of
medicines that have been manufactured to internationally
• Governments seeking to promote their countries export of
pharmaceuticals can do so by making GMP mandatory for
all pharmaceutical production and by training their
inspectors in GMP requirements.
• ALL aspects of production; from the starting materials,
premises and equipment to the training and personal
hygiene of staff.
• Detailed, written procedures are essential for each process
that could affect the quality of the finished product.
• There must be systems to provide documented proof that
correct procedures are consistently followed at each step in
the manufacturing process - every time a product is made.
• GMP as per Schedule “M” (INDIA)
• GMP as per WHO
• GMP as per MCA now known as MHRA (UK)
• GMP as per TGA (AUSTRALIA)
• GMP as per US FDA (US)
• GMP as per ICH guidelines
Ten Principles of GMP
1. Design and construct the facilities and equipment properly
2. Follow written procedures and Instructions
3. Document work
4. Validate work
5. Monitor facilities and equipment
6. Write step by step operating procedures and work on
7. Design ,develop and demonstrate job competence
8. Protect against contamination
9. Control components and product related processes
10. Conduct planned and periodic audits
• Organisation and personnel
• Buildings and facilities
• Materials management
• Manufacturing operations and control
• Packaging operations
• Laboratory control
• Records and reports
• Returned goods.
• The first thing is people, who are backbone of all the
• GMP expects all the people should be trained. i. e. they
should have appropriate knowledge, skill and attitude.
• All personnel should receive necessary training in areas
relevant to their work and to hygienic aspects.
• They should be aware of the principles of GMP that affect
the quality of final product.
• There are many methods of training employees during employment.
• One of the latest method to train people in employment is by Instructional
system design (ISD).
• The ISD training model is briefly can be shown as
ANALYZE DESIGN DEVELOP IMPLEMENT EVALUATE
• Key personnel responsible for supervising the manufacture and quality control of
pharmaceutical products should possess the qualifications of a scientific education
and practical experience required by national legislation.
• The head of the quality control generally has the following responsibilities
a) authorization of written procedures (SOPs, STPs etc) and other documents,
b) Monitoring and control of the manufacturing environment;
c) Process validation and calibration of analytical apparatus;
d) Training, including the application and principles of quality assurance;
e) Approval and monitoring of suppliers of materials;
f) Approval and monitoring of contract manufacturers;
g) Designation and monitoring of storage conditions for
h) Retention of records;
i) Monitoring of compliance with GMP requirements.
• The head of the production generally has the following responsibilities:
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
d) To check the maintenance of the department, premises, and
e) To ensure that the appropriate process validations and calibrations of
control equipment are performed and recorded and the reports made
f) To ensure that the required initial and continuing training of production
personnel is carried out and adapted according to need.
• The person responsible for approving a batch for release should always
ensure that the following requirements have been met:
a) All the necessary checks and tests have been performed and account
taken of the production conditions and manufacturing records;
b) Any planned changes or deviations in manufacturing or quality control
have been notified in accordance with a well defined reporting system
before any product is released.
c) Any additional sampling, inspection, tests and checks have been carried
out or initiated, as appropriate, to cover planned changes and deviations;
d) All necessary production and quality control documentation has been
completed and endorsed by supervisors trained in appropriate
e) Approval has been given by the head of quality control;
Personnel hygiene and
• All personnel should be trained in the practices of personnel hygiene. In
particular, personnel should be instructed to wash their hands before entering
• Any person having an apparent illness or open lesions that may adversely
affect the quality of products should not be allowed to handle starting
materials, packaging materials, in-process materials or drug products.
• To ensure protection of the product from contamination, personnel should
wear clean body coverings appropriate to the duties they perform, including
appropriate hair covering.
• Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking
material and personal medicines should not be permitted in production,
laboratory and storage areas, or in any other areas where they might adversely
influence product quality.
Surroundings, Buildings and
• Surroundings of the plant
“The factory buildings for manufacture of drugs shall be so situated and
shall have such measure as to avoid risks of contamination from external
environment, including external sewage, drain, public lavatory or any
factory which produces disagreeable or obnoxious odour, excessive dust,
smoke, chemicals or biological emissions.”
Only Indian cGMP guidelines specifically talk about “surrounding” of
pharmaceutical plant prescribed in part 1 of schedule M of D&C act, 1940.
Many countries have industrial zone concept, i.e. a particular type of
industry is planned by design in a particular part of the country.
General Requirements of
WHO and USFDA provide guidelines on general requirements of the pharmaceutical
facilities on following points.
(heating ventilation air control system)
Adequate ventilation shall be provided
Equipment for adequate control over air pressure, micro organisms, dust ,
humidity ( 50% R.H) and temperature ( 22 to 25o
c) shall be provided when
appropriate for the manufacturing.
Air filtration systems, including pre filters and particulate matter air filters,
shall be used when appropriate on air supplies to production areas in areas
where air contamination occurs during production, there shall be adequate
exhaust systems or other systems adequate to control contaminants.
Air handling systems for the manufacturing, processing and packing of
Penicillin shall be completely separated from those for other drug products
for human use.
A suitably designed vacuum cleaning system in the dusty areas like tablet
granulation, compression or capsule filling etc.
Potable water which meets the standards prescribed in ‘Environmental
Protection Agency shall be supplied continuous positive pressure in plumbing
system free of defects that could contribute contamination to any drug
Drains should be of adequate size and , where connected directly to a sewer ,
shall be provided with an air break or other mechanical device to prevent
Adequate lighting shall be provided in all areas
Sewage and refuse
Sewage, trash and other refuse in and from the building and immediate
premises shall be disposed of in a safe and sanitary manner.
Washing and Toilet facilities
Adequate washing facilities shall be provided, including hot and cold water,
soap, air driers or single service towels, and clean toilet facilities easily
accessible to working areas.
No. of users Min. No. of water closets
Over 150 One additional for each 40 users
Any building used in the manufacture, packing or holding of a drug product shall
be maintained in a cleaned and sanitary condition and shall be free of
infestations by rodents, birds , insects and other vermin.
There shall be written procedures assigning responsibility for sanitation and
describing in sufficient detail the cleaning schedules, methods, equipment and
materials to be used in cleaning the building and facilities: such written
procedures shall be followed.
There shall be written procedures for use of rodenticides, insecticides,
fungicides , fumigating agents and cleaning and sanitizing agents.
Sanitation procedures shall apply to work performed by contractors or
temporary employees as well as full time employees .
Any building used in the manufacture, packing or holding of a drug product shall
be maintained in a good state of repair.
Storage and Dispensing
Storage areas should be of sufficient capacity to allow orderly storage of the
various categories of materials and products like S.M,P.M,I.P,B.F.P and released,
rejected, returned or recalled products.
Storage areas should be designed to ensure good storage conditions.
Receiving and dispatch bays should protect materials and products from the
Where quarantine status is ensured by storages in separate areas.
There should normally be separate sampling areas for Starting materials.
Segregation should be provided for the storage of rejected, returned or recalled
Highly active materials, Narcotics and other dangerous drugs should be stored in
safe and secure areas.
The weighing of S.Ms and the estimation of yield by weighing should usually be
carried at in separate weighing areas.
In order to minimise the risk of a serious medical hazards due to cross
contamination, dedicated and contained facilities must be available for the
production of particular pharmaceutical products, such as any sensitizing
materials or biological preparations.
Premises should preferably 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 operation and to the requisite cleanliness levels.
Interior surface should be smooth and free from cracks and open joints, should
not shed particulate matter, and should permit easy and effective cleaning.
Pipe work, light fittings and ventilation points should be designed to clean
easily and effectively.
Drains should be of adequate size and equipped to prevent back flow.
Production areas should be effectively ventilated with air control facilities
appropriate to the products handled.
Premises for the packing of pharmaceutical products should be specifically
designed and laid out so as to avoid mix-ups or cross contamination.
Production areas should be well lit, particularly where visual on line controls are
Sterile Production Area
All premises should as per as possible be designed to allow only authorized
In clean areas all exposed surfaces should be smooth, impervious and unbroken in
order to minimize the shedding or accumulation of particles or micro organisms.
To reduce the accumulation of dust there should be minimum of projecting
ledges, shelves , cupboard and equipment.
Changing rooms should be designed such that the air locks used provide
separation of the different stages of changing so as to minimize microbial and
particulate contamination of protective clothing.
An interlocking system and a visual or audible warning system should be operated
to prevent the opening of more than one door at a time.
a filtered air supply should maintain a positive pressure.
it should be demonstrated that airflow patterns do not present a
a warning system should be provided to indicate failure in the air supply.
the airborne particulate classification for different grades is given as
Grade max. Permitted no. of particles/ m3
At rest in operation
0.5µm 5 µm 0.5µm 5 µm
A 3500 0 3500 0
B 3500 0 3,50,000 2000
C 3,50,000 2000 35,00,000 20,000
D 35,00,000 20000 not defined not defined
examples of operations of terminally sterilised products
A Filling of products, when unusually at risks
B Surroundings for Grade A
C Preparations of solutions, when unusually at risks
D Preparations of solutions and components for subsequent filling
examples of operations for aseptic preparations
A Aseptic preparation and filling
C Preparations of solutions to be filled
D Handling of components after washing.
Quality Control Area
QC laboratories should be separated from production areas. Areas where
biological, microbiological or radioisotopes test methods are employed should
be separated from each other.
Control labs should be designed to suit the operations to be carried out in
them. Sufficient space should be given to avoid mix-ups and cross
The design of the labs should take into account the suitability of construction
materials, prevention of fumes, and ventilation. A separate air handling units is
needed for biological, microbiological or radioisotope labs.
A separate room may be needed for instruments to isolate from other
Equipment is one of the major inputs, along with people, facilities and
The quality of the manufactured product much depends upon the quality,
suitability, and level of technology of the equipment used.
Two types of equipment are used in industry-
- a single piece: e.g.. HPLC, GC, tablet compression machine etc.
- an integrated system e.g.. Water demineralising plants, HVAC etc.
Since the equipment is one of the major inputs in the manufacture of the
pharmaceutical products, in the regulatory literature on GMP in various
countries given enough importance and hence describe and provide guidelines
on the management of equipment in the pharmaceutical plants.
Equipment management in the pharmaceutical industry has a life cycle, and the
GMP requirement cover the entire life cycle of the equipment. It starts with the
decision to purchase equipment and hence with the elimination from the
life cycle include:
– Decision to purchase an equipment
– Purchase of the equipment
– Installing and validating the equipment
– Using the equipment (operation, cleaning and maintenance)
– Preventive maintenance and revalidation
– Replacing the equipment
Equipment must be located, designed, constructed and maintained to suit the
operation to be carried out. The layout and design of the equipment must aim
to minimise the risk of errors and permit effective cleaning and maintenance
in order to avoid cross contamination.
Production equipment should be designed, located and maintained to serve its
Production equipment should be designed, so that it can be easily and
thoroughly cleaned on scheduled basis.
Production equipment should not present any hazard to the products. The parts
of the production equipment that come in to contact with the product must not
be reactive, additive, adsorptive . (M.O.C – SS 316 or SS 316 L)
Any substance required for operation, such as , lubricants shall not come in to
contact with components of drug products.
Identification is one of the four quality attributes in the quality of
pharmaceuticals and the identity of the equipment is also one of the important
All compounding and storage containers , processing lines, and major
equipment used during the production of a batch of a drug product shall be
properly identified at all times.
Major equipment shall be identified by a distinctive identification no. or code.
The identification no. shall be recorded in the B.P.R to show the specific
equipment used in the manufacture of each batch of a drug product, in case
where only one of a particular type equipment exists in manufacturing facility,
the name of the equipment may be used in stead of distinctive identification
no. or code.
Equipment Cleaning and
Use of cleaned equipment is one of the basic step in avoiding contamination and
meeting the ‘purity’ of the product being produced using the equipment.
Equipment shall be cleaned, maintained and sanitized at appropriate intervals
to prevent mal function or contamination.
Written procedures shall be established and followed for cleaning and
maintenance of equipment. These include:
Assignment of responsible person.
Maintenance and cleaning schedules, including, where appropriate sanitizing
A description in sufficient detail of the methods , equipment, and materials
used in cleaning and maintenance operations, and the methods of dis
assembling and re assembling equipment as necessary to assure proper
cleaning and maintenance.
– Removal of previous batch identification.
– Protection of clean equipment from contamination prior to use.
– Inspection of equipment for cleaning immediately before use.
– Defective equipment should be removed from production and QC or at
least be clearly labelled as defective.
• Records shall be kept of maintenance, cleaning, sanitizing and inspection.
• A planned preventive maintenance programme and SOP for carrying out the
maintenance should be in place.
Every equipment must have SOPs for operation, cleaning and maintenance.
There may be a system to distinguish the equipment in three categories.
Operational equipment (Green card) that means this equipment can be
used for processing.
Equipment under maintenance ( Yellow card ). This equipment can be used
only after the maintenance job is over.
Defective equipment (Red card ). This equipment should be removed from
operational area immediately.
Filtration is one of the process used in pharmaceutical operation and air
Filter for liquid filtration used in the manufacture, processing or packing of
injectable drug products intend for human use shall not release fibre into such
If use of fibre releasing filter is necessary and additional non fibre releasing
filter of 0.22 micron shall subsequently be used to reduce the content of
particles in the injectable drug products.
Where applicable , liquid products should pass through suitable filtration
equipment before being filled.
In pharma manufacturing weighing of materials is one of the crucial activity.
All raw materials and certain packaging materials are required to be weighed
Measuring , weighing, recording, and control equipment should be calibrated
and checked at defined intervals by appropriate method.
Adequate record of such tests should be maintained.
Automatic Mechanical and
Many programmable logic control device are today used for controlling
manufacturing and control process.
Automatic, mechanical, and electronic equipment or other types of equipment ,
including computers, that will perform a function satisfactorily.
Appropriate controls shall be exercised over computer or related systems to
assure the change in M.P.C.R or other records are instituted only by authorized
All computer system must be fully validated and records maintained for the
• As we all know that quality of a pharmaceutical product is required to be built in
to the product and one cannot only relay upon testing of the finished product.
• For this reason the management of materials from the G.M.P point of view
involve dealing with the following aspects.
– Raw materials – active and inactive
– Packaging materials – 1o
– Dispensing of RM /PM
– Intermediate and bulk materials
– Finished products
– Rejected and recovered materials
– Reagents and culture media
– Reference and working standards
– Waste materials
– Miscellaneous materials.
All materials that go into the manufacturing of a finished bulk product ( even
though it may not be present in the final product e.g. certain solvents and
excipients etc.) and which are consumed by the person using it are called raw
raw materials can be either active drugs or inactive substances.
– The main objective of pharmaceutical plant is to produce finished products
for patients use from a combination of materials ( active, auxiliary, packing).
Special attention should be given to the materials as such.
– All incoming materials and finished products should be quarantined
immediately after receipt or processing, until they are released for use or
– All materials and products should be stored under the appropriate
conditions established by the manufacture and in an orderly fashion to
permit batch segregation and stock rotation by a “ first in first out” rule.
Starting materials should be purchased only from supplier named in the
relevant specification and where possible, directly from the producer.
For each consignment, the containers should be checked for integrity of
package and seal, the delivery note and the suppliers labels.
Damage to containers and any other problem that might adversely affect the
quality of a material should be recorded and reported to Q.C. department
Starting materials in the storage area should be appropriately labelled.
Labels should bear at least
– The designated name of the product and the internal code reference
– The batch no. given by the supplier
– The status of the content
– Expiry date .
There should be appropriate procedure and measures to ensure the identity
of the contents of each container of RM.
RM should be dispensed only by designated persons, following a written
procedures to ensure that the correct materials are accurately weighed in to
clean and properly labelled containers.
Each dispensed materials and its weight or volume should independently
checked and recorded.
Materials dispensed for each batch of the final product should be kept
together and conspicuously labelled as such.
There shall be written procedures describing in sufficient detail the receipt,
identification, storage, handling, sampling, testing, and approval or rejection
of components and drug product containers and closures; such written
procedures shall be followed.
Packaging materials are divided into
– Primary packaging materials which come into contact with the product
(ampoules, vials, rubber plugs, bottles, foils etc.)
– Secondary packaging materials which come into contact with the sealed
Primary packaging materials. ( cartons, labels , inserts etc.)
– Tertiary packaging materials are other than 1o
( shippers, nylon straps, external labels, gum tapes etc.)
– Printed packaging materials.
– Unprinted packaging materials.
The purchase, handling and control of primary and printed packing materials
shall be as per staring materials.
Particular attention should be paid to printed packaging materials. They should
be stored in secure conditions so as to exclude the possibility of unauthorized
Each delivery or batch of printed and Primary packaging materials should be
given a specific reference no.
Out dated primary and Printed packaging materials should be destroyed and its
Labels for each different drug product, strength, dosage form or quantity of
content shall be stored separately with suitable identification.
Intermediate and Bulk
Technically all dispensed materials when undergo the first processing stage
till it gets converted into the packable finished bulk product is called
intermediate products ( sifted RM, granules, unfiltered liquids.)
The bulk product which has undergone all processing stages except the final
packaging into the primary containers is called bulk products.
Inprocess materials shall be tested for identity, strength, quality and purity
as appropriate and approved or rejected by the Q.C. unit, during production
Rejected in process materials shall be identified and controlled under a
quarantine system designed to prevent their use in manufacturing for which
they are unsuitable.
A product in the marketable pack is classified as finished product. Practically a
transportable pack i.e. a shipped containing the saleable pack in retail.
FPs should be held in quarantine until their final release.
For each batch of drug product, there should be an appropriate laboratory
determination of satisfactory conformity to its FPs specification prior to
Product failing to meet the established specification or any other relevant
quality criteria should be rejected.
Reprocessing may be performed if feasible but the Reprocessed product
should meet all the specifications.
Rejected Recovered and
Materials and products can be rejected at any stage of manufacturing starting
from the receipt of SMs till FPs.
Recovered products are those products, which are either reprocessed in
normal processing or materials which are not meeting the specifications at
any stage of manufacturing but can be brought to the desired specification
Rejected materials should be clearly marked as such and stored separately in
The reprocessed or rejected products should be exceptional. It is permitted
only if the quality of the final product is not affected.
The recovery should be carried out in accordance with a defined procedure
after evaluation of the risks involved, including any possible effect on shelf
life. The recovery should be recorded.
Recalled and Returned
Once the FPs that are sent out from the plant for distribution or sale may at
times required to be called back or returned from market:
– The quality product sent out was found to be sub standard.
– The goods being transported met with an accident and damaged in
– FDA officials has found some quality issues and advised the company to
recall the products.
– Some goods have been dispatched wrongly.
– Expired goods.
Recalled products should be identified and stored separately in a secure area
until a decision is taken on their fate. The decision should be made as soon as
Reagents and Culture
GMP related regulations about materials also cover reagents and culture
All reagents and culture media should be recorded upon receipt or
The reagents in the laboratory should be prepared according to written
procedures and appropriately labelled.
Both positive and negative controls should be applied to verify the
suitability of culture media.
Reference and working
Reference standards prepared by the producer should be tested and then
stored in the same way as official standards. They should be kept under the
responsibility of a designated person in a secure area.
Usually reference standards can be procured from NIST ( national Institute
of Standards and technology).
working standards may be established by the application of appropriate
tests and checks at regular intervals to ensure standardisation.
All reference standards should be stored and used in a manner that it will
not adversely affect their quality.
Waste materials can be divided into :
– Scrap: like rejected foils, bottles, cans tins etc. has a resale value and
needs to segregated and stored well to fetch a good price.
– Trash: like dust and unsalable materials does not have a resale value
and disposed by suitable means.
Provisions should be made for the proper and safe storage of waste
materials . Toxic substances and flammable materials should be stored in
suitable designed, separate, enclosed cupboards.
Waste materials should not be allowed to accumulate.
Rodenticides, insecticides, fumigating agents and sanitizing materials
should not be permitted to contaminate equipment, SMs, PMs, IPMs or FPs.
• The main objective of the manufacturing is to produce a quality product
which meets the following four characteristics:
» Purity to deliver a therapeutically efficient product.
• All the regulatory authorities world over emphasize following points to
• Production operation must follow clearly defined procedure in accordance
with manufacturing and marketing authorizations, with the objective of
obtaining products of desired quality.
• All handling of materials and products, such as receipts and quarantine,
sampling, storage, labelling, dispensing, processing, packaging, and
distribution should be done in accordance with written procedures and
• Any deviation from procedure should be avoided as far as possible. If
deviation occur, they should be approved in writing by a designated person.
• Checks on yields of quantities should be carried out as necessary to ensure
that there are not beyond the acceptable limits.
• Operation on different products should not be carried out simultaneously in
the same room unless there is no risk of mix-ups and cross contamination.
• At all the times during processing, all materials bulk containers major items of
equipment used be labelled with an indication of the product being
processed, its strength and the batch number.
• Access to production premises should be restricted to authorized personnel.
• Normally non-medical products should not be produced in areas or with
equipment destined for the production of pharmaceutical product.
• At every stage of processing products and materials should be protected
from microbial and the contamination.
Sanitation of Manufacturing
• Cleaning, sanitation and disinfection of manufacturing premises are
important to achieve purity in the finished pharmaceutical by avoiding
• The manufacturing premises shall be cleaned and maintained in an orderly
manner, so that it is free from accumulated waste, dust, and other similar
materials. A validated cleaning procedure shall be maintained.
• The manufacturing areas shall not be used for storage of materials, except
for the materials being processed.
• A routine sanitation programme which indicate
– Specified area to be cleaned and cleaning intervals.
– Cleaning procedures to be followed, including equipment and materials
to be used for cleaning.
– Personnel assigned to and responsible for cleaning operation.
Prevention of Mix-Ups and
• Things that can contaminate product include:
– Dust, grit, particles.
– Active chemical substances from other ingredients or other products.
– “Germs” and other micro organisms.
• Sources of contamination,
– Raw materials
• Where dry materials and products are used in production, special precaution
should be taken to prevent the generation and accumulation of dust.
• Contamination of a starting materials or of a product by another materials
has to be avoided.
• Cross-contamination should be avoided by:
– Production in segregated areas.
– Providing appropriate airlocks, pressure differentials, and air extraction.
– Wearing protective clothing.
– Using cleaning procedure of known effectiveness.
– Using a “ closed system ” of production.
– Testing for residues.
– Using cleanliness status on equipment.( clean immediately after use and
use after checking the cleanliness.)
Control of Microbial
• Appropriate written procedures, designed to prevent objectionable
microorganisms in drug products not required to be sterile, shall be
established and followed.
• Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be established
and followed. Such procedures shall include validation of any sterilization
• It is necessary to require many non-sterile products to be controlled for
microbial load. E.g. starch.
• All sterilizing systems must be fully validated.
Dispensing of Materials
• Dispensing of materials refers to issuing of batch-wise materials. This is the
first stage where manufacturing operation starts.
• Dispensing of Starting Materials:
– Starting materials should only be purchased from approved suppliers.
– Starting materials in the storage area should be appropriately labelled.
Labels should bear at least the following:
• The designated name and internal code reference.
• A batch no.
• The status of the contents
• An expiry date.
• Starting materials should only be dispensed and countersigned by designated
• The purchase , handling and control of primary and printed packaging materials
shall be accorded attention similar to that given to starting materials.
• Packaging materials should be issued for use only by authorised personnel
following an approved and documented procedure.
• Each delivery or batch of packaging materials should be given a specific
reference number or identification number.
• Out-dated or obsolete packaging materials or printed packaging materials
should and this disposal recorded.
• There should be an SOP for disposal of out-dated packaging materials, which
– Name of the materials -Reason for becoming out-dated
– Quantity involved -management approval for
– Procedure for destruction like burning etc
– Date and time of destruction. -record of such destructions.
Dispensing of Packaging
Processing of Intermediate,
Bulk Product and Packaging
• Pharmaceutical manufacturing operation can be divided into 3 categories:
– Intermediate Product: The materials undergoes from dispensed stage of a
batch materials till it gets converted into the final stage of formulation ready
for primary packaging.
– Bulk Product: the stage of formulation ready for primary packing.
– Packaging of bulk product: is process of converting bulk product into the
saleable transportable goods.
• Processing operations : IM and BPs
– Prior to the processing , the work area and equipment shall be clean and
free from product residues, labels or documents not required for current
– Any necessary IP controls and environmental controls should be carried
out and recorded.
– Defective equipment should be withdrawn from use until the defect has
been rectified. Production equipment should be cleaned.
• When the programme for packaging operations is being set up, particular
attention should be given to minimizing the risk of cross-contamination or mix-
• Physical segregation is necessary for different products packaged in same
• Prior to packaging, the area and equipment should be free form any products,
materials, or documents previously used.
• The line clearance should be performed according to an appropriate checklist
and recorded. The correct performance of any printing should be checked and
• Online control of product during packaging should be performed.
• Process deviations can be defined as variation in the production from the
• Any deviation from the written procedure shall be recorded and justified.
• Actual yields and % of theoretical yield shall be determined at each
appropriate phase of manufacturing, processing. Such calculation shall be
performed by one person and independently verified by a second person.
– For e.g. tablets:
– End of lubrication stage
– End of compression
– End of coating etc.
Calculation of Yield
• Reprocessing is an activity which is carried out on manufactured batch when
it fails to meet the required specification.
• When reprocessing is necessary, written procedures shall be established and
approved by Q.A. department.
• Recovery of a product residue may be carried out based on the guidelines like:
– 5% to 10% recovery can be added in 1 st
– The recovery added should not be more than 3 months old, from the date
– Recovery mixture should be analysed and if found within specification then
only it should be added to the fresh batch.
– This batch must undergo in routine stability studies.
Time Limitation on
• When appropriate, time limits for the completion of each phase of production
shall be established to assure the quality of the drug product. Deviation from
established time limits may be acceptable if such deviation does not
compromise the quality of the drug product.
• Packaged and labelled products shall be examined during finishing operations to
provide assurance that containers and packages in the lot have the correct
• Results of these examinations shall be recorded.
Drug product inspection
• To assure that a drug product meets applicable standards of identity,
strength, quality, and purity at the time of use, it shall bear an expiration date
determined by appropriate stability testing.
• Expiration dates shall be related to any storage conditions stated on the
labelling, as determined by stability studies.
• Expiration dates shall appear on labelling.
• Homeopathic drug products shall be exempted from this section.
• New drug products for investigational use are exempt from the requirements
of this section.
• GMP AND cGMP CONSIDERATIONS by Dr. Basavaraj K. Nanjwade
• cGMP for pharmaceuticals by Manohar A. Potdar.
• FDA Food and Drug Administration. GMP Combination Handbook. 31 Aug.
• The Center for Professional Advancement. Good Manufacturing Practice.
1 Sep. 2008.