Project Pharma

8/11/2019 Project Pharma

1/55

GOOD MANUFACTURING PRACTICE FOR PHARMACEUTICAL PRODUCTS

INTRODUCTION

What is GMP?

Good manufacturing practice (GMP) comprises that part of quality assuranceaimed at ensuring that a product is consistently manufactured to a qualityappropriated to its intended use. GMP requires that the manufacturing process isfully de ned before it is initiated and that all necessary facilities are provided. Inpractice, this means that personnel must be adequately trained, suitable premisesand equipment used, correct materials used, approved procedures adopted,suitable and transport facilities available and appropriate records made.

he quality of pharmaceutical products depends on the degree of care ta!en in itspreparation. "inal chec!s carried out on the nished products are useful incon rming that the correct ingredients have been used and that that materials havebeen correctly processed. It is ho#ever essential that proper in process control ise$ercised and that it is adequately documented to provide reliable evidence thatthe correct procedures have been follo#ed. he need for GMP is recogni%edthroughout the #orld. More than &' countries have issued their o#n GMP guidelines.( he essential components of GMP are summari%ed in gure .)

Why it is required?

he Good Manufacturing Practices are prescribed to ensure that

(i) *a# materials used in the manufacture of pharmaceuticals are authentic, ofprescribed quality and are free from contamination.

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

(iii) +dequate quality control measures are adopted and

(iv) he manufactured drug #hich is released for sale has the prescribed quality.


2/55

(v) o achieve the ob ectives listed above, each licencee shall evolve methodologyand procedures for follo#ing the prescribed process of manufacture of drugs #hichshould be documented as a manual and !ept for reference and inspection. -o#ever,teaching institutions and registered quali ed aidyas, /iddhas and -a!eems #hoprepare medicines on their o#n to dispense to their patients and not selling such

drugs in the mar!et are e$empted from the purvie# of G.M.P.

W r!d Hea!th Or"a#i$ati # %WHO& GMP

0-1 de nes good manufacturing practice has 2that part of quality assurance#hich assures that products are consistently produced and controlled to the qualitystandards appropriate to their indented use and as required by the mar!etingauthori%ation2

GMP covers all aspects of the manufacturing process de ned manufacturingprocesses3 critical manufacturing steps3 suitable premises, storage, transport3quali ed and trained production and quality control personnel3 adequate laboratoryfacilities3 approved #ritten procedures and instructions3 records to sho# all steps ofde ned procedures have been ta!en3 full traceability of a product through batchre#ards and distribution records and systems for recall and investigation ofcomplaints.

GMP RE'UIREMENTS FOR PREMISES AND MATERIALS FORPHARMACEUTICAL PRODUCTS

() GENERAL RE'UIREMENTS

()() L *ati # a#d surr u#di#"s)+ he factory building(s) for manufacture ofdrugs shall be so situated and shall have such measures as to avoid ris! ofcontamination from e$ternal environment including open se#age, drain, public

lavatory or any factory #hich produces disagreeable or obno$ious, odour, fumes,e$cessive soot, dust, smo!e, chemical or biological emissions.

(),) -ui!di#"s a#d .re/ises)0 he building(s) used for the factory shall bedesigned, constructed, adapted and maintained to suit the manufacturingoperations so as to permit production of drugs under hygienic conditions. hey shallconform to the conditions laid do#n in the "actories +ct, 456 (78 of 456).


3/55

he premises used for manufacturing, processing, #arehousing, pac!aging, labelingand testing purposes shall be 9

. compatible #ith other drug manufacturing operations that may be carried outin the same or ad acent area : section3

&. adequately provided #ith #or!ing space to allo# orderly and logicalplacement of equipment, materials and movement of personnel so as to

. avoid the ris! of mi$9up bet#een di;erent categories of drugs or #ithra# materials, intermediates and in9process material3

&. avoid the possibilities of contamination and cross9contamination byproviding suitable mechanism3

(iii) designed : constructed : maintained to prevent entry of insects, pests, birds,vermins, and rodents. Interior surface (#alls,


4/55

0ater conforming to Pharmacopoeial speci cation. Puri ed 0ater so produced shallonly be used for all the operations e$cept #ashing and cleaning operations #herepotable #ater may be used. 0ater shall be stored in tan!s, #hich do not adverselya;ect quality of #ater and ensure freedom from microbiological gro#th. he tan!shall be cleaned periodically and records maintained by the licensee in this behalf.

()2 Dis. sa! 3 4aste

(i) he disposal of se#age and e@uents (solid, liquid and gas) from the manufactoryshall be in conformity #ith the requirements of Anvironment Pollution Bontrol >oard.

(ii) +ll bio9medical #aste shall be destroyed as per the provisions of the >io9Medical0aste (Management and -andling) *ules, 447.

(iii) +dditional precautions shall be ta!en for the storage and disposal of re ecteddrugs. *ecords shall be maintained for all disposal of #aste.

(iv) Provisions shall be made for the proper and safe storage of #aste materialsa#aiting disposal. -a%ardous, to$ic substances and


5/55

equivalent assurance of segregation. +ccess to these areas shall be restrictedto authori%ed persons.

D. here shall be a separate sampling area in the #arehousing area for activera# materials and e$cipients. If sampling is performed in any other area, it

shall be conducted in such a #ay as to prevent contamination, cross9contamination and mi$9 up.

7. /egregation shall be provided for the storage of re ected, recalled or returnedmaterials or products. /uch areas, materials or products shall be suitablymar!ed and secured. +ccess to these areas and materials shall be restricted.

E. -ighly ha%ardous, poisonous and e$plosive materials such as narcotics,psychotropic drugs and substances presenting potential ris!s of abuse, re ore$plosion shall be stored in safe and secure areas. +dequate re protectionmeasures shall be provided in conformity #ith the rules of the concernedcivic authority.

6. Printed pac!aging materials shall be stored in safe, separate and secureareas.

4. /eparate dispensing areas for (>eta)lactum, /e$ -ormones and Byto9to$ic substances or any such specialcategories of products shall be provided #ith proper supply of ltered air andsuitable measures for dust control to avoid contamination. /uch areas shallbe under di;erential pressure.

'./ampling and dispensing of sterile materials shall be conducted under asepticconditions conforming to Grade +, #hich can also be performed in adedicated area #ithin the manufacturing facility.

.*egular chec!s shall be made to ensure adequate steps are ta!en againstspillage, brea!age and lea!age of containers.

&.*odent treatments (pest control) should be done regularly and at least oncein a year and record maintained.

1) PRODUCTION AREA

. he production area shall be designed to allo# the production preferably in uni9


6/55

contamination causing and potent products such as >eta lactum, /e$ -ormones andByto9to$ic substances.

8.0or!ing and in9process space shall be adequate to permit orderly and logicalpositioning of equipment and materials and movement of personnel to avoid cross9

contamination and to minimi%e ris! of omission or #rong application of any ofmanufacturing and control measures.

5.Pipe9#or!, electrical ttings, ventilation openings and similar service lines shall bedesigned, $ed and constructed to avoid creation of recesses. /ervice lines shallpreferably be identi ed by colours and thenature of thesupply and direction of the


7/55

cross9contamination. /uCcient and suitable storage space shall be provided for testsamples, retained samples, reference standards, reagents and records.

8. he design of the laboratory shall ta!e into account the suitability of constructionmaterials and ventilation. /eparate air handling units and other requirements shall

be provided for biological, microbiological and radioisotopes testing areas. helaboratory shall be provided #ith regular supply of #ater of appropriate quality forcleaning and testing purposes.

.5. uality Bontrol ?aboratory shall be divided into separate sections i.e. forchemical, microbiological and #herever required, biological esting. hese shallhave adequate area for basic installation and for ancillary purposes. hemicrobiology section shall have arrangements such as airloc!s and laminar air


8/55

E. . he personnel handling >eta9lactum antibiotics shall be tested for Penicillinsensitivity before employment and those handling se$ hormones, cytoto$icsubstances and other potent drugs shall be periodically e$amined for adversee;ects. hese personnel should be moved out of these sections(e$cept in dedicated facilities), by rotation, as a health safeguard.

E.&. Prior to employment, all personnel, shall undergo medical e$aminationincluding eye e$amination, and shall be free from uberculosis, s!in and othercommunicable or contagious diseases. hereafter, they should be medicallye$amined periodically, at least once a year. *ecords shall be maintained thereof.

he licensee shall provide the services of a quali ed physician for assessing thehealth status of personnel involved in di;erent activities.

E.8 +ll persons, prior to and during employment, shall be trained in practices #hichensure personnel hygiene. + high level of personal hygiene shall be observed by allthose engaged in the manufacturing processes. Instructions to this e;ect shall be

displayed in change9rooms and other strategic locations.

E.5 Ho person sho#ing 9 at any time 9 apparent illness or open lesions #hich mayadversely a;ect the quality of products, shall be allo#ed to handle startingmaterials, pac!aging materials, In9process materials, and drug products until hiscondition is no longer udged to be a ris!.

E.D +ll employees shall be instructed to report about their illness or abnormal healthcondition to their immediate supervisor so that appropriate action can be ta!en.

E.7 Firect contact shall be avoided bet#een the unprotected hands of personneland ra# materials, intermediate or nished 9 unpac!ed products.

E.E +ll personnel shall #ear clean body coverings appropriate to their duties. >eforeentry into the manufacturing area, there shall be change rooms separate for eachse$ #ith adequate facilities for personal cleanliness such as #ash basin #ith running#ater,clean to#els, hand dryers, soaps, disinfectants etc. he change rooms shall beprovided #ith cabinets for the storage of personal belongings of the personnel.

E.6 /mo!ing, eating, drin!ing, che#ing or !eeping plants, food, drin! and personalmedicines shall not be permitted in production, laboratory, storage and other areas#here they might adversely in


9/55

he contents of all vessels and containers used in manufacture and storage duringthe various manufacturing stages shall be conspicuously labeled #ith the name ofthe product, batch no., batch si%e and stage of manufacture. Aach label should beinitialed and dated by the authori%edtechnical sta;.

Products not prepared under aseptic conditions are required to be free frompathogens li!e Salmonella, Escherichia coli, Pyocyanea etc.

;) ,) Pre*auti #s a"ai#st /ieta9?actumantibiotics, se$ hormones and cycoto$ic substances in segregated areas or isolatedproduction areas #ithin the building #ith independent air9handling unit and properpressure di;erentials. he e;ective segregation of these areas shall bedemonstrated #ith adequate records of maintenance and services.

6. &. 8. o prevent mi$9ups during production stages, material under9 process shallbe conspicuously labeled to demonstrate their status. +ll equipment used forproduction shall be labeled #ith their current status.

6. &. 5. Pac!aging lines shall be independent and adequately segregated. It shall beensured that all left9overs of the previous pac!aging operations, including labels,cartons and caps are cleared before theclosing hour.

6. &. D. >efore pac!aging operations are begun, steps shall be ta!en to ensure thatthe #or! area, pac!aging lines, printing machines, and other equipment are cleanand free from any products, materials and spillages. he line clearance shall beperformed according to an appropriate chec!list and recorded.

6. &. 7. he correct details of any printing (for e$ample of batch numbers or e$pirydates) done separately or in the course of the pac!aging shall be re9chec!ed atregular intervals. +ll printing and over9printing shall be authorised in #riting.

6. &. E. he manufacturing environment shall be maintained at the required levels of temperature, humidity and cleanliness.

6. &. 6. +uthorised persons shall ensure change9over into speci c uniforms beforeunderta!ing any manufacturing operations including pac!aging.


10/55

6. &. 4. here shall be segregated enclosed areas, secured for recalled or re ectedmaterial and for such material #hich are to be re9processed or recovered.

=) SANITATION IN THE MANUFACTURING PREMISES

4. . he manufacturing premises shall be cleaned and maintained in an orderlymanner, so that it is free from accumulated #aste, dust, debris and other similarmaterial. + validated cleaning procedureshall be maintained.

4. &. he manufacturing areas shall not be used for storage of materials, e$cept forthematerial being processed. It shall not be used as a general thoroughfare.

4. 8. + routine sanitation program shall be dra#n up and observed, #hich shall beproperly recorded and #hich shall indicate

. speci c areas to be cleaned and cleaning intervals3

&. cleaning procedure to be follo#ed, including equipment and materials to beused for cleaning3 and

8. personnel assigned to and responsible for the cleaning operation.

4. 5. he adequacy of the #or!ing and in9process storage space shall permit theorderly and logical positioning of equipment and materials so as to minimise the ris!of mi$9up bet#een di;erent pharmaceutical products or their components to avoidcross9contamination, and to minimise the ris! of omission or #rong application ofany of the manufacturing or control steps.

4. D. Production areas shall be #ell lit, particularly #here visual on9line controls arecarried out.

(>) RAW MATERIALS

'. . he licensee shall !eep an inventory of all ra#9materials to be used at anystage of manufacture of drugs and maintain records as per /chedule =.

'. &. +ll incoming materials shall be quarantined immediately after receipt orprocessing. +ll materials shall be stored under appropriate conditions and in anorderly fashion to permit batch segregation and stoc! rotation by a J rst in: rste$piryJ 9 J rst9outJ principle. +ll incoming materials shall be chec!ed to ensure thatthe consignment corresponds to the order placed.


11/55

'. 8. +ll incoming materials shall be purchased from approved sources under validpurchase vouchers. 0herever possible, ra# materials should be purchased directlyfrom the producers.

'. 5. +uthorised sta; appointed by the

licensee in this behalf, #hich may include personnel from the quality controldepartment, shall e$amine each consignment on receipt and shall chec! eachcontainer for integrity of pac!age and seal. Famaged containers shall be identi ed,recorded and segregated.

'. D. If a single delivery of material is made up of di;erent batches, each batchshall be considered as a separate batch for sampling, testing and release.

'. 7. *a# materials in the storage area shall be appropriately labeled. ?abels shallbe clearly mar!ed #ith the follo#ing information

. designated name of the product and the internal code reference, #hereapplicable, and analytical reference number3

&. manufacturerJs name, address and batch number3

8. the status of the contents (e.g. quarantine, under test, released, approved,re ected)3

5. the manufacturing date, e$piry date and re9test date.

'. E. here shall be adequate separate areas for materials 2under test2, 2approved2, and 2re ected2 #ith arrangements and equipment to allo# dry, clean and orderly

placement of stored materials and products, #herever necessary, under controlledtemperature and humidity.

'. 6. Bontainers from #hich samples have been dra#n shall be identi ed.

'. 4. 1nly ra# materials #hich have been released by the uality BontrolFepartment and #hich are #ithin their shelf9life shall be used. It shall be ensuredthat shelf9life of formulation product shall not e$ceed #ith that of active ra#materials used.

'. '. It shall be ensured that all the containers of ra# materials are placed on theraised platforms:rac!s and not placed directly on the


12/55

general, any adverse e;ect on the quality of products. Aach equipment shall beprovided #ith a log boo! 9 #herever necessary.

. &. >alances and other measuring equipment of an appropriate range, accuracyand precision shall be available in the ra#9material stores, production and in9

process control operations and these shall be calibrated and chec!ed on ascheduled basis in accordance #ith /tandard 1perating Procedures and recordsmaintained.

. 8. he parts of the production equipment that come into contact #ith theproduct shall not be reactive, additive or adsorptive to an e$tent that #ould a;ectthe quality of the product.

. 5. o avoid accidental contamination, #herever possible, non9to$ic:edible gradelubricants shall be used and the equipment shall be maintained in a #ay thatlubricants do not contaminate the products being produced.

. D. Fefective equipment shall be removed from production and uality Bontrolareas or appropriately labeled.

(,) DOCUMENTATION AND RECORDS

Focumentation is an essential part of the uality assurance system and, as such,shall be related to all aspects of Good Manufacturing Practices (GMP). Its aim is tode ne the speci cations for all materials, method of manufacture and control, toensure that all personnel concerned #ith manufacture !no# the informationnecessary to decide #hether or not to release a batch of a drug for sale and toprovide an audit trail that shall permit investigation of the history of any suspecteddefective batch.

&. . Focuments designed, prepared, revie#ed and controlled, #herever applicable,shall comply #ith these rules.

&. &. Focuments shall be approved, signed and dated by appropriate andauthori%ed persons.

&. 8. Focuments shall specify the title, nature and purpose. hey shall be laid outin an orderly fashion and be easy to chec!. *eproduced documents shall be clearand legible. Focuments shall be regularly revie#ed and !ept up to date. +ny

alteration made in the entry of a document shall be signed and dated.

&. 5. he records shall be made or completed at the time of each operation in sucha #ay that all signi cant activities concerning the manufacture of pharmaceuticalproducts are traceable. *ecords and associated /tandard 1perating Procedures(/1P) shall be retained for at least one year after the e$piry date of the nishedproduct.


13/55

&. D. Fata may be recorded by electronic data processing systems or other reliablemeans, but master formulae and detailed operating procedures relating to thesystem in use shall alsobe available in a hard copy to facilitate chec!ing of the accuracy of the records.0herever documentation is handled by electronic data processing methods,

authori%ed persons shall enter or modify data in the computer. here shall be recordof changes and deletions. +ccess shall be restricted by Jpass#ordsJ or other meansand the result of entry of critical data shall be independently chec!ed. >atch recordselectronically stored shall be protected by a suitable bac!9up. Furing the period ofretention, all relevant data shall be readily available.

(1) LA-ELS AND OTHER PRINTED MATERIALS

?abels are absolutely necessary for identi cation of the drugs and their use. heprinting shall be done in bright colours and in a legible manner. he label shall carryall the prescribed details about the product.

8. . +ll containers and equipment shall bear appropriate labels. Fi;erent colourcoded labels shall be used to indicate the status of a product (for e$ample undertest, approved, passed, re ected).

8. &. o avoid chance of mi$9up in printed pac!aging materials, product lea


14/55

the ob ect of ensuring that products are of the quality required for their intendeduse.

5. . he system of quality assurance appropriate to the manufacture ofpharmaceutical products shall ensure that

. the pharmaceutical products are designed and developed in a #ay that ta!esaccount of the requirements of Good Manufacturing Practices (hereinafterreferred as GMP) and other associated codes such as those of Good?aboratory Practices (hereinafter referred as G?P) and Good Blinical Practices(herein after referred as GBP).

&. adequate arrangements are made for manufacture, supply, and use of thecorrect starting and pac!aging materials.

8. adequate controls on starting materials, intermediate products, and bul!products and other in9process controls, calibrations, and validations arecarried out.

5. the nished product is correctly processed and chec!ed in accordance #ithestablished procedures.

D. the pharmaceutical products are not released for sale or supplied beforeauthori%ed persons have certi ed that each production batch has beenproduced and controlled in accordance #ith the requirements of the labelclaim and any other provisions relevant to production, control and release ofpharmaceutical products.

(6) SELF INSPECTION AND 'UALIT5 AUDIT

It may be useful to constitute a self inspection team supplemented #ith a qualityaudit procedure for assessment of all or part of a system #ith the speci c purposeof improving it.

D . o evaluate the manufacturerJs compliance #ith GMP in all aspects ofproduction and quality control, concept of self9inspection shall be follo#ed. hemanufacturer shall constitute a team of independent, e$perienced, quali edpersons from #ithin or outside the company, #ho can audit ob ectively theimplementation of methodology and procedures evolved. he procedure for self9inspection shall be documented indicating self9inspection results, evaluation,


15/55

conclusions and recommended corrective actions #ith e;ective follo# up program. he recommendations for corrective action shall be adopted.

D. &. he program shall be designed to detect shortcomings in the implementationof Good Manufacturing Practice and to recommend the necessary corrective actions.

/elf9inspections shall be performed routinely and on speci c occasions, li!e #henproduct recalls or repeated re ectionsoccur or #hen an inspection by the licensing authorities is announced. he teamresponsible for self9inspection shall consist of personnel #ho can evaluate theimplementation of Good Manufacturing Practice ob ectively3 all recommendationsfor corrective action shall be implemented.

D. 8. 0ritten instructions for self9inspection shall be dra#n up #hich shall includethe follo#ing

. Premises including personnel facilities.

&. Maintenance of buildings and equipment.

8. /torage of starting materials and nished products.

5. Aquipment.

D. Production and in9process controls.

7. uality control.

E. Focumentation.

6. /anitation and hygiene.

4. alidation and revalidation programmes.

'.Balibration of instruments or measurement systems.

.*ecall procedures.

&.Bomplaints management.

8.?abels control.

5.*esults of previous self9inspections and any corrective steps ta!en.(7) 'UALIT5 CONTROL S5STEM

uality control shall be concerned #ith sampling, speci cations, testing,documentation, release procedures #hich ensure that the necessary and relevanttests are actually carried and that the materials are not released for use, norproducts released for sale or supply until their quality has been udged to be


16/55

satisfactory. It is not con ned to laboratory operations but shall be involved in alldecisions concerning the quality of the product. It shall be ensured that all qualitycontrol arrangements are e;ectively and reliably carried out. he department as a#hole shall have other duties such as to establish, evaluate, validate and implementall uality Bontrol Procedures and methods.

7. . Avery manufacturing establishment shall establish its o#n quality controllaboratory managed by quali ed and e$perienced sta;.

7. &. he area of the quality control laboratory may be divided into Bhemical,Instrumentation, Microbiological and >iological testing. /eparate provision should bemade for testing radio active material is used for manufacturing.

7. 8. +dequate area having the required storage conditions shall be provided for!eeping reference samples. he quality control department shall evaluate, maintainand store reference samples.

7. 5. /tandard operating procedures shall be available for sampling, inspecting,and testing of ra# materials, intermediate, bul! nished products and pac!ingmaterials and, #herever necessary, for monitoring environmental conditions.

7. D. here shall be authori%ed and dated speci cations for all materials, products,reagents and solvents including test of identity, content, purity and quality. heseshall include speci cations for #ater, solvents and reagents used in analysis.

7. 7. Ho batch of the product shall be released for sale or supply until it has beencerti ed by the authorised person(s) that it is in accordance #ith the requirementsof the standards laid do#n.

7. E. *eference:retained samples from each batch of the products manufacturedshall be maintained in a quantity #hich is at least t#ice the quantity of the drugrequired to conduct all the tests, e$cept sterility and pyrogen:>acterial Andoto$in

est performed on the active material and the product manufactured. he retainedproduct shall be !ept in its nal pac! or a simulated pac! for a period of threemonths after the date of e$piry.

7. 6. +ssessment of records pertaining to nished products shall include allrelevant factors, including the production conditions, the results of inprocesstesting, the manufacturing (including pac!aging) documentation, compliance #iththe speci cation for the nished product, and an e$amination of the nished pac!.+ssessment records should be signed by the person incharged of production andcountersigned by the authorised quality control personnel before a product isreleased for sale or distribution.

7. 4. uality control personnel shall have access to production areas for samplingand investigation 9 as appropriate.


17/55

7. '. he quality control department shall conduct stability studies of theproducts to ensure and assign their shelf life at the prescribed conditions of storage.+ll records of such studies shall be maintained.

7. . he in9charge of uality +ssurance shall investigate all product complaints

and records thereof shall be maintained.7. &. +ll instruments shall be calibrated and testing procedures validated before

these are adopted for routine testing. Periodical calibration of instrument andvalidation of procedures should be carried out.

7. 8. Aach speci cations for ra# materials, intermediates, nal products, andpac!ing materials shall be approved and maintained by the uality BontrolFepartment. Periodic revisions of the speci cations shall be carried out #heneverchanges are necessary.

7. 5. Pharmacopoeiae, reference standards, #or!ing standards, reference spectra,other reference materials and technical boo!s, as required, shall be made availablein the uality Bontrol ?aboratory of the licensee.

(8) SPECIFICATION

E. . "or *a# materials and Pac!aging materials 9

hey shall include,9

. the designated name and internal code reference3

&. reference, if any , to a pharmacopoeial monograph3

8. qualitative and quantitative requirements #ith acceptance limits3

5. name and address of manufacturer or supplier and original manufacturer ofthe material3

D. specimen of printed material3

7. directions for sampling and testing or reference to procedures3

E. storage conditions3 and

6. ma$imum period of storage before re9testing.

E. &. "or Product Bontainers and Blosures


18/55

E. &. . +ll containers and closures intended for use shall comply #ith thepharmacopoeial requirements. /uitable validated test methods, sample si%es,speci cations, cleaning procedure and sterili%ation procedure, #herever indicated,shall be strictly follo#ed to ensure that these are not reactive, additive, adsorptive,or leach to an e$tent that signi cantly a;ects the quality or purity of the drug. Ho

second hand or used containers and closures shall be used.

E. &. &. 0henever bottles are being used, the #ritten schedule of cleaning shall belaid do#n and follo#ed. 0here bottles are not dried after #ashing, they should berinsed #ith de9ionised #ater or distilled #ater, as the case may be.

E. 8. "or in9process and bul! products.K /peci cations for in9process material,intermediate and bul! products shall be available. he speci cations should beauthenticated.

E. 5. "or "inished Products. +ppropriate speci cations for nished products shallinclude 9

. the designated name of the product and the code reference.

&. the formula or a reference to the formula and the pharmacopoeial reference.

8. directions for sampling and testing or a reference to procedures.

5. a description of the dosage form and pac!age details.

D. the qualitative and quantitative requirements, #ith the acceptance limits forrelease.

7. the storage conditions and precautions, #here applicable 9 and

E. the shelf9life.

E.D"or preparation of containers and closures. he requirements mentioned in the/chedule do not include requirements of machinery, equipments and premisesrequired for preparation of containers and closures for di;erent dosage forms andcategories of drugs. he suitability and adequacy of the machinery, equipment andpremises shall be e$amined ta!ing into consideration the requirements of eachlicensee in this respect .

(; MASTER FORMULA RECORDS

here shall be Master "ormula records relating to all manufacturing procedures foreach product and batch si%e to be manufactured. hese shall be prepared andendorsed by the competent technical sta; i.e. head of production and qualitycontrol. he Master "ormula shall include 9


19/55

. the name of the product together #ith product reference code relating to itsspeci cations.

&. the patent or proprietary name of the product along #ith the generic name, adescription of the dosage form, strength, composition of the product and

batch si%e.8. name, quantity, and reference number of all the starting materials to be

used. Mention any substance that may JdisappearJ in the course ofprocessing.

5. a statement of the e$pected nal yield #ith the acceptable limits, and ofrelevant intermediate yields, #here applicable.

D. a statement of the processing location and the principal equipment to beused.

7. the methods, or reference to the methods, to be used for preparing thecritical equipment including cleaning, assembling, calibrating, sterili%ing.

E. detailed step#ise processing instructions and the time ta!en for each step.

6. the instructions for in9process controls #ith their limits.

4. the requirements for storage conditions of the products, including thecontainer, labelling and special storage conditions #here applicable.

'.any special precautions to be observed.

.pac!ing details and specimen labels.

(= PAC:AGING RECORDS

here shall be authorisedpac!aging instructions for each product, pac! si%e and type. hese shall include orhave a reference to the follo#ing 9

. name of the product.

&. description of the dosage form, strength and composition.

8. the pac! si%e e$pressed in terms of the number or doses, #eight or volume of the product in the nal container.

5. complete list of all the pac!aging materials required for a standard batchsi%e, including quantities, si%es and types, #ith the code or reference numberrelating to the speci cations of each pac!aging material.


20/55

D. reprocessing of the relevant printed pac!aging materials and specimensindicating #here batch number and e$piry date of the product have beenapplied.

7. special precautions to be observed, including a careful e$amination of the

area and equipment in order to ascertain the line clearance before theoperations begin.

E. description of the pac!aging operation, including any signi cant subsidiaryoperations and equipment to be used.

6. details of in9process controls #ith instructions for sampling and acceptance.

4. upon completion of the pac!ing and labeling operation, a reconciliation shallbe made bet#een number of labeling and pac!aging units issued, number ofunits labeled, pac!ed and e$cess returned or destroyed. +ny signi cant orunusual discrepancy in the numbers shall be carefully investigated beforereleasing the nal batch.

,>) -ATCH PAC:AGING RECORDS

&'. . + batch pac!aging record shall be !ept for each batch or part batchprocessed. It shall be based on the relevant parts of the pac!aging instructions, andthe method of preparation of such records shall be designed to avoid transcriptionerrors.

&'. &. >efore any pac!aging operations begins, chec!s shall be made and recordedthat the equipment and the #or! stations are clear of the previous products,

documents or materials not required for the planned pac!aging operations, and thattheequipment is clean and suitable for use.

,() -ATCH PROCESSING RECORDS

& . here shall be >atch Processing *ecord for each product. It shall be based onthe relevant parts of the currently approved Master "ormula. he method ofpreparation of such records included in theMaster "ormula shall be designed to avoid transcription errors.

& .&. >efore starting of any process inspect all the manufacturing area and ensurethat the equipment and #or! station are clear of previous products. his should bedocumented and recorded.

& .8. Furing processing, the follo#ing information shall be recorded at the timeeach action is ta!en and the record shall be dated and signed by the personresponsible for the processing operations

( a ) the name of the product,


21/55

( b ) the number of the batch being manufactured,

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

( d ) initials of the operator of di;erent signi cant steps of production and #hereappropriate, of the person #ho chec!ed each of these operations,

( e ) the batch number and:or analytical control number as #ell as the quantities ofeach starting material actually #eighed,

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

( g ) a record of the in9process controls and the initials of the person(s) carryingthem out, and the results obtained,

(h ) the amount of product obtained after di;erent and critical stages of

manufacture (yield),( i ) comments or e$planations for signi cant deviations from the e$pected yieldlimits shall be given,

( ) notes on special problems including details, #ith signed authori%ation, for anydeviation from the master formula,

(!) addition of any recovered or reprocessed material #ith reference to recovery orreprocessing stages.

,,) STANDARD OPERATING PROCEDURES %SOPS& AND RECORDS9

REGARDING

&&. . *eceipt of Materials3

&&. . . here shall be #ritten /tandard 1perating Procedures and records for thereceipt of each delivery of ra#, primary and printed pac!aging material.

&&. . &. he records of the receipts shall include

(a) container number

(b) the date of receipt

(c) the manufacturerJs and : or supplierJs name

(d) the manufacturerJs batch or reference number

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

(f) the control reference number assigned after receipt


22/55

(g) any other relevant comment or information.

&&. . 8 here shall be #ritten standard operating procedures for the internallabelling, quarantine and storage of starting materials, pac!aging materials andother materials, as appropriate.

&&. . 5. here shall be /tandard 1perating Procedures available for eachinstrument and equipment and these shall be placed in close pro$imity to therelated instrument and equipment.

&&. &. /ampling.9

&&. &. . here shall be #ritten /tandard 1perating Procedures for sampling, #hichinclude the person(s) authori%ed to ta!e the samples.

&&. &. &. he sampling instructions shall include

. the method of sampling and the sampling plan,

&. the equipment to be used,

8. any precautions to be observed to avoid contamination of the material or anydeterioration in its quality,

5. the quantity of samples to be ta!en,

D. instructions for any required sub9division or pooling of the samples,

7. the type of sample container to be used,

E. any speci c precautions to be observed, especially in regard to sampling ofsterile or ha%ardous material.

&&. 8. >atch Humbering.9

&&. 8. . here shall be /tandard 1perating Procedures describing the details of thebatch ( lot ) numbering set up #ith the ob ective of ensuring that each batch ofintermediate, bul! or nished product is identi ed #ith a speci c batch number.

&&.8. &. >atch numbering standard operating procedures applied to a processingstage and to the respective pac!aging stage shall be same or traceable todemonstrate that they belong to one homogenous mi$.


23/55

&&. 8. 8. >atch number allocation shall be immediately recorded in a logboo! or byelectronic data processing system. he record shall include date of allocation,product identity and si%e of batch.

&&. 5. esting

&&. 5. . here shall be #ritten procedures for testing materials and products atdi;erent stages of manufacture, describing the methods and equipment to be used.

he tests performed shall be recorded.

&&. D. *ecords of analysis. +

&&. D. . he records shall include the follo#ing data.

. name of the material or product and the dosage form,

&. batch number, details of manufacturer and : or supplier3

8. references of relevant speci cations and testing procedures,

5. test results, including observations and calculations, and reference to anyspeci cations ( limits ),

D. dates of testing3

7. initials of the persons #ho performed the testing3

E. initials of the persons #ho veri ed the testing and the detailed calculations,

6. a statement of release or re ection, and

4. signature and date of the designated responsible person.

&&. D. &. here shall be #ritten standard operating procedures and the associatedrecords of actions ta!en for

. equipment assembly and validation3

&. analytical apparatus and calibration3

8. maintenance, cleaning and sanitation3

5. personnel matters including quali cation, training, clothing, hygiene3

D. environmental monitoring3

7. pest control3

E. complaints3

6. recalls made3


24/55

4. returns received.

,1) REFERENCE SAMPLES

&8. . Aach lot of every active ingredient, in a quantity suCcient to carry out all thetests 9 e$cept sterility and pyrogens:>acterial Andoto$in est, shall be retained for aperiod of 8 months after the date of e$piry of the last batch produced from thatactive ingredient.

&8. &. /amples of nished formulations shall be stored in the same or simulatedcontainers in #hich the drug has been actually mar!eted.

,2) REPROCESSING AND RECO ERIES

&5. . 0here reprocessing is necessary, #ritten procedures shall be established andapproved by the uality +ssurance Fepartment that shall specify the conditions andlimitations of repeating chemical reactions. /uch re9processing shall be validated.

&5. &. If the product batch has to be reprocessed, the procedure shall be authori%edand recorded. +n investigation shall be carried out into the causes necessitating re9processing and appropriate corrective measures shall be ta!en for prevention ofrecurrence. *e9processed batch shall be sub ected to stability evaluation.

&5. 8. *ecovery of product residue may be carried out, if permitted, in the masterproduction and control records by incorporating it in subsequent batches of theproduct.

,6) DISTRI-UTION RECORDS

&D. . Prior to distribution or dispatch of given batch of a drug, it shall be ensuredthat the batch has been duly tested, approved and released by the quality controlpersonnel. Pre9dispatch inspection shall be performed on each consignment on arandom basis to ensure that onlythe correct goods are dispatched. Fetailed instructions for #arehousing andstoc!ing of ?arge olume Parenterals, if stoc!ed, shall be in e$istence and shall becomplied #ith after the batch is released for distribution. Periodic audits of#arehousing practices follo#ed at distribution centers shall be carried out andrecords thereof shall be maintained. /tandard 1perating Procedures shall bedeveloped for #arehousing of products.

&D. &. *ecords for distribution shall be maintained in a mannersuchthat nished batch of a drug can be traced to the retail level to facilitate prompt andcomplete recall of the batch, if and #hen necessary.

,7 ALIDATION AND PROCESS ALIDATION


25/55

&7. . alidation studies shall be an essential part of Good Manufacturing Practicesand shall be conducted as per the pre9de ned protocols. hese shall includevalidation of processing, testing and cleaning procedures.

&7. &. + #ritten report summari%ing recorded results and conclusions shall be

prepared, documented and maintained.&7. 8. Processes and procedures shall be established on the basis of validation studyand undergo periodic revalidation to ensure that they remain capable of achievingthe intended results. Britical processes shall be validated, prospectively orretrospectively.

&7. 5. 0hen any ne# master formula or method of preparation is adopted, stepsshall be ta!en to demonstrate its suitability for routine processing. he de nedprocess, using the materials and equipment speci ed shall be demonstrated to yielda product consistently of therequired quality.

&7. D. /igni cant changes to the manufacturing process, including any change inequipment or materials that may a;ect product quality and : or the reproducibilityof the process, shall be validated.

,7) PRODUCT RECALLS

&E. . + prompt and e;ective product recall system of defective products shall bedevised for timely information of all concerned stoc!ists, #holesalers, suppliers, upto the retail level #ithin the shortest period. he licensee may ma!e use of bothprint and electronic media in this regard.

&E. &. here shall be an established #ritten procedure in the form of /tandard1perating Procedure for e;ective recall of products distributed by the licensee.*ecall operations shall be capable of being initiated promptly so as to e;ectivelyreach at the level of each distribution channel.

&E. 8. he distribution records shall be readily made available to the personsdesignated for recalls.

&E. 5. he designated person shall record a nal report issued 9including areconciliation bet#een the delivered and the recovered quantities of the products.

&E. D. he e;ectiveness of the arrangements for recalls shall be evaluated fromtime to time.

&E. 7. he recalled products shall be stored separately in a secured segregated areapending nal decision on them.

,8 COMPLAINTS AND AD ERSE REACTIONS


26/55


27/55

8. outline for arrangements for basic and in9service training and ho# the recordsare maintained3

5. health requirements for personal engaged in production3

D. personnel hygiene requirements, including clothing.

&4. 8. Premises

. simple plan or description of manufacturing areas dra#n to scale3

&. nature of construction and $tures : ttings3

8. brief description of ventilation systems. More details should be given forcritical areas #ith potential ris! of airborne contamination (schematic dra#ingof systems). Blassi cation of the rooms used for the manufacture of sterileproducts should be mentioned3

5. special areas for the handling of the highly to$ic, ha%ardous and sensiti%ingmaterials3

D. brief description of #ater systems (schematic dra#ings of systems), includingsanitation3

7. description of planned preventive maintenance programs for premises and ofthe recording system.

&4. 5. Equipment

. brief description of ma or equipment used in production and quality controllaboratories (a list of equipment required)3

&. description of planned preventive maintenance programs for equipment andof the recording system3

8. quali cation and calibration, including the recording systems andarrangements for computerised systems validation.

&4. D. Sanitation

(a) availability of #ritten speci cations and procedures for cleaning manufacturing

areas and equipment.

&4. 7. Documentation

. arrangements for the preparation, revision and distribution of

&. necessary documentation for the manufacture3


28/55

8. any other documentation related to product quality that is not mentionedelse#here ( e.g. microbiological controls about air and #ater )

&4. E. Production

. brief description of production operations using, #herever possible,


29/55

/terile products, being very critical and sensitive in nature, a very high degree ofprecautions, prevention and preparations are needed. Fampness, dirt and dar!nessare to be avoided to ensure aseptic conditions in all areas. here shall be strictcompliance in the prescribed standards especially in the matter of supply of #ater,air, active materials and in the maintenance of hygienic environment.

,) -ui!di#"s A#d Ci@i! W r s0

&. . he building shall be built on proper foundation #ith standardised materials toavoid crac!s in critical areas li!e aseptic solution preparation, lling and sealingrooms.

&. &. ?ocation of services li!e #ater, steam, gases etc. shall be such that theirservicing or repair shall not pose any threat to the integrity of the facility. 0aterlines shall not pose any threat of lea!age to aseptic area.

&. 8. he manufacturing areas shall be clearly separated into support areas (e.g.#ashing and component preparation areas, storage areas etc.), preparation areas(e.g. bul! manufacturing area, non9aseptic blending areas etc.) change areas andaseptic areas. 1perations li!e removal of outer cardboard #rappings of primarypac!aging materials shall be done in the de9cartoning areas #hich are segregatedfrom the #ashing areas. 0ooden pallets, ber board drums, cardboard and otherparticle shedding materials shall not be ta!en inside the preparation areas.

&. 5. In aseptic areas

0alls,


30/55

used. Foors shall open to#ards the higher9pressure area so that theyclose automatically due to air pressure.

&. 0indo#s shall be made of similar material as thedoors, preferably #ith double panel and shall be


31/55

8. . +ir -andling =nits for sterile product manufacturing areas shall be di;erentfrom those for other areas. Britical areas, such as the aseptic lling area, sterili%edcomponents unloading area and change rooms conforming to Grades >, B and Frespectively shall have separate +ir -andling =nits. he lter con guration in the airhandling system shall be suitably designed to achieve the Grade of air as given in

able I. ypical operational activities for clean areas are highlighted in able II and able III.

8. &. "or products #hich are lled aseptically, the lling room shall meet Grade >conditions at rest unmanned. his condition shall also be obtained #ithin a period of about 8' minutes of the personnel leaving the room after completion of operations.

8. 8. he lling operations shall ta!e place under Grade + conditions #hich shall bedemonstrated under #or!ing of simulated conditions #hichshall be achieved by providing ?aminar +ir and Grade B areas shall not be less than&' air changes per hour in a room #ith good air


32/55

'. D m D mini '. D m D m

+ 8D&' &4 8D'' &4

> (a) 8D,&'' &48 8,D&,''' &,48'

B (a)

8,D&,''' &,48' 8D,&',''' &4,8''

F (a)

8D,&',''' &4,8'' Hot de ned (c) Hot de ned (c)

(otes )

". In order to reach the *, + and D air !rades, the number of air chan!esshall be related to the si e of the room and the equipment and

personnel present in the room. he air system shall be pro ided /iththe appropriate 0lters such as 1EP2 for Grades 2, * and +. hema imum permitted number of particle 3at rest3 condition shallappro imately be as under)

Grade 2 corresponds /ith +lass "44 or 5 $.& or IS6 class &7 Grade * /ith class"444 or 5 %.& or IS6 +lass '7 Grade + /ith +lass "4444 or 5 &.& or IS6 +lass 87Grade D /ith +lass "44,444 or 5 '.& or IS6 +lass 9.

#. he requirement and limit for the area shall depend on the nature oftheoperation carried out

$. ype of operations to be carried out in the arious !rades are !i en inable II and able III as under)

+>?A II

ypes of 1perations o >e Barried 1ut In he arious Grades "or +septicPreparations

Grade

ypes of operations for aseptic preparations.


33/55

+ +septic preparation and lling.

>>ac!ground room conditions for activities requiringGrade +.

B Preparation of solution to be ltered.

F -andling of components after #ashing.

+>?A III

ypes of 1perations o >e Barried 1ut In he arious Grades "or erminally/terili%ed Products

Grade

ypes of operations for terminally sterili%ed products.

+"illing of products 9 #hichare usually at ris!.

B Placement of lling and sealing machines, preparation of solutions,#hen usually at ris!. "illing of product #hen unusually at ris!.

FMoulding, blo#ing (pre9forming) operations of plastic containers,Preparations of solutions and components for subsequent lling.

2 . E#@ir #/e#ta! M #it ri#"

5. . +ll environmental parameters listed under para 8. to 8. ' shall be veri edand established at the time of installation and thereafter monitored at periodicintervals. he recommended frequencies of periodic monitoring shall be as follo#s

%. Particulate monitoring in air 7 Monthly

&. -AP+ lter integrity testing ( smo!e testing ) early


34/55

'. +ir change rates 7 Monthly

8. +ir pressure di;erentials Faily

9. emperature and humidity Faily

:. Microbiological monitoring by settle plates and:or s#abs in asepticareas Faily, and at decreased frequency in other areas

(ote ) he abo e frequencies of monitorin! shall be chan!ed as per therequirements and load in indi idual cases.

5. &. here shall be a #ritten environmental monitoring program and microbiologicalresults shall be recorded. *ecommended limits for microbiological monitoring ofclean areas 2in operation2 are as given in the table belo#

+>?A

*ecommended ?imits "or Microbiological Monitoring 1f Blean +reas 2In9operation2

Grade

+ir sampleBfu : m 8

/ettle plates ( dia.4' mm. Bfu : &hrs.

Bontact plates (dia.DD mm) cfu perplate

Glove points ( vengers) cfu per

glove

+ N N N N

> ' D D D

B '' D' &D 9

F D'' '' D' 9

(otes )

"4. hese are a era!e alues.

"".Indi idual settle plates may be e posed for not less than t/o hours inGrade *, + and D areas and for not less than thirty minutes in Grade 2area.

5. 8. +ppropriate action shall be ta!en immediately if the result of particulate andmicrobiological monitoring indicates that the counts e$ceed the limits. he /tandard


35/55

1perating Procedures shall contain corrective action. +fter ma or engineeringmodi cation to the - +B system of any area, all monitoring shall be re9performedbefore production commences.

6) Gar/e#ts

D. . his section covers garments required for use by personnel #or!ing only inaseptic areas. 1utdoor clothing shall not be brought into the sterile areas.

D. &. he garments shall be made of non9shedding and tight #eave material. Bottongarments shall not be used. he garments shall shed virtually no bers orparticulate matter.

D. 8. he clothing and its quality shall be adopted to the process and the #or! placeand #orn in such a #ay as to protect the product from contamination. Garmentsshall be single piece #ith fastenings at cu;s, nec! and at legs to ensure close t.

rouser legs shall be tuc!ed inside the cover boots. /uitable design of garmentsshall either include a hood (head9cover) or a separate hood #hich can be tuc!edinside the over9all. Poc!ets, pleats and belts shall be avoided in garments. Oips (ifany) shall be of Plastic material. Garments #ith damaged %ips shall not be used.

D. 5. 1nly clean, sterili%ed and protective garments shall be used at each #or!session #here aseptic ltration and lling operations are underta!en and at each#or! shift for products intended to be sterili%ed 9 post9 lling. he mas! and glovesshall be changed at every #or! session in both instances.

D. D. Gloves shall be made of late$ or other suitable plastic materials and shall bepo#der9free. hese shall be long enough to cover #rists completely and allo# theover9all cu; to be tuc!ed in.

D. 7. he foot#ear shall be of suitable plastic or rubber material and shall be dailycleaned #ith a bactericide.

D. E. /afety goggles or numbered glasses #ith side e$tensions shall be used insideaseptic areas. hese shall be sanitised by a suitable method.

D. 6. Garment changing procedure shall be documented and operators trained inthis aspect. + full si%e mirror shall be provided in the nal change room for theoperator to verify that he is appropriately attired in the garments. Periodic

inspection of the garments shall be done by responsible sta;.

7) Sa#itati #

7. . here shall be #ritten procedures for the sanitation of sterile processingfacilities. Amployees carrying out sanitation of aseptic areas shall be trainedspeci cally for this purpose.


36/55

7. &. Fi;erent saniti%ing agents shall be used in rotation and the concentrations ofthe same shall be as per the recommendations of the manufacturer. *ecords ofrotational use of saniti%ing agents shall be maintained.

7. 8. Fistilled #ater freshly collected directly from the distilled #ater plant or #ater

maintained above E' degree centigrade from the re9circulation loop shall be usedfor dilution of disinfectants. +lternately, distilled #ater sterilised by autoclaving ormembrane ltration shall be used. he dilution shall be carried out in the J#hiteJchange room.

7. 5. 0here alcohol or Isopropyl alcohol is used for dilution of disinfectants for useas hand sprays, the preparation of the same shall be done in the bul! preparationarea and the diluted solution membrane9 ltered into suitable sterile containers heldin aseptic area.

7. D. Filuted disinfectants shall bear the label Juse beforeJ 9based on microbiologicalestablishment of their germicidal properties. he solutions shall be adequatelylabeled and documents maintained.

7. 7. "ormaldehyde or any other equally e;ective fumigant is recommended for thefumigation of aseptic areas or after ma or civil modi cations. here shall be/tandard 1perating Procedures for this purpose . Its use for routine purposes shallbe discouraged and anequally e;ective surface cleaning regime shall be follo#ed.

7. E. Bleaning of sterile processing facilities shall be underta!en #ith air suctiondevices or #ith non9linting sponges or clothes.

7. 6. +ir particulate quality shall be evaluated on a regular basis and recordsmaintained.

8) Equi./e#t

E. . he special equipment required for manufacturing sterile products includescomponent #ashing machines, steam sterilisers, dry heat sterilisers, membrane

lter assemblies, manufacturing vessels, blenders, liquid lling machines, po#der

lling machines, sealing and labeling machines, vacuum testing chambers,inspection machines, lyophilisers, pressure vessels etc. /uitable and fully integrated#ashing9sterili%ing9 lling lines may be provided 9depending upon the type andvolume of activity.

E. &. =nit9sterilisers shall be double9ended #ith suitable inter9loc!ing arrangementsbet#een the doors. he e;ectiveness of the sterili%ation process shall beestablished initially by biological inactivation studies using microbial spore


37/55

indicators and then at least once a year by carrying out thermal mapping of thechamber. arious sterili%ation parameters shall be established based on thesestudies and documented. "or membrane lters used for ltration, appropriate lterintegrity tests that ensure sterili%ation shall be carried out before and after ltration.

E. 8. "illing machines shall be challenged initially and then at periodic intervals bysimulation trials including sterile media ll. /tandard 1perating Procedures andacceptance criteria for media lls shall be established, usti ed and documented./pecial simulation trial procedures shall be developed, validated and documentedfor special products li!e ophthalmic ointments.

E. 5. he constructionmaterial usedfor the parts #hich are in direct contact #ith products and themanufacturing vessels may be stainless steel 8 7 or >oro9silicate glass (if glasscontainers) and the

tubing shall be capable of being #ashed and autoclaved.

E. D. 1n procurement, installation quali cation of each of the equipment shall bedone by engineers #ith the support of production and quality assurance personnel.Aquipment for critical processes li!e aseptic lling and sterili%ers shall be suitablyvalidated according to a #ritten program before putting them to use.

E. 7. /tandard 1perating 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 a #rittenprogram. Balibration status of equipment and gauges shall be adequately

documented and displayed.

;)Water a#d Stea/ Syste/s

6. . Potable #ater meeting microbiological speci cation of not more than D''cfu:ml and indicating absence of individual pathogenic micro9organisms. Escherichiacoli , Salmonella , Staphylococcus aureus and Pseudomonas aeru!inosa per '' mlsample shall be used for the preparation of puri ed #ater.

6. &. Puri ed #ater prepared by de9minerali%ation shall meet the microbiologicalspeci cation of not more than '' cfu per ml and indicateabsence of pathogenic micro9organisms in '' ml. Puri ed #ater shall also meet IPspeci cations for chemical quality. Puri ed #ater shall be used for hand #ashing inchange rooms. Bontainers, closures and machine parts may be #ashed #ith potable#ater follo#ed by suitably ltered puri ed #ater. Puri ed #ater shall be stored instainless steel tan!s or plastic tan!s.


38/55

6. 8. 0ater for In ection (hereinafter referred as 0"I) shall be prepared from potable#ater or puri ed #ater meeting the above speci cations by distillation. 0ater forIn ection shall meet microbiological speci cation of not more than ' cfu per ''ml. 0"I shall also meet IP speci cation for 0ater for In ection and shall have anendoto$in level of not more than '.&D A= : ml. >ul! solutions of liquid parenterals

shall be made in 0"I. "inal rinse of product containers and machine parts shall bedone #ith 0"I. Fisinfectant solutions for use in aseptic areas shall be prepared in0"I.

6. 5. 0ater for In ection for the manufacture of liquid in ectables shall be freshlycollected from the distillation plant or from a storage or circulation loop #here the#ater has been !ept at above E' degree centigrade. +t the point of collection, #atermay be cooled using suitable heat e$changer.

6. D. 0ater for non9in ectable sterile products li!e eye drops shall meet IPspeci cations for puri ed #ater. In addition, microbiological speci cation of not

more than ' cfu per '' ml and absence of Pseudomonasaeru!inosa and Enterobacter coli in '' ml shall also be met.

6. 7. 0ater for In ection shall be stored in steam ac!etted stainless steel tan!s ofsuitable si%e and the tan!s shall have hydrophobic bacterial retention #ith '.&&microns vent lters. he lters shall be suitably sterili%ed at periodic intervals. hedistribution lines for puri ed #ater and distilled #ater shall be of stainless steel 8 7construction and shall not shed particles.

6. E. here shall be a #ritten procedure and program for the sanitation of di;erent#ater systems including storage tan!s, distribution lines, pumps and other related

equipment. *ecords of sanitation shall be maintained.

6. 6. here shall be #ritten microbiological monitoring program for di;erent types of #ater. he results shall ustify the frequency of sampling and testing. Investigationshall be carried out and corrective action ta!en in case of deviation from prescribedlimits.

6. 4. /team coming in contact #ith the product, primary containers and otherproduct contact surfaces shall be sterile and pyrogen free. he steam condensateshall meet microbiological speci cation of not more than ' cfu per '' ml. hecondensate shall also meet IP speci cation for 0ater for In ection and shall have an

endoto$in levels of not more than '.&D A=:ml. here shall be a suitable schedule forthe monitoring of steam quality.

=) Ma#u3a*turi#" Pr *ess

4. . Manufacture of sterile products shall be carried out only in areas under de nedconditions.


39/55

4. &. >ul! ra# materials shall be monitored for bio9burden periodically. >io9burden of bul! solution prior to membrane ltration shall be monitored periodically and a limitof not more than '' cfu per ml is recommended.

4. 8. he time bet#een the start of the preparation of the solution and its

sterili%ation or ltration through a micro9organism retaining lter shall beminimised. here shall be a set ma$imum permissible time for each product thatta!es into account its composition and method of storage mentioned in theMaster formula record.

4. 5. Gases coming in contact #ith thesterile product shall be ltered through t#o '.&& microns hydrophobic ltersconnected in +series. hese lters shall be tested for integrity. Gas cylinders shall notbe ta!en inside aseptic areas.

4. D. 0ashed containers shall be sterili%ed immediately before use. /terili%edcontainers, if not used #ithin an established time, shall be rinsed #ith distilled or

ltered puri ed #ater and re9sterili%ed.

4. 7. Aach lot of nished product shall be lled in one continuous operation. In eachcase, #hereone batch is lledin using more than one operation, each lot shall be tested separately for sterilityand held separately till sterility test results are !no#n.

4. E. /pecial care shall be e$ercised #hile lling products in po#der form so as notto contaminate the environment during transfer of po#der to lling machine9hopper.

(>)FORM+FILL+SEAL TECHNOLOG5 OR -LOW9 FILL+SEAL TECHNOLOG5

'. . "orm9"ill9/eal units are specially built automated machines in #hich throughone continuous operation, containers are formed from thermoplastic granules, lledand then sealed. >lo#, ll 9 seal units are machines in #hich containers aremoulded:blo#n (pre9formed) in separate clean rooms, by non continuousoperations.

(ote )

"#. hese shall be installed in at least Grade + en ironment.

"$. hese shall comply /ith the limits as recommended in able at item%.#.

'. &. "orm 9 "ill 9 /eal : >lo#, "ill 9 /eal machines used for the manufacture ofproducts for terminal sterili%ation shall be installed in at least Grade B environmentand the lling %one #ithin the machine shall ful ll Grade + requirements.

(>) 1 . Ter/i#a!!y Steri!i$ed Pr du*ts


40/55

"%. Preparation of primary pac!aging material such as glass bottles,ampoules andrubber stoppers shall be done in at least Grade F environment. 0herethere is unusual ris! to the product from microbial contamination, theabove operation shall be done in Grade B environment. +ll the

processes used for component preparation shall be validated.

"&. "illing of products requiring terminal sterili%ation shall be done underGrade + environment #ith a Grade B bac!ground.

'. 5. Preparation of solutions, #hich are to be sterili%ed by ltration, shall be donein Grade B environment, and if not to be ltered, the preparation of materials andproducts shall be in a Grade + environment #ith Grade > in bac!ground.

(>) 6) Fi!trati # % Me/Bra#e &

( i ) /olutions for ?arge olume Parenterals shall be ltered through a non9 berreleasing, sterili%ing grade cartridge:membrane lter of nominal pore si%e of '.&&microns for aseptic lling #hereas '.5D microns porosity shall be used for terminallysterili%ed products.

( ii ) + second ltration using another '.&& microns sterili%ing gradecartridge:membrane lter shall be performed immediately prior to lling. Processspeci cations shall indicate the ma$imum time during #hich a ltration system maybe used #ith a vie# to precludingmicrobial build9up to levels that may a;ect the microbiological quality of the ?argeolume Parenterals.

( iii ) he integrity of the sterili%ed lter shall be veri ed and con rmed immediatelyafter use by an appropriate method such as >ubble Point, Fi;usive "lo# or Pressure-old est.

(>) 7 . Steri!i$ati # % Aut *!a@i#" &

'.7. . >efore any sterili%ation process is adopted, its suitability for the product andits eCcacy in achieving the desired sterili%ing conditions in all parts of each type ofload pattern to be processed, shall be demonstrated by physical measurements andby biological indicators, #here appropriate.

'.7.&. +ll the sterili%ation processes shall be appropriately validated. he validity of the process shall be veri ed at regular intervals, but at least annually. 0heneversigni cant modi cations have been made to the equipment and product, recordsshall be maintained thereof.

'.7.8. he sterili%er shall be double ended to prevent mi$9ups.


41/55

'.7.5.Periodic bio9burden monitoring of products before terminal sterili%ation shallbe carried out and controlled to limits speci ed for the product in the Master"ormula.

'.7.D. he use of biological indicators shall be considered as an additional method

for monitoring the sterili%ation. hese shall be stored and used according to themanufactureJs instructions. heir quality shall be chec!ed by positive controls. Ifbiological indicators are used, strict precautions shall be ta!en to avoid transferringmicrobial contamination from them.

'.7.7. here shall be clear means of di;erentiating Jsterili%edJ and Junsterili%edJproducts. Aach bas!et, tray or other carrier of products or components shall beclearly labeled #ith the name of the material, its batch number, and sterili%ationstatus. Indicators shall be used, #here appropriate, to indicate #hether a batch (orsub9batch) has passed through the sterili%ation process.

'.7.E./terili%ation records shall be available for each sterili%ation9run and may alsoinclude thermographs and sterili%ation monitoring strips. hey shall be maintainedas part of the batch release procedure.

(>) 8 . Steri!i$ati # % -y Dry Heat &

'.E. . Aach heat sterili%ation cycle shall be recorded on a time : temperature chartof a suitable si%e by appropriate equipment of the required accuracy and precision.

he position of temperature probes used for controlling and : or recording shall bedetermined during the validation and, #here applicable, shall also be chec!edagainst a second independent temperature probe located in the same position. hechart shall form a part of the batch record. Bontainer mapping may also be carriedout in the case of ?arge olume Parenterals.

'.E.&. Bhemical or biological indicators may also be used, but shall not ta!e theplace of physical validation.

'.E.8. /uCcient time shall be allo#ed for the load to reach the requiredtemperature before measurement of sterili%ation time commences. his time shallbe separatelydetermined for each type of load to be processed.

'.E.5. +fter the high temperature phase of a heat sterili%ation cycle, precautionsshall be ta!en against contamination of sterili%ed load during cooling. +ny cooling


42/55

retaining lters. 0here this process of sterili%ation by dry heat is also intended toremove pyrogens, challenge tests using endoto$ins #ould be required as part of thevalidation process.

(>) ;)

Steri!i$ati # %-y M ist Heat&'.6. . >oth the temperature and pressure shall be used to monitor the process.

Bontrol instrumentation shall normally be independent of monitoringinstrumentation and recording charts. 0here automated control and monitoringsystems are used for these applications, these shall be validated to ensure thatcritical process requirements are met. /ystem and cycle faults shall be registered bythe system and observed by the operator. he reading of the independenttemperature indicator shall be routinely chec!ed against the chart9recorder duringthe sterili%ation period. "or sterili%ers tted #ith a drain at the bottom of thechamber, it may also be necessary to record the temperature at this position

throughout the sterili%ation period. here shall be frequent lea! tests done on thechamber during the vacuum phase of the cycle.

'.6.&. he items to be sterili%ed, other than products in sealed containers, shall be#rapped in a material #hich allo#s removal of air and penetration of steam but#hich prevents re9contamination after sterili%ation. +ll parts of the load shall be incontact #ith the sterili%ing agent at the required temperature for the required time.

'.6.8. Ho ?arge olume Parenteral shall be sub ected to steam sterili%ation cycleuntil it has been lled and sealed.

'.6.5. Bare shall be ta!en to ensure that the steam used for sterili%ation is of asuitable quality and does not contain additives at a level #hich could causecontamination of the product or equipment.

(>) = . C /.!eti # Fi#a!isati # 3 Steri!e Pr du*ts

'.4. . +ll unit operations and processes in the manufacture of a batch shall have aminimum time speci ed and the shortest validated time shall be used from thestart of a batch to its ultimate release for distribution.

'.4.&. Bontainers shall be closed by appropriately validated methods. Bontainersclosed by fusion, e.g. glass or plastic ampoules shall be sub ected to '' L integritytesting. /amples of other containers shall be chec!ed for integrity according toappropriate procedures.

'.4.8. Bontainers sealed under vacuum shall be tested for required vacuumconditions.

'.4.5. "illed containers of parenteral products shall be inspected individually fore$traneous contamination or other defects. 0hen inspection is done visually, it shall


43/55

be done under suitably controlled conditions of illumination and bac!ground.1perators doing the inspection shall pass regular eye9sight chec!s #ith spectacles,if #orn, and be allo#ed frequent rest from inspection. 0here other methods ofinspection are used, the process shall be validated and the performance of theequipment chec!ed at suitable intervals. *esults shall be recorded.

(( . Pr du*t C #tai#ers A#d *! sures

. . +ll containers and closures intended for use shall comply #ith thepharmacopoeial and other speci ed requirements. /uitable sample si%es,speci cations, test methods, cleaning procedures and sterili%ation procedures, shallbe used to assure that containers, closures and other component parts of drugpac!ages are suitable and are not reactive, additive, adsorptive or leachable orpresents the ris! of to$icity to an e$tent that signi cantly a;ects the quality orpurity of the drug. Ho second hand or used containers and closures shall be used.

. &. Plastic granules shall also comply #ith the Pharmacopoeial requirementsincluding physio9chemical and biological tests.

. 8. +ll containers and closures shall be rinsed prior to sterili%ation #ith #ater forin ection according to #ritten procedure.

. 5. he design of closures, containers and stoppers shall be such as to ma!ecleaning, easy and also to ma!e an airtight seal #hen tted to the bottles.

. D. It shall be ensured that containers and closures chosen for a particularproduct are such that #hen coming into contact they are not absorbed into theproduct and they do not a;ect the product adversely. he closures and stoppersshould be of such quality substances as not to a;ect the quality of the product andavoid the ris! of to$icity.

. 7. 0henever glass bottles are used, the #ritten schedule of cleaning shall belaid do#n and follo#ed. 0here bottles are not dried after #ashing, these shall be

nally rinsed #ith distilled #ater or pyrogen free #ater, as the case may be,according to #ritten procedure.

. E. Individual containers of parenteral preparations, ophthalmic preparationsshall be e$amined against blac!:#hite bac!ground tted #ith di;used light after

lling so as to ensure freedom from foreign matters.

(() ;G!ass B tt!es


44/55

.6. . /hape and design of the glass bottle shall be rational and standardi%ed.Glass bottles made of =/P ype9I and =/P ype9II glass shall only be used. Glassbottles shall not be reused. >efore use, =/P ype9II bottles shall be validated for theabsence of particulate matter generated over a period of the shelf9life of theproduct and shall be regularly monitored after production 9 follo#ing statistical

sampling methods. =/P ype9III glass containers may be used for non9 parenteralsterile products such as 1tic /olutions.

(() = . P!asti* C #tai#ers

.4. . Pre9formed plastic containers intended to be used for the pac!ing of ?argeolume Parenteral shall be moulded in9house by one9continuous operation through

an automatic machine.

.4.&. >lo#ing, lling and sealing (plugging) operations shall be conducted inroom(s) conforming to requirements as mentioned in able III of Item 8. '. Antry tothe area #here such operations are underta!en, shall be through a series of airloc!s. >lo#ers shall have an air supply #hich is ltered though '.&& microns lters.*emoval of runners and plugging operations shall be conducted under a laminarair)RuBBer st ..ers

. '. . he rubber stoppers used for ?arge olume Parenterals shall comply #ithspeci cations prescribed in the current edition of theIndian Pharmacopoeia.

(, . D *u/e#tati #

&. . he manufacturing records relating to manufacture of sterile products shallindicate the follo#ing details 9

"'. /erial number of the >atch Manufacturing *ecord.

"8. Hame of the product.

"9. *eference to Master "ormula *ecord.

":. >atch : ?ot number.

#4. >atch : ?ot si%e.

#". Fate of commencement of manufacture and date of completion ofmanufacture.

##. Fate of manufacture and assigned date of e$piry.

#$. Fate of each step in manufacturing.


45/55

#%.Hames of all ingredients #ith thegrade given by the quality control department.

#&. uantity of all ingredients.

#'. Bontrol reference numbers for all ingredients.

#8. ime and duration of blending, mi$ing etc. #henever applicable.

#9. p- of solution #henever applicable.

#:. "ilter integrity testing records.

$4. emperature and humidity records #henever applicable.

$". *ecords of plate9counts #henever applicable.

$#. *esults of pyrogen and:or bacterial endoto$in to$icity.

$$. *ecords of #eight or volume of drug lled in containers.

$%.>ul! sterility in case of aseptically lled products.

$&. ?ea! test records.

$'. Inspection records.

$8. /terili%ation records including autoclave lea!age test records, loaddetails, date, duration , temperature, pressure etc.

$9. Bontainer #ashing records.$:. otal number of containers lled.

%4. otal numbers of containers re ected at each stage.

%". heoretical yield, permissible yield, actual yield and variation thereof.

%#.Blari cation for variation in yield beyond permissible yield.

%$.*eference numbers of relevant analytical reports.

%%.Fetails of reprocessing, if any.

%&.Hame of all operators carrying out di;erent activities.

%'. Anvironmental monitoring records.

%8./pecimens of printed pac!aging material.


46/55

%9.*ecords of destruction of re ected containers and printed pac!agingmaterials.

%:. /ignature of the competent technical sta; responsible for manufactureand testing.

(otes )-

&4.Products shall be released only after complete 0llin! and testin!.

&".;esult of the tests relatin! to sterility, pyro!ens, and*acterial endoto ins shall be maintained in the analytical records.

.


47/55

and processes shall be provided. "ilters shall be installed to retain dust and toprotect the factory and local environment.

. 8 /pecial care shall be ta!en to protect against subsequent contamination of theproduct by particles of metal or #ood. he use of metal detector is recommended.

0ooden equipment should be avoided. /creens, sieves, punches and dies shall bee$amined for #ear and tear or for brea!age before and after each use.

. 5. +ll ingredients for a dry product shall be sifted before use unless the quality ofthe input material can be assured. /uch sifting shall normally be carried out atdedicated areas.

. D. 0here the facilities are designed to provide special environmental conditionsof pressure di;erentials bet#een rooms, these conditions shall be regularlymonitored and any speci cation results brought to the immediate attention of theProduction and uality assurance departments #hich shall be immediately attendedto.

. 7. Bare shall be ta!en to guard against any material lodging and remainingundetected in any processing or pac!aging equipment. Particular care shall be ta!ento ensure that any vacuum, compressed air or air9e$traction no%%les are !ept cleanand that there is no evidence of lubricants lea!ing into the product from any part ofthe equipments.

6) Si3ti#"9 /i


48/55

8. . Aach tablet compressing machine shall be provided #ith e;ective dust controlfacilities to avoid cross contamination. =nless the same product is being made oneach machine, or unless the compression machine itself provides its o#n enclosedair controlled environment, the machine shall be installed in separate cubicles.

8. &. /uitable physical, procedural and labeling arrangements shall be made toprevent mi$9up of materials, granules and tablets on compression machinery.

8. 8. +ccurate and calibrated #eighing equipment shall be readily available andused for in9process monitoring of tablet #eight variation. Procedures used shall becapable of detecting out9of9limits tablets.

8. 5. +t the commencement of each compression run and in case of multiplecompression points in a compression machine, suCcient individual tablets shall bee$amined at $ed intervals to ensure that a tablet from each compression station orfrom each compression point has been inspected for suitable pharmacopoeialparameters li!e JappearanceJ, J#eight variationJ, JdisintegrationJ, JhardnessJ,JfriabilityJ and Jthic!nessJ. he results shall be recorded as part of the batchdocumentation.

8. D. ablets shall be de9dusted, preferably by automatic device and shall bemonitored for the presence of foreign materials besides any other defects.

8. 7. ablets shall be collected into clean, labeled containers.

8. E. *e ected or discarded tablets shall be isolated in identi ed containers and theirquantity recorded in the >atch Manufacturing *ecord.

8. 6. In9process control shall be employed to ensure that the products remain #ithinspeci cation. Furing compression, samples of tablets shall be ta!en at regularintervals of not greater than 8' minutes to ensure that they are being produced incompliance #ith speci ed in9process speci cation. he tablets shall also beperiodically chec!ed for additional parameters such as JappearanceJ, J#eightvariationJ, JdisintegrationJ, JhardnessJ, Jfriability J and Jthic!nessJ and contaminationby lubricating oil.

8) C ati#" %TaB!ets&

5. . +ir supplied to coating pans for drying purposes shall be ltered air and of

suitable quality. he area shall be provided #ith suitable e$haust system andenvironmental control (temperature, humidity) measures.

5. &. Boating solutions and suspensions shall be made afresh and used in a manner,#hich shall minimise the ris! of microbial gro#th. heir preparation and use shall bedocumented and recorded.

;) Fi!!i#" 3 Hard Ge!ati# Ca.su!e


49/55

Ampty capsules shells shall be regarded as Jdrug componentJ and treatedaccordingly. hey shall be stored under conditions #hich shall ensure their safetyfrom the e;ects of e$cessive heat and moisture.

=) Pri#ti#" %TaB!ets A#d Ca.su!es&

7. . /pecial care shall be ta!en to avoid product mi$9up during any printing oftablets and capsules. 0here di;erent products, or di;erent batches of the sameproduct, are printed simultaneously, the operations shall adequately be segregated.Adible grade colours and suitable printing in! shall be used for such printing.

7. &. +fter printing, tablets and capsules shall be approved by uality Bontrol beforerelease for pac!aging or sale.

(>) Pa* a"i#" %Stri. a#d -!ister&

E. . Bare shall be ta!en #hen using automatic tablet and capsule counting, strip

and blister pac!aging equipment to ensure that all JrogueJ tablets, capsules or foilsfrom pac!aging operation are removed before a ne# pac!aging operation iscommenced. here shall be an independent recorded chec! of the equipmentbefore a ne# batch of tablets or capsules is handled.

E. &. =ncoated tablets shall be pac!ed on equipment designed to minimise the ris!of cross9contamination. /uch pac!aging shall be carried out in an isolated area#hen potent tablets or >eta9lactum containing tablets are being pac!ed.

E. 8. he strips coming out of the machine shall be inspected for defects such asmisprint, cuts on the foil, missing tablets and improper sealing.

E. 5. Integrity of individual pac!aging strips and blisters shall be sub ected tovacuum test periodically to ensure lea! proofness of each poc!et stripand blisterand records maintained.

ORAL LI'UIDS %S5RUPS9 ELI IRS9 EMULSIONS AND SUSPENSIONS&

Note : he General ;equirements as !i en in Good 5anufacturin! Practices forPremises and 5aterials for pharmaceutical products shall be complied /ith themanufacture of @ Syrups , Eli irs, Emulsions and Suspensions A. In addition to theserequirements, the follo/in! Speci0c ;equirements shall also be follo/ed, namely

(() -ui!di#" A#d Equi./e#t

. . he premises and equipment shall be designed, constructed and maintained tosuit the manufacturing of 1ral ?iquids. he layout and design of the manufacturingarea shall strive to minimi%e the ris! of cross9 contamination and mi$9ups.


50/55

. &. Manufacturing area shall have entry through double door air9loc! facility. Itshall be made


51/55

8. 8. Bare shall be ta!en to maintain the homogenity of emulsion by use ofappropriate emulsi er and suspensions by use of appropriate stirrer during lling.Mi$ing and lling processes shall be speci ed and monitored. /pecial care shall beta!en at the beginning of the lling process, after stoppage due to any interruptionand at the end of the process to ensure that the product is uniformly homogenous

during the lling process.

8. 5. he primary pac!aging area shall have an air supply #hich is ltered through Dmicron lters. he temperature of the area shall not e$ceed 8' degrees centigrade.

8. D. 0hen the bul! product is not immediately pac!ed, the ma$imum period ofstorage and storage conditions shall be speci ed in the Master "ormula. hema$imum period of storage time of a product in the bul! stage shall be validated.

E TERNAL PREPARATIONS %CREAMS9 OINTMENTS9 PASTES9 EMULSIONS9LOTIONS9 SOLUTIONS9 DUSTING POWDERS AND IDENTICAL PRODUCTS&

Note : he General ;equirements as !i en in Good 5anufacturin! Practices for premises and 5aterials for pharmaceutical products shall be complied /ith themanufacture of opical Products i.e. E ternal Preparations @+reams, 6intments,Pastes, Emulsions, Lotions, Solutions, Dustin! po/ders and identical products usedfor e ternal applicationsA. In addition to these requirements, the follo/in! Speci0c;equirements shall also be follo/ed, namely )

. he entrance to the area #here topical products are manufactured shall bethrough a suitable airloc!. 1utside the airloc!, insectocutors shall be installed.

&. he air to this manufacturing area shall be ltered through at least &' air ltersand shall be air9conditioned. he area shall be ventilated.

8. he area shall be tted #ith an e$haust system

Date post:	02-Jun-2018
Category:	Documents
Upload:	aaravkumar
View:	225 times
Download:	1 times

Project Pharma

Documents