Good Manufacturing Practice for Pharmaceutical Products

By: Pharma Tips | Views: 13138 | Date: 12-Jan-2013

Good manufacturing practice (GMP) comprises that part of quality assurance aimed at ensuring that a product is consistently manufactured to a quality appropriated to its intended use. GMP requires that the manufacturing process is fully defined before it is initiated and that all necessary facilities are provided. In practice, this means that personnel must be adequately trained, suitable premises and equipment used, correct materials used, approved procedures adopted, suitable and transport facilities avai

Good Manufacturing Practicefor Pharmaceutical Product



Good Morning Practice



Good Manufacturing Practicefor Pharmaceutical Products




What is GMP?

Good manufacturing practice (GMP) comprises that part of qualityassurance aimed at ensuring that a product is consistently manufactured to aquality appropriated to its intended use. GMP requires that the manufacturingprocess is fully defined before it is initiated and that all necessaryfacilities are provided. In practice, this means that personnel must beadequately trained, suitable premises and equipment used, correct materialsused, approved procedures adopted, suitable and transport facilities availableand appropriate records made.


The quality of pharmaceutical products depends on the degree ofcare taken in its preparation. Final checks carried out on the finishedproducts are useful in confirming that the correct ingredients have been usedand that that materials have been correctly processed. It is however essentialthat proper in process control is exercised and that it is adequatelydocumented to provide reliable evidence that the correct procedures have beenfollowed. The need for GMP is recognized throughout the world. More than 20countries have issued their own GMP guidelines. (The essential components ofGMP are summarized in figure 1.)



Why it is required?

The Good Manufacturing Practices are prescribed to ensure that:

(i) Rawmaterials used in the manufacture of pharmaceuticals are authentic, ofprescribed quality and are free from contamination.

(ii)The manufacturing process is as has been prescribed to maintain the standards.

(iii)Adequate quality control measures are adopted and

(iv)The manufactured drug which is released for sale has the prescribed quality.

(v) Toachieve the objectives listed above, each licencee shall evolve methodology andprocedures for following the prescribed process of manufacture of drugs whichshould be documented as a manual and kept for reference and inspection.However, teaching institutions and registered qualified Vaidyas, Siddhas andHakeems who prepare medicines on their own to dispense to their patients andnot selling such drugs in the market are exempted from the purview of G.M.P.


World Health Organization (WHO) GMP

WHO defines good manufacturing practice has "that part ofquality assurance which assures that products are consistently produced andcontrolled to the quality standards appropriate to their indented use and asrequired by the marketing authorization"


GMP covers all aspects of the manufacturing process: definedmanufacturing processes; critical manufacturing steps; suitable premises,storage, transport; qualified and trained production and quality controlpersonnel; adequate laboratory facilities; approved written procedures andinstructions; records to show all steps of defined procedures have been taken;full traceability of a product through batch rewards and distribution recordsand systems for recall and investigation of complaints.




1.1. Location and surroundings.- Thefactory building(s) for manufacture of drugs shall be so situated and shallhave such measures as to avoid risk of contamination from external environmentincluding open sewage, drain, public lavatory or any factory which producesdisagreeable or obnoxious, odour, fumes, excessive soot, dust, smoke, chemicalor biological emissions.

1.2. Buildings and premises.– Thebuilding(s) used for the factory shall be designed, constructed, adapted andmaintained to suit the manufacturing operations so as to permit production ofdrugs under hygienic conditions. They shall conform to the conditions laid downin the Factories Act, 1948 (63 of 1948).

The premises used for manufacturing, processing, warehousing,packaging, labeling and testing purposes shall be -

1.     compatiblewith other drug manufacturing operations that may be carried out in the same oradjacent area / section;

2.     adequatelyprovided with working space to allow orderly and logical placement ofequipment, materials and movement of personnel so as to :

3.     avoidthe risk of mix-up between different categories of drugs or with raw materials,intermediates and in-process material;

4.     avoidthe possibilities of contamination and cross-contamination by providingsuitable mechanism;

(iii) designed / constructed / maintained to prevent entry ofinsects, pests, birds, vermins, and rodents. Interior surface (walls, floors,and ceilings) shall be smooth and free from cracks, and permit easy cleaning,painting and disinfection;

(iv)air conditioned, where prescribed for the operations and dosage forms underproduction. The production and dispensing areas shall be well lighted,effectively ventilated, with air control facilities and may have proper AirHandling Units (wherever applicable) to maintain conditions includingtemperature and,wherever necessary, humidity
as defined for the relevant product. These conditions shall be appropriateto the category of drugs and nature of the operation. These shall also besuitable to the comforts of the personnel working with protective clothing,products handled, operations undertaken within them in relation to the externalenvironment. These areas shall be regularly monitored for compliance withrequired specifications;

(v)provided with drainage system, as specified for the various categories ofproducts, which shall be of adequate size and so designed as to prevent back-flow and/or to prevent insects and rodents entering the premises. Open channelsshall be avoided in manufacturing areas and, where provided, these shall beshallow to facilitate cleaning and disinfection;

(vi)The walls and floors of the areas where manufacture of drugs is carried outshall be free from cracks and open joints to avoid accumulation of dust. Theseshall be smooth, washable, coved and shall permit easy and effective cleaningand disinfection. The interior surfaces shall not shed particles. A periodicalrecord of cleaning and painting of the premises shall be maintained.

1.3 Water system

There shall be validated system for treatment of water drawnfrom own or any other source to render it potable in accordance with standardsspecified by the Bureau of Indian Standards or Local Municipality, as the casemay be, so as to produce Purified Water conforming to Pharmacopoeialspecification. Purified Water so produced shall only be used for all theoperations except washing and cleaning operations where potable water may beused. Water shall be stored in tanks, which do not adversely affect quality ofwater and ensure freedom from microbiological growth. The tank shall be cleanedperiodically and records maintained by the licensee in this behalf.


1.4 Disposal of waste

(i) The disposal of sewage and effluents (solid, liquid and gas)from the manufactory shall be in conformity with the requirements of EnvironmentPollution Control Board.

(ii) All bio-medical waste shall be destroyed as per theprovisions of the Bio-Medical Waste (Management and Handling) Rules, 1996.

(iii) Additional precautions shall be taken for the storage anddisposal of rejected drugs. Records shall be maintained for all disposal ofwaste.

(iv) Provisions shall be made for the proper and safe storage ofwaste materials awaiting disposal. Hazardous, toxic substances and flammablematerials shall be stored in suitably designed and segregated enclosed areas inconformity with Central and State Legislations.


  1. Adequate areas shall be designed to allow sufficient and orderly warehousing of various categories of materials and products like starting and packaging materials, intermediates, bulk and finished products, products in quarantine, released, rejected, returned or recalled, machine and equipment spare parts and change items.
  2. Warehousing areas shall be designed and adapted to ensure good storage conditions. They shall be clean, dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g., temperature, humidity), these shall be provided, monitored and recorded. Storage areas shall have appropriate house-keeping and rodent, pests and vermin control procedures and records maintained. Proper racks, bins and platforms shall be provided for the storage of materials.
  3. Receiving and dispatch bays shall protect materials and products from adverse weather conditions.
  4. Where quarantine status is ensured by warehousing in separate earmarked areas in the same warehouse or store, these areas shall be clearly demarcated. Any system replacing the physical quarantine, shall give equivalent assurance of segregation. Access to these areas shall be restricted to authorized persons.
  5. There shall be a separate sampling area in the warehousing area for active raw materials and excipients. If sampling is performed in any other area, it shall be conducted in such a way as to prevent contamination, cross- contamination and mix- up.
  6. Segregation shall be provided for the storage of rejected, recalled or returned materials or products. Such areas, materials or products shall be suitably marked and secured. Access to these areas and materials shall be restricted.
  7. Highly hazardous, poisonous and explosive materials such as narcotics, psychotropic drugs and substances presenting potential risks of abuse, fire or explosion shall be stored in safe and secure areas. Adequate fire protection measures shall be provided in conformity with the rules of the concerned civic authority.
  8. Printed packaging materials shall be stored in safe, separate and secure areas.
  9. Separate dispensing areas for (Beta)
    lactum, Sex Hormones and Cyto-toxic substances or any such special categories of products shall be provided with proper supply of filtered air and suitable measures for dust control to avoid contamination. Such areas shall be under differential pressure.
  10. Sampling and dispensing of sterile materials shall be conducted under aseptic conditions conforming to Grade A, which can also be performed in a dedicated area within the manufacturing facility.
  11. Regular checks shall be made to ensure adequate steps are taken against spillage, breakage and leakage of containers.
  12. Rodent treatments (pest control) should be done regularly and at least once in a year and record maintained.


1.Theproduction area shall be designed to allow the production preferably inuni-flow and with logical sequence of operations.

2.In orderto avoid the risk of cross-contamination, separate dedicated and self-containedfacilities shall be made available for the production of sensitivepharmaceutical products like penicillin or biological preparations with livemicro-organisms. Separate dedicated facilities shall be provided for themanufacture of contamination causing and potent products such as Beta lactum,Sex Hormones and Cyto-toxic substances.

3.Workingand in-process space shall be adequate to permit orderly and logicalpositioning of equipment and materials and movement of personnel to avoidcross-contamination and to minimize risk of omission or wrong application ofany of manufacturing and control measures.

4.Pipe-work,electrical fittings, ventilation openings and similar service lines shall bedesigned, fixed and constructed to avoid creation of recesses. Service linesshall preferably be identified by colours and the
nature of the
supply and direction of the flow
shall be marked/indicated.


  1. Rest and refreshment rooms shall be separate from other areas. These areas shall not lead directly to the manufacturing and storage areas.
  2. Facilities for changing, storing clothes and for washing and toilet purposes shall be easily accessible and adequate for the number of users. Toilets, separate for males and females, shall not be directly connected with production or storage areas. There shall be written instructions for cleaning and disinfection for such areas.
  3. Maintenance workshops shall be separate and away from production areas. Whenever spares, changed parts and tools are stored in the production area, these shall be kept in dedicated rooms or lockers. Tools and spare parts for use in sterile areas shall be disinfected before these are carried inside the production areas.
  4. Areas housing animals shall be isolated from other areas. The other requirements regarding animal houses shall be those as prescribed in rule 150-C(3) of the Drugs and Cosmetics Rules, 1945 which shall be adopted for production purposes.


1.QualityControl Laboratories shall be independent of the production areas. Separateareas shall be provided each for physico-chemical, biological, microbiologicalor radio-isotope analysis. Separate instrument room with adequate area shall beprovided for sensitive and sophisticated instruments employed for analysis.

2.QualityControl Laboratories shall be designed appropriately for the operations to becarried out in them. Adequate space shall be provided to avoid mix-ups andcross-contamination. Sufficient and suitable storage space shall be providedfor test samples, retained samples, reference standards, reagents and records.

3.Thedesign of the laboratory shall take into account the suitability ofconstruction materials and ventilation. Separate air handling units and otherrequirements shall be provided for biological, microbiological andradioisotopes testing areas. The laboratory shall be provided with regularsupply of water of appropriate quality for cleaning and testing purposes.

.4.QualityControl Laboratory shall be divided into separate sections i.e. for chemical,microbiological and wherever required, biological Testing. These shall haveadequate area for basic installation and for ancillary purposes. Themicrobiology section shall have arrangements such as airlocks and laminar airflow work station, wherever considered necessary.




1.Themanufacture shall be conducted under the direct supervision of competenttechnical staff with prescribed qualifications and practical experience in therelevant dosage form and / or active pharmaceutical products.

2.Thehead of the Quality Control Laboratory shall be independent of themanufacturing unit. The testing shall be conducted under the direct supervisionof competent technical staff who shall be whole time employees of the licensee.

3.Personnelfor Quality Assurance and Quality Control operations shall be suitablyqualified and experienced.

4.Writtenduties of technical and Quality Control personnel shall be laid and followedstrictly.

5.Numberof personnel employed shall be adequate and in direct proportion to theworkload.

6.Thelicensee shall ensure in accordance with a written instruction that allpersonnel in production area or into Quality Control Laboratories shall receivetraining appropriate to the duties and responsibility assigned to them. Theyshall be provided with
regular in-service training.


7.1.The personnel handling Beta-lactum antibiotics shall betested for Penicillin sensitivity before employment and those handling sexhormones, cytotoxic substances and other potent drugs shall be periodicallyexamined for adverse effects. These personnel should be moved out of thesesections
(except in dedicated facilities), by rotation, as a health safeguard.

7.2. Prior to employment, all personnel, shall undergo medicalexamination including eye examination, and shall be free from Tuberculosis,skin and other communicable or contagious diseases. Thereafter, they should bemedically examined periodically, at least once a year. Records shall bemaintained thereof. The licensee shall provide the services of a qualifiedphysician for assessing the health status of personnel involved in differentactivities.

7.3 All persons, prior to and during employment, shall betrained in practices which ensure personnel hygiene. A high level of personalhygiene shall be observed by all those engaged in the manufacturing processes.Instructions to this effect shall be displayed in change-rooms and otherstrategic locations.

7.4 No person showing, at any time, apparentillness or open lesions which may adversely affect the quality of products,shall be allowed to handle starting materials, packaging materials, In-processmaterials, and drug products until his condition is no longer judged to be arisk.

7.5 All employees shall be instructed to report about theirillness or abnormal health condition to their immediate supervisor so thatappropriate action can be taken.

7.6 Direct contact shall be avoided between the unprotectedhands of personnel and raw materials, intermediate or finished, unpackedproducts.

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

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


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

The contents of all vessels and containers used in manufactureand storage during the various manufacturing stages shall be conspicuouslylabeled with the name of the product, batch no., batch size and stage ofmanufacture. Each label should be initialed and dated by the authorized
technical staff.

Products not prepared under aseptic conditions are required tobe free from pathogens like Salmonella, Escherichia coli, Pyocyanea etc.

8. 2. Precautions against mix–up and cross-contamination –

8. 2.1. The licensee shall prevent mix-up and cross- contamination of drug materialand drug product (from environmental dust) by proper air-handling system,pressure differential, segregation, status labeling and cleaning. Properrecords and Standard Operating Procedures thereof shall be maintained.

8. 2.2. The licensee shall ensure processing of sensitive drugs like Beta-Lactumantibiotics, sex hormones and cycotoxic substances in segregated areas orisolated production areas within the building with independent air-handlingunit and proper pressure differentials. The effective segregation of theseareas shall be demonstrated with adequate records of maintenance and services.

8. 2.3. To prevent mix-ups during production stages, material under- process shallbe conspicuously labeled to demonstrate their status. All equipment used forproduction shall be labeled with their current status.

8. 2.4. Packaging lines shall be independent and adequately segregated. It shall beensured that all left-overs of the previous packaging operations, includinglabels, cartons and caps are cleared before the
closing hour.

8. 2.5. Before packaging operations are begun, steps shall be taken to ensure thatthe work area, packaging lines, printing machines, and other equipment areclean and free from any products, materials and spillages. The line clearanceshall be performed according to an appropriate checklist and recorded.

8. 2.6. The correct details of any printing (for example of batch numbers or expirydates) done separately or in the course of the packaging shall be re-checked atregular intervals. All printing and over-printing shall be authorised inwriting.

8. 2.7. The manufacturing environment shall be maintained at the required levels oftemperature, humidity and cleanliness.

8. 2.8. Authorised persons shall ensure change-over into specific uniforms beforeundertaking any manufacturing operations including packaging.

8. 2.9. There shall be segregated enclosed areas, secured for recalled or rejectedmaterial and for such material which are to be re-processed or recovered.



9. 1. The manufacturing premises shall be cleaned and maintainedin an orderly manner, so that it is free from accumulated waste, dust, debrisand other similar material. A validated cleaning procedure
shall be maintained.

9. 2. The manufacturing areas shall not be used for storage ofmaterials, except for the
material being processed. It shall not be used as a general thoroughfare.

9. 3. A routine sanitation program shall be drawn up andobserved, which shall be properly recorded and which shall indicate –

1.     specificareas to be cleaned and cleaning intervals;

2.     cleaningprocedure to be followed, including equipment and materials to be used forcleaning; and

3.     personnelassigned to and responsible for the cleaning operation.

9. 4. The adequacy of the working and in-process storage spaceshall permit the orderly and logical positioning of equipment and materials soas to minimise the risk of mix-up between different pharmaceutical products ortheir components to avoid cross-contamination, and to minimise the risk ofomission or wrong application of any of the manufacturing or control steps.

9. 5. Production areas shall be well lit, particularly wherevisual on-line controls are carried out.


10. 1. The licensee shall keep an inventory of all raw-materialsto be used at any stage of manufacture of drugs and maintain records as perSchedule U.

10. 2. All incoming materials shall be quarantined immediatelyafter receipt or processing. All materials shall be stored under appropriateconditions and in an orderly fashion to permit batch segregation and stockrotation by a 'first in/first expiry' - 'first-out' principle. All incomingmaterials shall be checked to ensure that the consignment corresponds to theorder placed.

10. 3. All incoming materials shall be purchased from approvedsources under valid purchase vouchers. Wherever possible, raw materials shouldbe purchased directly from the producers.

10. 4. Authorised staff appointed by the
licensee in this behalf, which may include personnel from the quality controldepartment, shall examine each consignment on receipt and shall check eachcontainer for integrity of package and seal. Damaged containers shall beidentified, recorded and segregated.

10. 5. If a single delivery of material is made up of differentbatches, each batch shall be considered as a separate batch for sampling,testing and release.

10. 6. Raw materials in the storage area shall be appropriatelylabeled. Labels shall be clearly marked with the following information :

1.     designatedname of the product and the internal code reference, where applicable, andanalytical reference number;

2.     manufacturer'sname, address and batch number;

3.     thestatus of the contents (e.g. quarantine, under test, released, approved,rejected);

4.     themanufacturing date, expiry date and re-test date.

10. 7. There shall be adequate separate areas for materials"under test", "approved ", and "rejected" witharrangements and equipment to allow dry, clean and orderly placement of storedmaterials and products, wherever necessary, under controlled temperature andhumidity.

10. 8. Containers from which samples have been drawn shall beidentified.

10. 9. Only raw materials which have been released by theQuality Control Department and which are within their shelf-life shall be used.It shall be ensured that shelf-life of formulation product shall not exceedwith that of active raw materials used.

10. 10. It shall be ensured that all the containers of rawmaterials are placed on the raised platforms/racks and not placed directly onthe floor.


11. 1. Equipment shall be located, designed, constructed,adapted and maintained to suit the operations to be carried out. The layout anddesign of the equipment shall aim to minimise the risk of errors and permiteffective cleaning and maintenance in order to avoid cross-contamination,build-up of dust or dirt and, in general, any adverse effect on the quality ofproducts. Each equipment shall be provided with a log book, wherevernecessary.

11. 2. Balances and other measuring equipment of an appropriaterange, accuracy and precision shall be available in the raw-material stores,production and in-process control operations and these shall be calibrated andchecked on a scheduled basis in accordance with Standard Operating Procedures andrecords maintained.

11. 3. The parts of the production equipment that come intocontact with the product shall not be reactive, additive or adsorptive to anextent that would affect the quality of the product.

11. 4. To avoid accidental contamination, wherever possible,non-toxic/edible grade lubricants shall be used and the equipment shall bemaintained in a way that lubricants do not contaminate the products beingproduced.

11. 5. Defective equipment shall be removed from production andQuality Control areas or appropriately labeled.


Documentation is an essential part of the Quality assurancesystem and, as such, shall be related to all aspects of Good ManufacturingPractices (GMP). Its aim is to define the specifications for all materials,method of manufacture and control, to ensure that all personnel concerned withmanufacture know the information necessary to decide whether or not to releasea batch of a drug for sale and to provide an audit trail that shall permit investigationof the history of any suspected defective batch.

12.1. Documents designed, prepared, reviewed and controlled,wherever applicable, shall comply with these rules.

12. 2. Documents shall be approved, signed and dated byappropriate and authorized persons.

12. 3. Documents shall specify the title, nature and purpose.They shall be laid out in an orderly fashion and be easy to check. Reproduceddocuments shall be clear and legible. Documents shall be regularly reviewed andkept up to date. Any alteration made in the entry of a document shall be signedand dated.

12. 4. The records shall be made or completed at the time ofeach operation in such a way that all significant activities concerning themanufacture of pharmaceutical products are traceable. Records and associatedStandard Operating Procedures (SOP) shall be retained for at least one yearafter the expiry date of the finished product.

12. 5. Data may be recorded by electronic data processingsystems or other reliable means, but master formulae and detailed operatingprocedures relating to the system in use shall also
be available in a hard copy to facilitate checking of the accuracy of therecords. Wherever documentation is handled by electronic data processingmethods, authorized persons shall enter or modify data in the computer. Thereshall be record of changes and deletions. Access shall be restricted by'passwords' or other means and the result of entry of critical data shall beindependently checked. Batch records electronically stored shall be protectedby a suitable back-up. During the period of retention, all relevant data shallbe readily available.


Labels are absolutely necessary for identification of the drugsand their use. The printing shall be done in bright colours and in a legiblemanner. The label shall carry all the prescribed details about the product.

13. 1. All containers and equipment shall bear appropriatelabels. Different colour coded labels shall be used to indicate the status of aproduct (for example: under test, approved, passed, rejected).

13. 2. To avoid chance of mix-up in printed packaging materials,product leaflets, relating to different products, shall be stored separately.

13. 3. Prior to release, all labels for containers, cartons andboxes and all circulars, inserts and leaflets shall be examined by the QualityControl Department of the licensee.

13. 4. Prior to packaging and labeling of a given batch of adrug, it shall be ensured by the licensee that samples are drawn from the bulkand duly tested, approved and released by the quality control personnel.

13. 5. Records of receipt of all labelling and packagingmaterials shall be maintained for each shipment received indicating receipt,control reference numbers and whether accepted or rejected. Unused coded anddamaged labels and packaging materials shall be destroyed and recorded.

13.6. The label or accompanying document of reference standardsand reference culture shall indicate concentration, lot number, potency, dateon which container was first opened and storage conditions, where appropriate.


is a wide ranging concept concerning all matters that individually orcollectively influence the quality of a product. It is the totality of the arrangementsmade with the object of ensuring that products are of the quality required fortheir intended use.

14. 1. The system of quality assurance appropriate to themanufacture of pharmaceutical products shall ensure that:

1.     thepharmaceutical products are designed and developed in a way that takes accountof the requirements of Good Manufacturing Practices (hereinafter referred asGMP) and other associated codes such as those of Good Laboratory Practices(hereinafter referred as GLP) and Good Clinical Practices (herein afterreferred as GCP).

2.     adequatearrangements are made for manufacture, supply, and use of the correct startingand packaging materials.

3.     adequatecontrols on starting materials, intermediate products, and bulk products andother in-process controls, calibrations, and validations are carried out.

4.     thefinished product is correctly processed and checked in accordance withestablished procedures.

5.     thepharmaceutical products are not released for sale or supplied before authorizedpersons have certified that each production batch has been produced andcontrolled in accordance with the requirements of the label claim and any otherprovisions relevant to production, control and release of pharmaceuticalproducts.




It may be useful to constitute a self inspection teamsupplemented with a quality audit procedure for assessment of all or part of asystem with the specific purpose of improving it.

15 1. To evaluate the manufacturer's compliance with GMP in allaspects of production and quality control, concept of self-inspection shall befollowed. The manufacturer shall constitute a team of independent, experienced,qualified persons from within or outside the company, who can audit objectivelythe implementation of methodology and procedures evolved. The procedure forself-inspection shall be documented indicating self-inspection results,evaluation, conclusions and recommended corrective actions with effectivefollow up program. The recommendations for corrective action shall be adopted.

15. 2. The program shall be designed to detect shortcomings inthe implementation of Good Manufacturing Practice and to recommend thenecessary corrective actions. Self-inspections shall be performed routinely andon specific occasions, like when product recalls or repeated rejections
occur or when an inspection by the licensing authorities is announced. Theteam responsible for self-inspection shall consist of personnel who canevaluate the implementation of Good Manufacturing Practice objectively; allrecommendations for corrective action shall be implemented.

15. 3. Written instructions for self-inspection shall be drawnup which shall include the following :

1.     Premisesincluding personnel facilities.

2.     Maintenanceof buildings and equipment.

3.     Storageof starting materials and finished products.

4.     Equipment.

5.     Productionand in-process controls.

6.     Qualitycontrol.

7.     Documentation.

8.     Sanitationand hygiene.

9.     Validationand revalidation programmes.

10. Calibrationof instruments or measurement systems.

11. Recallprocedures.

12. Complaintsmanagement.

13. Labelscontrol.

14. Resultsof previous self-inspections and any corrective steps taken.


Quality control shall be concerned with sampling,specifications, testing, documentation, release procedures which ensure thatthe necessary and relevant tests are actually carried and that the materialsare not released for use, nor products released for sale or supply until theirquality has been judged to be satisfactory. It is not confined to laboratoryoperations but shall be involved in all decisions concerning the quality of theproduct. It shall be ensured that all quality control arrangements areeffectively and reliably carried out. The department as a whole shall haveother duties such as to establish, evaluate, validate and implement all QualityControl Procedures and methods.

16. 1. Every manufacturing establishment shall establish its ownquality control laboratory managed by qualified and experienced staff.

16. 2. The area of the quality control laboratory may be dividedinto Chemical, Instrumentation, Microbiological and Biological testing.Separate provision should be made for testing radio active material is used formanufacturing.

16. 3. Adequate area having the required storage conditionsshall be provided for keeping reference samples. The quality control departmentshall evaluate, maintain and store reference samples.

16. 4. Standard operating procedures shall be available forsampling, inspecting, and testing of raw materials, intermediate, bulk finishedproducts and packing materials and, wherever necessary, for monitoringenvironmental conditions.

16. 5. There shall be authorized and dated specifications forall materials, products, reagents and solvents including test of identity,content, purity and quality. These shall include specifications for water,solvents and reagents used in analysis.

16. 6. No batch of the product shall be released for sale orsupply until it has been certified by the authorised person(s) that it is inaccordance with the requirements of the standards laid down.

16. 7. Reference/retained samples from each batch of theproducts manufactured shall be maintained in a quantity which is at least twicethe quantity of the drug required to conduct all the tests, except sterilityand pyrogen/Bacterial Endotoxin Test performed on the active material and theproduct manufactured. The retained product shall be kept in its final pack or asimulated pack for a period of three months after the date of expiry.

16. 8. Assessment of records pertaining to finished productsshall include all relevant factors, including the production conditions, theresults of inprocess testing, the manufacturing (including packaging)documentation, compliance with the specification for the finished product, andan examination of the finished pack. Assessment records should be signed by theperson incharged of production and countersigned by the authorised qualitycontrol personnel before a product is released for sale or distribution.

16. 9. Quality control personnel shall have access to productionareas for sampling and investigation, as appropriate.

16. 10. The quality control department shall conduct stabilitystudies of the products to ensure and assign their shelf life at the prescribedconditions of storage. All records of such studies shall be maintained.

16. 11. The in-charge of Quality Assurance shall investigate allproduct complaints and records thereof shall be maintained.

16. 12. All instruments shall be calibrated and testingprocedures validated before these are adopted for routine testing. Periodicalcalibration of instrument and validation of procedures should be carried out.

16. 13. Each specifications for raw materials, intermediates,final products, and packing materials shall be approved and maintained by theQuality Control Department. Periodic revisions of the specifications shall becarried out whenever changes are necessary.

16. 14. Pharmacopoeiae, reference standards, working standards,reference spectra, other reference materials and technical books, as required,shall be made available in the Quality Control Laboratory of the licensee.



17. 1. For Raw materials and Packaging materials :-

They shall include,-

1.     thedesignated name and internal code reference;

2.     reference,if any , to a pharmacopoeial monograph;

3.     qualitativeand quantitative requirements with acceptance limits;

4.     nameand address of manufacturer or supplier and original manufacturer of thematerial;

5.     specimenof printed material;

6.     directionsfor sampling and testing or reference to procedures;

7.     storageconditions; and

8.     maximumperiod of storage before re-testing.

17. 2. For Product Containers and Closures –

17. 2.1. All containers and closures intended for use shall comply with thepharmacopoeial requirements. Suitable validated test methods, sample sizes,specifications, cleaning procedure and sterilization procedure, whereverindicated, shall be strictly followed to ensure that these are not reactive,additive, adsorptive, or leach to an extent that significantly affects thequality or purity of the drug. No second hand or used containers and closuresshall be used.

17. 2.2. Whenever bottles are being used, the written schedule of cleaning shall belaid down and followed. Where bottles are not dried after washing, they shouldbe rinsed with de-ionised water or distilled water, as the case may be.

17. 3. For in-process and bulk products.— Specifications forin-process material, intermediate and bulk products shall be available. Thespecifications should be authenticated.

17. 4. For Finished Products. – Appropriate specifications forfinished products shall include :-

1.     thedesignated name of the product and the code reference.

2.     theformula or a reference to the formula and the pharmacopoeial reference.

3.     directionsfor sampling and testing or a reference to procedures.

4.     adescription of the dosage form and package details.

5.     thequalitative and quantitative requirements, with the acceptance limits forrelease.

6.     thestorage conditions and precautions, where applicable, and

7.     theshelf-life.

For preparation of containers and closures. – The requirements mentioned inthe Schedule do not include requirements of machinery, equipments and premisesrequired for preparation of containers and closures for different dosage formsand categories of drugs. The suitability and adequacy of the machinery,equipment and premises shall be examined taking into consideration therequirements of each licensee in this respect.


There shall be Master Formula records relating to allmanufacturing procedures for each product and batch size to be manufactured.These shall be prepared and endorsed by the competent technical staff i.e. headof production and quality control. The Master Formula shall include :-

1.     thename of the product together with product reference code relating to itsspecifications.

2.     thepatent or proprietary name of the product along with the generic name, adescription of the dosage form, strength, composition of the product and batchsize.

3.     name,quantity, and reference number of all the starting materials to be used.Mention any substance that may 'disappear' in the course of processing.

4.     astatement of the expected final yield with the acceptable limits, and ofrelevant intermediate yields, where applicable.

5.     astatement of the processing location and the principal equipment to be used.

6.     themethods, or reference to the methods, to be used for preparing the criticalequipment including cleaning, assembling, calibrating, sterilizing.

7.     detailedstepwise processing instructions and the time taken for each step.

8.     theinstructions for in-process controls with their limits.

9.     therequirements for storage conditions of the products, including the container,labelling and special storage conditions where applicable.

10. anyspecial precautions to be observed.

11. packingdetails and specimen labels.


There shall be authorised
packaging instructions for each product, pack size and type. These shallinclude or have a reference to the following : -

1.     name ofthe product.

2.     descriptionof the dosage form, strength and composition.

3.     thepack size expressed in terms of the number or doses, weight or volume of theproduct in the final container.

4.     completelist of all the packaging materials required for a standard batch size,including quantities, sizes and types, with the code or reference numberrelating to the specifications of each packaging material.

5.     reprocessingof the relevant printed packaging materials and specimens indicating wherebatch number and expiry date of the product have been applied.

6.     specialprecautions to be observed, including a careful examination of the area andequipment in order to ascertain the line clearance before the operations begin.

7.     descriptionof the packaging operation, including any significant subsidiary operations andequipment to be used.

8.     detailsof in-process controls with instructions for sampling and acceptance.

9.     uponcompletion of the packing and labeling operation, a reconciliation shall bemade between number of labeling and packaging units issued, number of unitslabeled, packed and excess returned or destroyed. Any significant or unusualdiscrepancy in the numbers shall be carefully investigated before releasing thefinal batch.


20. 1. A batch packaging record shall be kept for each batch orpart batch processed. It shall be based on the relevant parts of the packaginginstructions, and the method of preparation of such records shall be designedto avoid transcription errors.

20. 2. Before any packaging operations begins, checks shall bemade and recorded that the equipment and the work stations are clear of theprevious products, documents or materials not required for the plannedpackaging operations, and that the
equipment is clean and suitable for use.


21.1 There shall be Batch Processing Record for each product. Itshall be based on the relevant parts of the currently approved Master Formula.The method of preparation of such records included in the
Master Formula shall be designed to avoid transcription errors.

21.2. Before starting of any process inspect all themanufacturing area and ensure that the equipment and work station are clear ofprevious products. This should be documented and recorded.

21.3. During processing, the following information shall berecorded at the time each action is taken and the record shall be dated andsigned by the person responsible for the processing operations:

( a )the name of the product,

( b )the number of the batch being manufactured,

( c )dates and time of commencement, of significant intermediate stages and ofcompletion of production,

( d )initials of the operator of different significant steps of production and whereappropriate, of the person who checked each of these operations,

( e )the batch number and/or analytical control number as well as the quantities ofeach starting material actually weighed,

( f )any relevant processing operation or event and major equipment used,

( g ) arecord of the in-process controls and the initials of the person(s) carryingthem out, and the results obtained,

(h )the amount of product obtained after different and critical stages ofmanufacture (yield),

( i )comments or explanations for significant deviations from the expected yieldlimits shall be given,

( j )notes on special problems including details, with signed authorization, for anydeviation from the master formula,

(k)addition of any recovered or reprocessed material with reference to recovery orreprocessing stages.


22. 1. Receipt of Materials;

22. 1. 1. There shall be written Standard Operating Proceduresand records for the receipt of each delivery of raw, primary and printedpackaging material.

22. 1. 2. The records of the receipts shall include

(a)container number

(b) thedate of receipt

(c) themanufacturer's and / or supplier's name

(d) themanufacturer's batch or reference number

(e) thetotal quantity, and number of containers, quantity in each container received

(f) thecontrol reference number assigned after receipt

(g) anyother relevant comment or information.

22. 1. 3 There shall be written standard operating proceduresfor the internal labelling, quarantine and storage of starting materials,packaging materials and other materials, as appropriate.

22. 1. 4. There shall be Standard Operating Procedures availablefor each instrument and equipment and these shall be placed in close proximityto the related instrument and equipment.



22. 2. Sampling.-

22. 2. 1. There shall be written Standard Operating Proceduresfor sampling, which include the person(s) authorized to take the samples.

22. 2. 2. The sampling instructions shall include:

1.     themethod of sampling and the sampling plan,

2.     theequipment to be used,

3.     anyprecautions to be observed to avoid contamination of the material or anydeterioration in its quality,

4.     thequantity of samples to be taken,

5.     instructionsfor any required sub-division or pooling of the samples,

6.     the typeof sample container to be used,

7.     anyspecific precautions to be observed, especially in regard to sampling ofsterile or hazardous material.

22. 3. Batch Numbering.-

22. 3. 1. There shall be Standard Operating Proceduresdescribing the details of the batch ( lot ) numbering set up with the objectiveof ensuring that each batch of intermediate, bulk or finished product isidentified with a specific batch number.

22.3. 2. Batch numbering standard operating procedures appliedto a processing stage and to the respective packaging stage shall be same ortraceable to demonstrate that they belong to one homogenous mix.

22. 3. 3. Batch number allocation shall be immediately recordedin a logbook or by electronic data processing system. The record shall includedate of allocation, product identity and size of batch.

22. 4. Testing

22. 4. 1. There shall be written procedures for testingmaterials and products at different stages of manufacture, describing themethods and equipment to be used. The tests performed shall be recorded.

22. 5. Records of analysis.-

22. 5. 1. The records shall include the following data.

1.     name ofthe material or product and the dosage form,

2.     batchnumber, details of manufacturer and / or supplier;

3.     referencesof relevant specifications and testing procedures,

4.     testresults, including observations and calculations, and reference to anyspecifications ( limits ),

5.     datesof testing;

6.     initialsof the persons who performed the testing;

7.     initialsof the persons who verified the testing and the detailed calculations,

8.     astatement of release or rejection, and

9.     signatureand date of the designated responsible person.

22. 5. 2. There shall be written standard operating proceduresand the associated records of actions taken for:

1.     equipmentassembly and validation;

2.     analyticalapparatus and calibration;

3.     maintenance,cleaning and sanitation;

4.     personnelmatters including qualification, training, clothing, hygiene;

5.     environmentalmonitoring;

6.     pestcontrol;

7.     complaints;

8.     recallsmade;

9.     returnsreceived.


23. 1. Each lot of every active ingredient, in a quantitysufficient to carry out all the tests, except sterility andpyrogens/Bacterial Endotoxin Test, shall be retained for a period of 3 monthsafter the date of expiry of the last batch produced from that activeingredient.

23. 2. Samples of finished formulations shall be stored in thesame or simulated containers in which the drug has been actually marketed.


24. 1. Where reprocessing is necessary, written procedures shallbe established and approved by the Quality Assurance Department that shallspecify the conditions and limitations of repeating chemical reactions. Suchre-processing shall be validated.

24. 2. If the product batch has to be reprocessed, the procedureshall be authorized and recorded. An investigation shall be carried out intothe causes necessitating re -processing and appropriate corrective measuresshall be taken for prevention of recurrence. Re-processed batch shall besubjected to stability evaluation.

24. 3. Recovery of product residue may be carried out, ifpermitted, in the master production and control records by incorporating it insubsequent batches of the product.


25. 1. Prior to distribution or dispatch of given batch of adrug, it shall be ensured that the batch has been duly tested, approved andreleased by the quality control personnel. Pre-dispatch inspection shall beperformed on each consignment on a random basis to ensure that only
the correct goods are dispatched. Detailed instructions for warehousing andstocking of Large Volume Parenterals, if stocked, shall be in existence andshall be complied with after the batch is released for distribution. Periodicaudits of warehousing practices followed at distribution centers shall becarried out and records thereof shall be maintained. Standard OperatingProcedures shall be developed for warehousing of products.

25. 2. Records for distribution shall be maintained in a manner
that finished batch of a drug can be traced to the retail level tofacilitate prompt and complete recall of the batch, if and when necessary.


26. 1. Validation studies shall be an essential part of GoodManufacturing Practices and shall be conducted as per the pre-definedprotocols. These shall include validation of processing, testing and cleaningprocedures.

26. 2. A written report summarizing recorded results andconclusions shall be prepared, documented and maintained.

26. 3. Processes and procedures shall be established on thebasis of validation study and undergo periodic revalidation to ensure that theyremain capable of achieving the intended results. Critical processes shall bevalidated, prospectively or retrospectively.

26. 4. When any new master formula or method of preparation isadopted, steps shall be taken to demonstrate its suitability for routineprocessing. The defined process, using the materials and equipment specifiedshall be demonstrated to yield a product consistently of the
required quality.

26. 5. Significant changes to the manufacturing process,including any change in equipment or materials that may affect product qualityand / or the reproducibility of the process, shall be validated.


27. 1. A prompt and effective product recall system of defectiveproducts shall be devised for timely information of all concerned stockists,wholesalers, suppliers, up to the retail level within the shortest period. Thelicensee may make use of both print and electronic media in this regard.

27. 2. There shall be an established written procedure in theform of Standard Operating Procedure for effective recall of productsdistributed by the licensee. Recall operations shall be capable of beinginitiated promptly so as to effectively reach at the level of each distributionchannel.

27. 3. The distribution records shall be readily made availableto the persons designated for recalls.

27. 4. The designated person shall record a final report issued,including a reconciliation between the delivered and the recovered quantitiesof the products.

27. 5. The effectiveness of the arrangements for recalls shallbe evaluated from time to time.

27. 6. The recalled products shall be stored separately in asecured segregated area pending final decision on them.


28. 1. All complaints thereof concerning product quality shallbe carefully reviewed and recorded according to written procedures. Eachcomplaint shall be investigated/evaluated by the designated personnel of thecompany and records of investigation and remedial action taken thereof shall bemaintained.

28. 2. Reports of serious adverse drug reactions resulting fromthe use of a drug along with comments and documents shall be forthwith reportedto the concerned Licensing Authority.

28. 3. There shall be written procedures describing the actionto be taken, recall to be made of the defective product.


The licensee shall prepare a succinct document in the form of'Site Master File' containing specific and factual Good Manufacturing Practicesabout the production and/or control of pharmaceutical manufacturingpreparations carried out at the licensed premises. It shall contain thefollowing : -

29. 1. General information.-

1.     briefinformation of the firm;

2.     pharmaceuticalmanufacturing activities as permitted by the licensing authority;

3.     othermanufacturing activities, if any, carried out on the premises;

4.     type ofproducts licensed for manufacture with flowcharts mentioning procedures andprocess flow;

5.     numberof employees engaged in the production, quality control, storage anddistribution;

6.     Use ofoutside scientific, analytical or other technical assistance in relation tomanufacture and analysis;

7.     shortdescription of the Quality Management system of the firm;

8.     productsdetails registered with foreign countries.

29. 2. Personnel

1.     organisationalchart showing the arrangement for quality assurance including production andquality control;

2.     qualification,experience and responsibilities of key personnel;

3.     outlinefor arrangements for basic and in-service training and how the records aremaintained;

4.     healthrequirements for personal engaged in production;

5.     personnelhygiene requirements, including clothing.

29. 3. Premises

1.     simpleplan or description of manufacturing areas drawn to scale;

2.     natureof construction and fixtures / fittings;

3.     briefdescription of ventilation systems. More details should be given for criticalareas with potential risk of airborne contamination (schematic drawing ofsystems). Classification of the rooms used for the manufacture of sterileproducts should be mentioned;

4.     specialareas for the handling of the highly toxic, hazardous and sensitizingmaterials;

5.     briefdescription of water systems (schematic drawings of systems), includingsanitation;

6.     descriptionof planned preventive maintenance programs for premises and of the recordingsystem.

29. 4. Equipment

1.     briefdescription of major equipment used in production and quality controllaboratories (a list of equipment required);

2.     descriptionof planned preventive maintenance programs for equipment and of the recordingsystem;

3.     qualificationand calibration, including the recording systems and arrangements forcomputerised systems validation.

29. 5. Sanitation

(a)availability of written specifications and procedures for cleaningmanufacturing areas and equipment.

29. 6. Documentation

1.     arrangementsfor the preparation, revision and distribution of

2.     necessarydocumentation for the manufacture;

3.     anyother documentation related to product quality that is not mentioned elsewhere( e.g. microbiological controls about air and water )

29. 7. Production

1.     briefdescription of production operations using, wherever possible, flow sheets andcharts specifying important parameters;

2.     arrangementsfor the handling of starting materials, packaging materials, bulk and finishedproducts, including sampling, quarantine, release and storage;

3.     arrangementsfor the handling of rejected materials and products;

4.     briefdescription of general policy for process validation.

29. 8. Quality control

1.     descriptionof the quality control system and of the activities of the quality controldepartment. Procedures for the release of the finished products.

29. 9. Loan licence manufacture and licensee

1.     descriptionof the way in which compliance of Good Manufacturing Practices by the loanlicensee shall be assessed.

29. 10. Distribution, complaints and product recall

1.     arrangementsand recording system for distribution;

2.     arrangementsfor the handling of complaints and product recalls.

29. 11. Self-Inspection

(a)short description of the self-inspection system indicating whether an outside,Independent and experienced external expert was involved in evaluating themanufacturer's compliance with Good Manufacturing Practices in all aspects ofproduction.

29.12. Export of drugs

( a )products exported to different countries;

( b )complaints and product recall, if any.



  1. General –

Sterileproducts, being very critical and sensitive in nature, a very high degree ofprecautions, prevention and preparations are needed. Dampness, dirt anddarkness are to be avoided to ensure aseptic conditions in all areas. Thereshall be strict compliance in the prescribed standards especially in the matterof supply of water, air, active materials and in the maintenance of hygienicenvironment.

  1. Buildings And Civil Works

2. 1.The building shall be built on proper foundation with standardised materials toavoid cracks in critical areas like aseptic solution preparation, filling andsealing rooms.

2. 2.Location of services like water, steam, gases etc. shall be such that theirservicing or repair shall not pose any threat to the integrity of the facility.Water lines shall not pose any threat of leakage to aseptic area.

2. 3.The manufacturing areas shall be clearly separated into support areas (e.g.washing and component preparation areas, storage areas etc.), preparation areas(e.g. bulk manufacturing area, non-aseptic blending areas etc.) change areasand aseptic areas. Operations like removal of outer cardboard wrappings ofprimary packaging materials shall be done in the de-cartoning areas which aresegregated from the washing areas. Wooden pallets, fiber board drums, cardboardand other particle shedding materials shall not be taken inside the preparationareas.

2. 4.In aseptic areas –

Walls,floors and ceiling should be impervious, non-shedding, non-flaking and non-cracking.Flooring should be unbroken and provided with a cove both at the junctionbetween the wall and the floor as well as the wall and the celing.

1.     wallsshall be flat,
and ledges and recesses shall be avoided. Wherever other surfaces join thewall (e.g. sterilisers, electric sockets, gas points etc.) these shall be flush
with the walls. Walls shall be provided with a cove
at the joint between
the ceiling and floor.

2.     ceilingshall be solid and joints shall be sealed. Light-fittings and air-grills shallbe flush with the walls and not hanging from the ceiling, so as toprevent contamination.

3.     thereshall be no sinks and drains in Grade A and Grade B areas;

4.     doorsshall be made of non-shedding material. These may be made preferably ofAluminium or Steel material. Wooden doors shall not be used. Doors shall opentowards the higher-pressure area so that they close automatically due to airpressure.

5.     Windowsshall be made of similar material as the
doors, preferably with double panel and shall be flush with the walls. Iffire escapes are to be provided, these shall be suitably fastened to the wallswithout any gaps.

6.     thefurniture used shall be smooth, washable and made of stainless steel or anyother appropriate material other than wood.

2. 5.The manufacturing and the support areas shall have the same quality of civilstructure described above for aseptic areas, except the environmentalstandards which may vary in the
critical areas.

2. 6.Change rooms with entrance in the form of air-locks shall be provided beforeentry into the sterile product manufacturing areas and then to the asepticarea. Separate exit space from the
aseptic areas is advisable. Change rooms to the
aseptic areas shall be clearly demarcated into 'black', 'gray' and 'whiterooms' with different levels of activity and air cleanliness. The 'black'change room shall be provided with a hand-washing sink. The sink and its drainin the un- classified (first) change rooms may be kept clean all the time. Thespecially designed drain shall be periodically monitored to avoid presence ofpathogenic micro-organisms. Change room doors shall not be openedsimultaneously. An appropriate inter-locking system and a visual and/ oraudible warning system may be installed to prevent the opening of more than onedoor at a time.

2. 7.For communication between aseptic areas and non-aseptic areas, intercomtelephones or speak-phones shall be used. These shall be minimum in number.

2. 8.Material transfer between aseptic areas and outside shall be through suitableair-locks or pass-boxes. Doors of such air-locks and pass-boxes shall havesuitable interlocking arrangements.

2. 9.Personal welfare areas like rest rooms, tea room, canteen and toilets shall beoutside and separated from the
sterile product manufacturing area.

2.10.Animal houses shall be away from the sterile product manufacturing area andshall not share a common entrance or air handling system with the manufacturingarea.

  1. Air Handling System (Central Air-Conditioning)

3. 1.Air Handling Units for sterile product manufacturing areas shall be differentfrom those for other areas. Critical areas, such as the aseptic filling area,sterilized components unloading area and change rooms conforming to Grades B, Cand D respectively shall have separate Air Handling Units. The filterconfiguration in the air handling system shall be suitably designed to achievethe Grade of air as given in Table I. Typical operational activities for cleanareas are highlighted in Table II and Table III.

3. 2.For products which are filled aseptically, the filling room shall meet Grade Bconditions at rest unmanned. This condition shall also be obtained within aperiod of about 30 minutes of the personnel leaving the room after completionof operations.

3. 3.The filling operations shall take place under Grade A conditions which shall bedemonstrated under working of simulated conditions which
shall be achieved by providing Laminar Air flow work stations with suitableHEPA filters or isolator technology.

3. 4.For products, which are terminally sterilized, the filling room shall meetGrade C conditions at rest. This condition shall be obtainable within a periodof about 30 minutes of the
personnel leaving the room after completion of operations.

3. 5.Manufacturing and component preparation areas shall meet Grade C conditions.

3. 6.After completion of preparation, washed components and vessels shall beprotected with Grade C background and if necessary, under Laminar Air Flow workstation.

3. 7.The minimum air changes for Grade B and Grade C areas shall not be less than 20air changes per hour in a room with good air flow pattern and appropriate HEPAfilters. For Grade A Laminar Air Flow work stations, the air flow rates shallbe 0.3 meter per second 20 % (for vertical flows) and 0.45 meter per second 20% (for horizontal flows).


AirBorne Particulate Classification For Manufacture Of Sterile Products


At rest (b)

In Operation (a)

Maximum number of permitted particles per cubic metre equal to or above

0. 5 m

5 mini

0. 5 m

5 m






B (a)





C (a)





D (a)



Not defined (c)

Not defined (c)


Notes :

1.     Inorder to reach the B, C and D air grades, the number of air changes shall berelated to the size of the room and the equipment and personnel present in theroom. The air system shall be provided with the appropriate filters such asHEPA for Grades A, B and C. The maximum permitted number of particle "atrest" condition shall approximately be as under:

Grade Acorresponds with Class 100 or M 3.5 or ISO class 5; Grade B with class 1000 orM 4.5 or ISO Class 6; Grade C with Class 10000 or M 5.5 or ISO Class 7; Grade Dwith Class 100,000 or M 6.5 or ISO Class 8.

2.     The requirementand limit for the area shall depend on the nature of the
operation carried out

3.     Type ofoperations to be carried out in the various grades are given in Table II andTable III as under:


Typesof Operations To Be Carried Out In The Various Grades For Aseptic Preparations



Types of operations for aseptic preparations.


Aseptic preparation and filling.


Background room conditions for activities requiring Grade A.


Preparation of solution to be filtered.


Handling of components after washing.



Typesof Operations To Be Carried Out In The Various Grades For Terminally SterilizedProducts


Types of operations for terminally sterilized products.


Filling of products, which
are usually at risk.


Placement of filling and sealing machines, preparation of solutions, when usually at risk. Filling of product when unusually at risk.


Moulding, blowing (pre-forming) operations of plastic containers, Preparations of solutions and components for subsequent filling.


4. EnvironmentalMonitoring

4. 1.All environmental parameters listed under para 3.1 to 3.10 shall be verifiedand established at the time of installation and thereafter monitored atperiodic intervals. The recommended frequencies of periodic monitoring shall beas follows:

    1. Particulate monitoring in air – 6 Monthly
    2. HEPA filter integrity testing ( smoke testing ) – Yearly
    3. Air change rates – 6 Monthly
    4. Air pressure differentials – Daily
    5. Temperature and humidity – Daily
    6. Microbiological monitoring by settle plates and/or swabs in aseptic areas – Daily, and at decreased frequency in other areas

Note :The above frequencies of monitoring shall be changed as per the requirementsand load in individual cases.

4. 2.There shall be a written environmental monitoring program and microbiologicalresults shall be recorded. Recommended limits for microbiological monitoring ofclean areas "in operation" are as given in the table below :



RecommendedLimits For Microbiological Monitoring Of Clean Areas "In-operation"


Air sample Cfu / m3

Settle plates ( dia. 90 mm. Cfu / 2 hrs.

Contact plates (dia. 55 mm) cfu per plate

Glove points (five fingers) cfu per glove


< 1

< 1

< 1

< 1
















Notes :

10. Theseare average values.

11. Individualsettle plates may be exposed for not less than two hours in Grade B, C and Dareas and for not less than thirty minutes in Grade A area.

4. 3.Appropriate action shall be taken immediately if the result of particulate andmicrobiological monitoring indicates that the counts exceed the limits. TheStandard Operating Procedures shall contain corrective action. After majorengineering modification to the HVAC system of any area, all monitoring shallbe re-performed before production commences.


5. 1.This section covers garments required for use by personnel working only inaseptic areas. Outdoor clothing shall not be brought into the sterile areas.

5. 2.The garments shall be made of non-shedding and tight weave material. Cottongarments shall not be used. The garments shall shed virtually no fibers orparticulate matter.

5. 3.The clothing and its quality shall be adopted to the process and the work placeand worn in such a way as to protect the product from contamination. Garmentsshall be single piece with fastenings at cuffs, neck and at legs to ensureclose fit. Trouser legs shall be tucked inside the cover boots. Suitable designof garments shall either include a hood (head-cover) or a separate hood which canbe tucked inside the over-all. Pockets, pleats and belts shall be avoided ingarments. Zips (if any) shall be of Plastic material. Garments with damagedzips shall not be used.

5. 4.Only clean, sterilized and protective garments shall be used at each worksession where aseptic filtration and filling operations are undertaken and ateach work shift for products intended to be sterilized, post-filling.The mask and gloves shall be changed at every work session in both instances.

5. 5.Gloves shall be made of latex or other suitable plastic materials and shall bepowder-free. These shall be long enough to cover wrists completely and allowthe over-all cuff to be tucked in.

5. 6.The footwear shall be of suitable plastic or rubber material and shall be dailycleaned with a bactericide.

5. 7.Safety goggles or numbered glasses with side extensions shall be used insideaseptic areas. These shall be sanitised by a suitable method.

5. 8.Garment changing procedure shall be documented and operators trained in thisaspect. A full size mirror shall be provided in the final change room for theoperator to verify that he is appropriately attired in the garments. Periodicinspection of the garments shall be done by responsible staff.


6. 1.There shall be written procedures for the sanitation of sterile processingfacilities. Employees carrying out sanitation of aseptic areas shall be trainedspecifically for this purpose.

6. 2.Different sanitizing agents shall be used in rotation and the concentrations ofthe same shall be as per the recommendations of the manufacturer. Records ofrotational use of sanitizing agents shall be maintained.

6. 3.Distilled water freshly collected directly from the distilled water plant orwater maintained above 70 degree centigrade from the re-circulation loop shallbe used for dilution of disinfectants. Alternately, distilled water sterilisedby autoclaving or membrane filtration shall be used. The dilution shall becarried out in the 'white' change room.

6. 4.Where alcohol or Isopropyl alcohol is used for dilution of disinfectants foruse as hand sprays, the preparation of the same shall be done in the bulkpreparation area and the diluted solution membrane-filtered into suitablesterile containers held in aseptic area.

6. 5.Diluted disinfectants shall bear the label 'use before', based onmicrobiological establishment of their germicidal properties. The solutionsshall be adequately labeled and documents maintained.

6. 6.Formaldehyde or any other equally effective fumigant is recommended for thefumigation of aseptic areas or after major civil modifications. There shall beStandard Operating Procedures for this purpose . Its use for routine purposesshall be discouraged and an
equally effective surface cleaning regime shall be followed.

6. 7.Cleaning of sterile processing facilities shall be undertaken with air suctiondevices or with non-linting sponges or clothes.

6. 8.Air particulate quality shall be evaluated on a regular basis and recordsmaintained.



7. 1.The special equipment required for manufacturing sterile products includescomponent washing machines, steam sterilisers, dry heat sterilisers, membranefilter assemblies, manufacturing vessels, blenders, liquid filling machines,powder filling machines, sealing and labeling machines, vacuum testingchambers, inspection machines, lyophilisers, pressure vessels etc. Suitable andfully integrated washing-sterilizing- filling lines may be provided,depending upon the type and volume of activity.

7. 2.Unit-sterilisers shall be double-ended with suitable inter-locking arrangementsbetween the doors. The effectiveness of the sterilization process shall beestablished initially by biological inactivation studies using microbial sporeindicators and then at least once a year by carrying out thermal mapping of thechamber. Various sterilization parameters shall be established based on thesestudies and documented. For membrane filters used for filtration, appropriatefilter integrity tests that ensure sterilization shall be carried out beforeand after filtration.

7. 3.Filling machines shall be challenged initially and then at periodic intervalsby simulation trials including sterile media fill. Standard OperatingProcedures and acceptance criteria for media fills shall be established,justified and documented. Special simulation trial procedures shall bedeveloped, validated and documented for special products like ophthalmicointments.

7. 4.The construction
material used
for the parts which are in direct contact with products and the
manufacturing vessels may be stainless steel 316 or Boro-silicate glass (ifglass containers) and the
tubing shall be capable of being washed and autoclaved.

7. 5.On procurement, installation qualification of each of the equipment shall bedone by engineers with the support of production and quality assurancepersonnel. Equipment for critical processes like aseptic filling andsterilizers shall be suitably validated according to a written program beforeputting them to use.

7. 6.Standard Operating Procedures shall be available for each equipment for itscalibration and operation and cleaning. Gauges and other measuring devicesattached to equipment shall be calibrated at suitable intervals against awritten program. Calibration status of equipment and gauges shall be adequatelydocumented and displayed.

8.Waterand Steam Systems

8. 1.Potable water meeting microbiological specification of not more than 500 cfu/mland indicating absence of individual pathogenic micro-organisms. Escherichia
coli, Salmonella, Staphylococcus aureus and Pseudomonasaeruginosa per 100 ml sample shall be used for the preparation of purifiedwater.

8. 2.Purified water prepared by de-mineralization shall meet the microbiologicalspecification of not more than 100 cfu per ml and indicate
absence of pathogenic micro-organisms in 100 ml. Purified water shall alsomeet IP specifications for chemical quality. Purified water shall be used forhand washing in change rooms. Containers, closures and machine parts may bewashed with potable water followed by suitably filtered purified water.Purified water shall be stored in stainless steel tanks or plastic tanks.

8. 3.Water for Injection (hereinafter referred as WFI) shall be prepared frompotable water or purified water meeting the above specifications bydistillation. Water for Injection shall meet microbiological specification ofnot more than 10 cfu per 100 ml. WFI shall also meet IP specification for Waterfor Injection and shall have an endotoxin level of not more than 0.25 EU / ml.Bulk solutions of liquid parenterals shall be made in WFI. Final rinse ofproduct containers and machine parts shall be done with WFI. Disinfectantsolutions for use in aseptic areas shall be prepared in WFI.

8. 4.Water for Injection for the manufacture of liquid injectables shall be freshlycollected from the distillation plant or from a storage or circulation loopwhere the water has been kept at above 70 degree centigrade. At the point ofcollection, water may be cooled using suitable heat exchanger.

8. 5.Water for non-injectable sterile products like eye drops shall meet IPspecifications for purified water. In addition, microbiological specificationof not more than 10 cfu per 100 ml and absence of Pseudomonas aeruginosa andEnterobacter coli in 100 ml shall also be met.

8. 6.Water for Injection shall be stored in steam jacketted stainless steel tanks ofsuitable size and the tanks shall have hydrophobic bacterial retention with0.22 microns vent filters. The filters shall be suitably sterilized at periodicintervals. The distribution lines for purified water and distilled water shallbe of stainless steel 316 construction and shall not shed particles.

8. 7.There shall be a written procedure and program for the sanitation of differentwater systems including storage tanks, distribution lines, pumps and otherrelated equipment. Records of sanitation shall be maintained.

8. 8.There shall be written microbiological monitoring program for different typesof water. The results shall justify the frequency of sampling and testing.Investigation shall be carried out and corrective action taken in case ofdeviation from prescribed limits.

8. 9.Steam coming in contact with the product, primary containers and other productcontact surfaces shall be sterile and pyrogen free. The steam condensate shallmeet microbiological specification of not more than 10 cfu per 100 ml. Thecondensate shall also meet IP specification for Water for Injection and shallhave an endotoxin levels of not more than 0.25 EU/ml. There shall be a suitableschedule for the monitoring of steam quality.

9.Manufacturing Process

9. 1.Manufacture of sterile products shall be carried out only in areas underdefined conditions.

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

9. 3.The time between the start of the preparation of the solution and its sterilizationor filtration through a micro-organism retaining filter shall be minimised.There shall be a set maximum permissible time for each product that takes intoaccount its composition and method of storage mentioned in the
Master formula record.

9. 4. Gasescoming in contact with the
sterile product shall be filtered through two 0.22 microns hydrophobicfilters connected in-series. These filters shall be tested forintegrity. Gas cylinders shall not be taken inside aseptic areas.

9. 5.Washed containers shall be sterilized immediately before use. Sterilizedcontainers, if not used within an established time, shall be rinsed withdistilled or filtered purified water and re-sterilized.

9. 6.Each lot of finished product shall be filled in one continuous operation. Ineach case, where
one batch is filled
in using more than one operation, each lot shall be tested separately forsterility and held separately till sterility test results are known.

9. 7.Special care shall be exercised while filling products in powder form so as notto contaminate the environment during transfer of powder to fillingmachine-hopper.


10. 1.Form-Fill-Seal units are specially built automated machines in which throughone continuous operation, containers are formed from thermoplastic granules,filled and then sealed. Blow, fill - seal units are machines in whichcontainers are moulded/blown (pre-formed) in separate clean rooms, by noncontinuous operations.

Note :

12. Theseshall be installed in at least Grade C environment.

13. Theseshall comply with the limits as recommended in Table at item 4.2.

10. 2.Form - Fill - Seal / Blow, Fill - Seal machines used for the manufacture ofproducts for terminal sterilization shall be installed in at least Grade Cenvironment and the filling zone within the machine shall fulfill Grade Arequirements.

10. 3. TerminallySterilized Products

    1. Preparation of primary packaging material such as glass bottles, ampoules and
      rubber stoppers shall be done in at least Grade D environment. Where there is unusual risk to the product from microbial contamination, the above operation shall be done in Grade C environment. All the processes used for component preparation shall be validated.
    2. Filling of products requiring terminal sterilization shall be done under Grade A environment with a Grade C background.

10. 4.Preparation of solutions, which are to be sterilized by filtration, shall bedone in Grade C environment, and if not to be filtered, the preparation ofmaterials and products shall be in a Grade A environment with Grade B inbackground.

10. 5.Filtration ( Membrane )

( i )Solutions for Large Volume Parenterals shall be filtered through a non-fiberreleasing, sterilizing grade cartridge/membrane filter of nominal pore size of0.22 microns for aseptic filling whereas 0.45 microns porosity shall be usedfor terminally sterilized products.

( ii )A second filtration using another 0.22 microns sterilizing gradecartridge/membrane filter shall be performed immediately prior to filling.Process specifications shall indicate the maximum time during which afiltration system may be used with a view to precluding
microbial build-up to levels that may affect the microbiological quality ofthe Large Volume Parenterals.

( iii )The integrity of the sterilized filter shall be verified and confirmedimmediately after use by an appropriate method such as Bubble Point, DiffusiveFlow or Pressure Hold Test.

10. 6. Sterilization( Autoclaving )

10.6.1.Before any sterilization process is adopted, its suitability for the productand its efficacy in achieving the desired sterilizing conditions in all partsof each type of load pattern to be processed, shall be demonstrated by physicalmeasurements and by biological indicators, where appropriate.

10.6.2.All the sterilization processes shall be appropriately validated. The validityof the process shall be verified at regular intervals, but at least annually.Whenever significant modifications have been made to the equipment and product,records shall be maintained thereof.

10.6.3.Thesterilizer shall be double ended to prevent mix-ups.

10.6.4.Periodicbio-burden monitoring of products before terminal sterilization shall becarried out and controlled to limits specified for the product in the MasterFormula.

10.6.5.Theuse of biological indicators shall be considered as an additional method formonitoring the sterilization. These shall be stored and used according to themanufacture's instructions. Their quality shall be checked by positivecontrols. If biological indicators are used, strict precautions shall be takento avoid transferring microbial contamination from them.

10.6.6.Thereshall be clear means of differentiating 'sterilized' and 'unsterilized'products. Each basket, tray or other carrier of products or components shall beclearly labeled with the name of the material, its batch number, andsterilization status. Indicators shall be used, where appropriate, to indicatewhether a batch (or sub-batch) has passed through the sterilization process.

10.6.7.Sterilizationrecords shall be available for each sterilization-run and may also includethermographs and sterilization monitoring strips. They shall be maintained aspart of the batch release procedure.

10. 7. Sterilization( By Dry Heat )

10.7.1.Each heat sterilization cycle shall be recorded on a time / temperature chartof a suitable size by appropriate equipment of the required accuracy andprecision. The position of temperature probes used for controlling and / orrecording shall be determined during the validation and, where applicable,shall also be checked against a second independent temperature probe located inthe same position. The chart shall form a part of the batch record. Containermapping may also be carried out in the case of Large Volume Parenterals.

10.7.2.Chemical or biological indicators may also be used, but shall not take theplace of physical validation.

10.7.3.Sufficient time shall be allowed for the load to reach the required temperaturebefore measurement of sterilization time commences. This time shall beseparately
determined for each type of load to be processed.

10.7.4.After the high temperature phase of a heat sterilization cycle, precautionsshall be taken against contamination of sterilized load during cooling. Anycooling fluid or gas in contact with the product shall be sterilized unless itcan be shown that any leaking container would not be approved for use. Airinlet and outlets shall be provided with bacteria retaining filters.

10.7.5.Theprocess used for sterilization by dry heat shall include air-circulation withinthe chamber and the maintenance of a positive pressure to prevent the entry ofnon-sterile air. Air inlets and outlets should be provided with micro-organismretaining filters. Where this process of sterilization by dry heat is alsointended to remove pyrogens, challenge tests using endotoxins would be requiredas part of the validation process.

10. 8.
Sterilization (By Moist Heat)

10.8.1.Both the temperature and pressure shall be used to monitor the process. Controlinstrumentation shall normally be independent of monitoring instrumentation andrecording charts. Where automated control and monitoring systems are used forthese applications, these shall be validated to ensure that critical processrequirements are met. System and cycle faults shall be registered by the systemand observed by the operator. The reading of the independent temperatureindicator shall be routinely checked against the chart-recorder during thesterilization period. For sterilizers fitted with a drain at the bottom of thechamber, it may also be necessary to record the temperature at this positionthroughout the sterilization period. There shall be frequent leak tests done onthe chamber during the vacuum phase of the cycle.

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

10.8.3.No Large Volume Parenteral shall be subjected to steam sterilization cycleuntil it has been filled and sealed.

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

10. 9. Completion/ Finalisation of Sterile Products

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

10.9.2.Containers shall be closed by appropriately validated methods. Containersclosed by fusion, e.g. glass or plastic ampoules shall be subjected to 100 %integrity testing. Samples of other containers shall be checked for integrityaccording to appropriate procedures.

10.9.3.Containers sealed under vacuum shall be tested for required vacuum conditions.

10.9.4.Filled containers of parenteral products shall be inspected individually forextraneous contamination or other defects. When inspection is done visually, itshall be done under suitably controlled conditions of illumination andbackground. Operators doing the inspection shall pass regular eye-sight checkswith spectacles, if worn, and be allowed frequent rest from inspection. Whereother methods of inspection are used, the process shall be validated and theperformance of the equipment checked at suitable intervals. Results shall berecorded.

11. ProductContainers And closures

11. 1.All containers and closures intended for use shall comply with thepharmacopoeial and other specified requirements. Suitable sample sizes,specifications, test methods, cleaning procedures and sterilization procedures,shall be used to assure that containers, closures and other component parts ofdrug packages are suitable and are not reactive, additive, adsorptive orleachable or presents the risk of toxicity to an extent that significantlyaffects the quality or purity of the drug. No second hand or used containersand closures shall be used.

11. 2.Plastic granules shall also comply with the Pharmacopoeial requirementsincluding physio-chemical and biological tests.

11. 3.All containers and closures shall be rinsed prior to sterilization with waterfor injection according to written procedure.

11. 4.The design of closures, containers and stoppers shall be such as to makecleaning, easy and also to make an airtight seal when fitted to the bottles.

11. 5.It shall be ensured that containers and closures chosen for a particularproduct are such that when coming into contact they are not absorbed into theproduct and they do not affect the product adversely. The closures and stoppersshould be of such quality substances as not to affect the quality of theproduct and avoid the risk of toxicity.

11. 6.Whenever glass bottles are used, the written schedule of cleaning shall be laiddown and followed. Where bottles are not dried after washing, these shall befinally rinsed with distilled water or pyrogen free water, as the case may be,according to written procedure.

11. 7.Individual containers of parenteral preparations, ophthalmic preparations shallbe examined against black/white background fitted with diffused light afterfilling so as to ensure freedom from foreign matters.


11. 8
Glass bottles

11.8.1.Shape and design of the glass bottle shall be rational and standardized. Glassbottles made of USP Type-I and USP Type-II glass shall only be used. Glassbottles shall not be reused. Before use, USP Type-II bottles shall be validatedfor the absence of particulate matter generated over a period of the shelf-lifeof the product and shall be regularly monitored after production,following statistical sampling methods. USP Type-III glass containers may beused for non- parenteral sterile products such as Otic Solutions.

11. 9. PlasticContainers

11.9.1.Pre-formed plastic containers intended to be used for the packing of LargeVolume Parenteral shall be moulded in-house by one-continuous operation throughan automatic machine.

11.9.2.Blowing, filling and sealing (plugging) operations shall be conducted inroom(s) conforming to requirements as mentioned in Table III of Item 3.10.Entry to the area where such operations are undertaken, shall be through aseries of air locks. Blowers shall have an air supply which is filtered though0.22 microns filters. Removal of runners and plugging operations shall beconducted under a laminar airflow work station.

Rubber stoppers

11.10.1.The rubber stoppers used for Large Volume Parenterals shall comply withspecifications prescribed in the current edition of the
Indian Pharmacopoeia.

12. Documentation

12. 1.The manufacturing records relating to manufacture of sterile products shallindicate the following details : -

16. Serialnumber of the Batch Manufacturing Record.

17. Name ofthe product.

18. Referenceto Master Formula Record.

19. Batch /Lot number.

20. Batch /Lot size.

21. Date ofcommencement of manufacture and date of completion of manufacture.

22. Date ofmanufacture and assigned date of expiry.

23. Date ofeach step in manufacturing.

24. Namesof all ingredients with the
grade given by the quality control department.

25. Quantityof all ingredients.

26. Controlreference numbers for all ingredients.

27. Timeand duration of blending, mixing etc. whenever applicable.

28. pH ofsolution whenever applicable.

29. Filterintegrity testing records.

30. Temperatureand humidity records whenever applicable.

31. Recordsof plate-counts whenever applicable.

32. Resultsof pyrogen and/or bacterial endotoxin & toxicity.

33. Recordsof weight or volume of drug filled in containers.

34. Bulksterility in case of aseptically filled products.

35. Leaktest records.

36. Inspectionrecords.

37. Sterilizationrecords including autoclave leakage test records, load details, date, duration, temperature, pressure etc.

38. Containerwashing records.

39. Totalnumber of containers filled.

40. Totalnumbers of containers rejected at each stage.

41. Theoreticalyield, permissible yield, actual yield and variation thereof.

42. Clarificationfor variation in yield beyond permissible yield.

43. Referencenumbers of relevant analytical reports.

44. Detailsof reprocessing, if any.

45. Name ofall operators carrying out different activities.

46. Environmentalmonitoring records.

47. Specimensof printed packaging material.

48. Recordsof destruction of rejected containers and printed packaging materials.

49. Signatureof the competent technical staff responsible for manufacture and testing.


    1. Products shall be released only after complete filling and testing.
    2. Result of the tests relating to sterility, pyrogens, and
      Bacterial endotoxins shall be maintained in the analytical records.
    3. Validation details and simulation trial records shall be maintained separately.
    4. Records of environmental monitoring like temperature, humidity, microbiological data etc. shall be maintained. Records of periodic servicing of HEPA filters, sterilizers and other periodic maintenance of facilities and equipment carried out shall also be maintained.
    5. Separate facilities shall be provided for filling-cum-sealing of Small Volume Injectables and Large Volume Parenterals.
    6. Separate facilities shall be provided for manufacture of Large Volume parenterals in glass containers and plastic containers.



Note : GoodManufacturing Practices for Premises and materials for pharmaceutical productsshall be complied with the manufacture of oral Solid Dosage Forms (Tablets andcapsules). In addition to these requirements, the following SpecificRequirements shall also be followed, namely: -

  1. General

1. 1.The processing of dry materials and products creates problems of dust controland cross-contamination. Special attention is, therefore, needed in the design,maintenance and use of premises and equipment in order to overcome theseproblems. Wherever required, enclosed dust control manufacturing systems shallbe employed.

1.2.Suitable environmental conditions for the products handled shall be maintainedby installation of air-conditioning wherever necessary. Effectiveair-extraction systems, with discharge points situated to avoid contaminationof other products and processes shall be provided. Filters shall be installedto retain dust and to protect the factory and local environment.

1. 3Special care shall be taken to protect against subsequent contamination of theproduct by particles of metal or wood. The use of metal detector isrecommended. Wooden equipment should be avoided. Screens, sieves, punches anddies shall be examined for wear and tear or for breakage before and after eachuse.

1. 4.All ingredients for a dry product shall be sifted before use unless the qualityof the input material can be assured. Such sifting shall normally be carriedout at dedicated areas.

1. 5.Where the facilities are designed to provide special environmental conditionsof pressure differentials between rooms, these conditions shall be regularlymonitored and any specification results brought to the immediate attention ofthe Production and Quality assurance departments which shall be immediatelyattended to.

1. 6.Care shall be taken to guard against any material lodging and remainingundetected in any processing or packaging equipment. Particular care shall betaken to ensure that any vacuum, compressed air or air-extraction nozzles arekept clean and that there is no evidence of lubricants leaking into the productfrom any part of the equipments.

  1. Sifting, mixing and granulation

2. 1.Unless operated as a closed system, mixing, sifting and blending equipmentsshall be fitted with dust extractors.

2.2Residues from sieving operations shall be examined periodically for evidence ofthe presence of unwanted materials.

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

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

2. 5.Granulation and coating solutions shall be made, stored and used in a mannerwhich minimises the risk of contamination or microbial growth.

  1. Compression (Tablets)

3. 1.Each tablet compressing machine shall be provided with effective dust controlfacilities to avoid cross contamination. Unless the same product is being madeon each machine, or unless the compression machine itself provides its ownenclosed air controlled environment, the machine shall be installed in separatecubicles.

3. 2.Suitable physical, procedural and labeling arrangements shall be made toprevent mix-up of materials, granules and tablets on compression machinery.

3. 3.Accurate and calibrated weighing equipment shall be readily available and usedfor in-process monitoring of tablet weight variation. Procedures used shall becapable of detecting out-of-limits tablets.

3. 4.At the commencement of each compression run and in case of multiple compressionpoints in a compression machine, sufficient individual tablets shall beexamined at fixed intervals to ensure that a tablet from each compressionstation or from each compression point has been inspected for suitablepharmacopoeial parameters like 'appearance', 'weight variation','disintegration', 'hardness', 'friability' and 'thickness'. The results shallbe recorded as part of the batch documentation.

3. 5.Tablets shall be de-dusted, preferably by automatic device and shall bemonitored for the presence of foreign materials besides any other defects.

3. 6.Tablets shall be collected into clean, labeled containers.

3. 7.Rejected or discarded tablets shall be isolated in identified containers andtheir quantity recorded in the Batch Manufacturing Record.

3. 8.In-process control shall be employed to ensure that the products remain withinspecification. During compression, samples of tablets shall be taken at regularintervals of not greater than 30 minutes to ensure that they are being producedin compliance with specified in-process specification. The tablets shall alsobe periodically checked for additional parameters such as 'appearance', 'weightvariation', 'disintegration', 'hardness', 'friability ' and 'thickness' andcontamination by lubricating oil.

  1. Coating (Tablets)

4. 1.Air supplied to coating pans for drying purposes shall be filtered air and ofsuitable quality. The area shall be provided with suitable exhaust system andenvironmental control (temperature, humidity) measures.

4. 2.Coating solutions and suspensions shall be made afresh and used in a manner,which shall minimise the risk of microbial growth. Their preparation and useshall be documented and recorded.

  1. Filling of Hard Gelatin Capsule

Emptycapsules shells shall be regarded as 'drug component' and treated accordingly.They shall be stored under conditions which shall ensure their safety from theeffects of excessive heat and moisture.

  1. Printing (Tablets And Capsules)

6. 1. Specialcare shall be taken to avoid product mix-up during any printing of tablets andcapsules. Where different products, or different batches of the same product,are printed simultaneously, the operations shall adequately be segregated.Edible grade colours and suitable printing ink shall be used for such printing.

6. 2.After printing, tablets and capsules shall be approved by Quality Controlbefore release for packaging or sale.

  1. Packaging (Strip and Blister)

7. 1.Care shall be taken when using automatic tablet and capsule counting, strip andblister packaging equipment to ensure that all 'rogue' tablets, capsules orfoils from packaging operation are removed before a new packaging operation iscommenced. There shall be an independent recorded check of the equipment beforea new batch of tablets or capsules is handled.

7. 2.Uncoated tablets shall be packed on equipment designed to minimise the risk ofcross-contamination. Such packaging shall be carried out in an isolated areawhen potent tablets or Beta-lactum containing tablets are being packed.

7. 3.The strips coming out of the machine shall be inspected for defects such asmisprint, cuts on the foil, missing tablets and improper sealing.

7. 4.Integrity of individual packaging strips and blisters shall be subjected tovacuum test periodically to ensure leak proofness of each pocket strip
and blister
and records maintained.


Note : TheGeneral Requirements as given in Good Manufacturing Practices for Premises andMaterials for pharmaceutical products shall be complied with the manufacture of( Syrups , Elixirs, Emulsions and Suspensions ). In addition to theserequirements, the following Specific Requirements shall also be followed,namely

  1. Building And Equipment

1. 1.The premises and equipment shall be designed, constructed and maintained tosuit the manufacturing of Oral Liquids. The layout and design of themanufacturing area shall strive to minimize the risk of cross- contaminationand mix-ups.

1. 2.Manufacturing area shall have entry through double door air-lock facility. Itshall be made fly proof by use of ' fly catcher' and / or 'air curtain'.

1. 3.Drainage shall be of adequate size and have adequate traps, without openchannels and the
design shall be such as to prevent back flow. Drains shall be shallow tofacilitate cleaning and disinfecting.

1. 4.The production area shall be cleaned and sanitised at the end of everyproduction process.

1. 5.Tanks, containers, pipe work and pumps shall be designed and installed so thatthey can be easily cleaned and sanitized. Equipment design shall be such as toprevent accumulation of residual microbial growth or cross-contamination.

1. 6.Stainless Steel or any other appropriate material shall be used for parts ofequipments coming in direct contact with the products. The use of glassapparatus shall be minimum.

1. 7.Arrangements for cleaning of containers, closures and droppers shall be madewith the help of suitable machines/devices equipped with high pressure air,water and steam jets.

1. 8.The furniture used shall be smooth, washable and made of stainless steel.

  1. Purified Water

2. 1.The chemical and microbiological quality of purified water used shall bespecified and monitored routinely. The microbiological evaluation shall includetesting for absence of pathogens and shall not exceed 100 cfu / ml (as perAppendix 12.5 of IP 1996).

2. 2.There shall be a written procedure for operation and maintenance of the
purified water system. Care shall be taken to avoid the risk of microbialproliferation with appropriate methods like recirculation, use of UV treatment,treatment with heat and sanitizing agent. After any chemical sanitisation ofthe water system, a flushing shall be done to ensure that the
sanitizing agent has been effectively removed.

  1. Manufacturing

3. 1.Manufacturing personnel shall wear non-fiber shedding clothing to preventcontamination of the product.

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

3. 3.Care shall be taken to maintain the homogenity of emulsion by use ofappropriate emulsifier and suspensions by use of appropriate stirrer duringfilling. Mixing and filling processes shall be specified and monitored. Specialcare shall be taken at the beginning of the filling process, after stoppage dueto any interruption
and at the end of the process to ensure that the product is uniformlyhomogenous during the filling process.

3. 4.The primary packaging area shall have an air supply which is filtered through 5micron filters. The temperature of the area shall not exceed 30 degreescentigrade.

3. 5.When the bulk product is not immediately packed, the maximum period of storageand storage conditions shall be specified in the Master Formula. The maximumperiod of storage time of a product in the bulk stage shall be validated.


Note : TheGeneral Requirements as given in Good Manufacturing Practices for premises andMaterials for pharmaceutical products shall be complied with the manufacture ofTopical Products i.e. External Preparations (Creams, Ointments, Pastes,Emulsions, Lotions, Solutions, Dusting powders and identical products used forexternal applications). In addition to these requirements, the followingSpecific Requirements shall also be followed, namely :

1.Theentrance to the area where topical products are manufactured shall be through asuitable airlock. Outside the airlock, insectocutors shall be installed.

2.Theair to this manufacturing area shall be filtered through at least 20 airfilters and shall be air-conditioned. The area shall be ventilated.

3.Thearea shall be fitted with an exhaust system of
suitable capacity to effectively remove vapours, fumes, smoke or floatingdust particles.

equipment used shall be designed and maintained to prevent the product frombeing accidentally contaminated with any foreign matter or lubricant.

5.Norags or dusters shall be used in the process of cleaning or drying the processequipment or accessories used.

6.Waterused in compounding shall be Purified Water IP.

7.Powders,whenever used, shall be suitably sieved before use.

8.Heatingvehicles and a
base like petroleum jelly shall be done in a separate mixing area insuitable stainless steel vessels, using steam, gas, electricity, solar energyetc.

9.Aseparate packing section may be provided for primary packaging of the products.


Note :
The General Requirements as given inf Good Manufacturing Practices forpremises and Materials for pharmaceutical products shall be complied with themanufacture of Metered-Dose-Inhalers (MDI). In addition to these requirements,the following Specific Requirements shall also be followed, namely :

  1. General

Manufactureof Metered-Dose-Inhalers shall be done under conditions which shall ensureminimum microbial and particulate contamination. Assurance of the quality ofcomponents and the bulk product is very important. Where medicaments are insuspended state, uniformity of suspension shall be established.

  1. Building and civil works

2. 1.The building shall be located on a solid foundation to reduce risk of crackingwalls and floor due to the
movement of equipment and machinery.

2. 2.All building surfaces shall be impervious, smooth and non-shedding. Flooringshall be continuous and provided with a cover between the floor and the wall aswell as between the wall and the ceiling. Ceiling shall be solid, continuousand proceeded a cone with the walls. Light fittings and air-grills shall beflush with the ceiling. All service lines requiring maintenance shall beerected in such a manner that these are accessible from outside the productionarea.

2. 3.The manufacturing area shall be segregated into change rooms for personnel,container preparation area, bulk preparation and filling area, quarantine areaand spray testing and packing areas.

2. 4.Secondary change rooms shall be provided for operators to change from factoryclothing to special departmental clothing before entering the manufacturing andfilling area.

2. 5.Separate area shall be provided for de-cartoning of components before they areair washed.

2. 6.The propellants used for manufacture shall be delivered to the manufacturingarea distribution system by filtering them through 2 micron filters. The bulkcontainers of propellants shall be stored, suitably identified, away from themanufacturing facilities.

  1. Environmental Conditions

3. 1.Where products or clean components are exposed, the area shall be supplied withfiltered air of Grade C.

3. 2.The requirements of temperature and humidity in the manufacturing area shall bedecided depending on the type of product and propellants handled in thefacility. Other support areas shall have comfort levels of temperature andhumidity.

3. 3.There shall be a difference in room pressure between the manufacturing area andthe support areas and the differential pressure shall be not less than 15Pascals, (0.06 inches or 1.5 mm Water gauge).

3. 4.There shall be a written schedule for the monitoring of environmentalconditions. Temperature and humidity shall be monitored daily.

  1. Garments

4. 1.Personnel in the manufacturing and filling section shall wear suitablesingle-piece-garment made out of non-shedding, tight weave material. Personnelin support areas shall wear clean factory uniforms.

4. 2.Gloves made of suitable material having no interaction with the propellantsshall be used by the operators in the manufacturing and filling areas.Preferably, disposable gloves shall be used.

4. 3.Suitable department-specific personnel protective equipment likefootwear and safety glasses shall be used wherever hazard exists.

  1. Sanitation

5. 1.There shall be written procedures for the sanitation of the MDI manufacturingfacility. Special care should be taken to handle residues and rinses ofpropellants.

5. 2.Use of water for cleaning shall be restricted and controlled. Routinely useddisinfectants are suitable for sanitising the different areas. Records ofsanitation shall be maintained.

  1. Equipment

6. 1.Manufacturing equipment shall be of closed system. The vessels and supply linesshall be of stainless steel.

6. 2.Suitable check weights, spray testing machines and labelling machines shall beprovided in the department.

6. 3.All the equipment shall be suitably calibrated and their performance validatedon receipt and thereafter periodically.

  1. Manufacture

7. 1.There shall be an approved master formula records for the manufacture ofmetered dose inhalers. All propellants, liquids and gases shall be filteredthrough 2 micron filters to remove particles.

7. 2.The primary packing material shall be appropriately cleaned by compressed airsuitably filtered through 0.2 micron filter. The humidity of the compressed airshall be controlled as applicable.

7. 3.The valves shall be carefully handled and after de-cartoning, these shall bekept in clean, closed containers in the filling room.

7. 4.For suspensions, the bulk shall be kept stirred continuously.

7. 5.In-process controls shall include periodical checking of weight of bulkformulation filled in the containers. In a two-shot-filling process (liquidfilling followed by gaseous filling), it shall be ensured that 100 % check on
weight is carried out.

7. 6.Filled containers shall be quarantined for a
suitable period established by the manufacturer to detect leakingcontainers prior to testing, labelling and packing.

  1. Documentation

8. 1.In addition to the routine good manufacturing practices documentation ofmanufacturing records shall be show the following additional information:-

( 1 )Temperature and humidity in the manufacturing area.

( 2 )Periodic filled weights of the formulation.

( 3 )Records of rejections during on line check weighing.

( 4 )Records of rejection during spray testing.




Thequality and purity of the pharmaceutical product depends on the Conditionmaintained during the manufacturing process. The Good ManufacturingProcess(GMP) concept strictly adhere to stringent specifications followedduring the manufacturing process. This assure the quality of the final product.Hence GMP is very essential to provide quality products and thereby preventingthe market entry for counterfit drug.





    1. The principal rules were published in the official gazette vide notification No. F.28-10/45-H(1) dated 21st December 1945 and last amended vide GSR 700(E) dated 28-09-2001
    2. The drug and cosmetic rules, 1945, as amended upto 01-05-1979 is contained in the publication of the ministry of health and family welfare (department of health) containing the drug and cosmetics act 1940 (PDGHS-61).
    3. Global programme for vaccines supply and quality written by Gillian Chaloner – Larsson, Roger Anderson and Anik Egan.

    2. A plan for total quality control by P.P. Sharma
    3. Companion volume to a HANDBOOK OF DRUG LAWS by M.L. Mehra


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Ethylene oxide (ETO) - Sterilization process for pharmaceutical products

Articles | Production
11-Jul-2015  Views: 8865

Ethylene oxide (ETO) is a colorless liquid (it is liquid at temperatures below 10.8oC).ETO has been widely used as a low-temperature sterilant. It has ...
HEPA Filters Used in Pharmaceuticals Manufacturing

HEPA Filters Used in Pharmaceuticals Manufacturing

Articles | Production
05-Jun-2015  Views: 26090

Know about HEPA (High Efficiency Particulate Air) filters in detail including Particles and Relative Micron Size. ...
Pharmaceutical Products Manufacture & Analytical Testing Process

Pharmaceutical Products Manufacture & Analytical Testing Process

12-Mar-2015  Views: 15957

When you are sick and you reach for that box of tablets, how do you know that what you are about to take is safe? All pharmaceuticals are manufactured ...


26-Jan-2011  Views: 9112

1.General considerations2. Quality control3. Sanitation4. Manufacture of sterile preparations5. Sterilization6. Terminal sterilization7. Aseptic proce ...


03-Jun-2010  Views: 12973

Good Manufacturing Practice (cGMP) is the term used to define the latest best practice for the manufacture of pharmaceutical and allied products in va ...
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