Gmp final 97 03

Presented byP. 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 required quality.

QA, GMP & QC inter-relationship

QC

GMP

QA

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

use

QA

Is that part of Quality Assurance aimed at ensuring that products are

consistently manufactured to a quality appropriate to their intended

use(PRODUCTION BASED)

GMP

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 quality

(LAB BASED)

QC

Good Manufacturing Practices

• 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 manufacturing process.

• It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.

Quality Definit ion

• 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 recognized GMP.

• 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.

GMP Covers…

• 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 guidelines

• GMP as per Schedule “M” (INDIA) www.cdsco.nic.in• GMP as per WHO www.who.int• GMP as per MCA now known as MHRA (UK) www.mca.gov.uk• GMP as per TGA (AUSTRALIA) www.tga.gov.au• GMP as per US FDA (US) www.fda.gov• GMP as per ICH guidelines www.ich.org

Ten Principles of GMP1. 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 instructions

7. Design ,develop and demonstrate job competence

8. Protect against contamination

9. Control components and product related processes

10. Conduct planned and periodic audits

Certifying agencies

• ICH. www.ich.org

• WHO. www.who.int

• US FDA. www.fda.gov

• EU/EMEA. www.emea.europa.eu

GMP REQUIREMENTS• Organisation and personnel• Buildings and facilities• Equipment• Materials management• Manufacturing operations and control• Packaging operations• Laboratory control• Records and reports• Returned goods.

Organisation and personnel

• The first thing is people, who are backbone of all the activities.

• 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.

ORGANIZATION CHART

CHAIRMAN

MANAGING DIRECTOR

PRESIDENT PRODUCTION

PRESIDENT QAPRESIDENT

MARKETINGPRESIDENT FINANCE

PRESIDENT PERSONNEL

GM PRODUCTION

GM ENGINEERING

GM WAREHOUSING

GM FACTORY PERSONNEL

GM FACTORY ACCOUNTS

MANAGER TABLETS

MANAGER CAPSULES

MANAGER LIQUIDS

MANAGER INJECTION

EXCECUTIVES

SUPERVISORS

WORKERS

TRAINING

• 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

ISD MODEL

ANALYZE DESIGN DEVELOP IMPLEMENT EVALUATE

Key personnel responsibil i t ies

• 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

materials;

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 designated person;

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;

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 disciplines;

e) Approval has been given by the head of quality control;

Personnel hygiene and health

• All personnel should be trained in the practices of personnel hygiene. In particular, personnel should be instructed to wash their hands before entering production areas.

• 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 Facil i t ies

• 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 the Facil i t ies

WHO and USFDA provide guidelines on general requirements of the pharmaceutical facilities on following points.

HVAC systems(heating venti lat ion 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.

Plumbing 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 product.

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 back-siphonage.

Lighting 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

1-15 1

16-35 2

36-55 3

56-80 4

81-110 5

111-150 6

Over 150 One additional for each 40 users

Sanitation 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 .

Maintenance 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 Areas

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

weather. 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

products. 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.

Production 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 carried out.

Steri le Production Area All premises should as per as possible be designed to allow only authorized

persons.

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 contamination risks.

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 area

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

grade

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

grade

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 contamination.

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 instruments.

EQUIPMENT Equipment is one of the major inputs, along with people, facilities and

materials.

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.

General Requirements

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 operation.

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

Guidelines 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 intend purpose.

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.

Equipment Identif ication 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 items.

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 Maintenance

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

schedules. 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.

Filters

Filtration is one of the process used in pharmaceutical operation and air systems.

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 products.

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.

Weighing Balances

In pharma manufacturing weighing of materials is one of the crucial activity. All raw materials and certain packaging materials are required to be weighed accurately.

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 Electronic Equipment

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 personnel.

All computer system must be fully validated and records maintained for the same.

Material Management• 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 , 2o and others– 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.

Raw 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 materials.

raw materials can be either active drugs or inactive substances. General requirements

– 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 distribution.

– 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 and investigated.

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

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 and 2o packaging materials. ( 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 access.

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 disposal recorded.

Labels for each different drug product, strength, dosage form or quantity of content shall be stored separately with suitable identification.

Intermediate and Bulk Products

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 process.

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.

Finished Products 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 release.

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 Reprocessed products

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 after processing.

Rejected materials should be clearly marked as such and stored separately in restricted areas.

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 Products

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

transit– 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 possible.

Reagents and Culture media.

GMP related regulations about materials also cover reagents and culture media.

All reagents and culture media should be recorded upon receipt or preparation.

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 standards

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

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.

Miscellaneous materials: Rodenticides, insecticides, fumigating agents and sanitizing materials

should not be permitted to contaminate equipment, SMs, PMs, IPMs or FPs.

Manufacturing Operations and Control

• The main objective of the manufacturing is to produce a quality product which meets the following four characteristics:

» Identity» Strength» Safety» Purity to deliver a therapeutically efficient product.

• All the regulatory authorities world over emphasize following points to achieve this.

General Requirements

• 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 record.

• 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 Premises

• Cleaning, sanitation and disinfection of manufacturing premises are important to achieve purity in the finished pharmaceutical by avoiding contamination.(schedule M)

• 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 Cross-Contamination

• 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, – Building– Raw materials– Equipment– People– Facilities.

Guidelines • 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 Contamination

• 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 process.

• 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 person.

• 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 include-– Name of the materials -Reason for becoming out-dated– Quantity involved -management approval for

destruction– Procedure for destruction like burning etc– Date and time of destruction. -record of such destructions.

Dispensing of Packaging Materials

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 operation.

– 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.

Packaging Operations

• When the programme for packaging operations is being set up, particular attention should be given to minimizing the risk of cross-contamination or mix-ups.

• Physical segregation is necessary for different products packaged in same room.

• 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 recorded.

• Online control of product during packaging should be performed.

PROCESS DEVIATIONS• Process deviations can be defined as variation in the production from the

predetermined procedure.• 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

• 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 batch.– The recovery added should not be more than 3 months old, from the date

of manufacturing.– 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 Production

• 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 label.

• Results of these examinations shall be recorded.

Drug product inspection

Expiration Dating

• 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.

References

• 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.

2008.• The Center for Professional Advancement. Good Manufacturing Practice.

1 Sep. 2008.