GOOD MANUFACTURING PRACTICE FOR PHARMACEUTICAL PRODUCTS

INTRODUCTION
What is GMP?
Good manufacturng practce (GMP) comprses that part of quaty assurance
amed at ensurng that a product s consstenty manufactured to a quaty
approprated to ts ntended use. GMP requres that the manufacturng process s
fuy dened before t s ntated and that a necessary factes are provded. In
practce, ths means that personne must be adequatey traned, sutabe premses
and equpment used, correct materas used, approved procedures adopted,
sutabe and transport factes avaabe and approprate records made.

The quaty of pharmaceutca products depends on the degree of care taken n ts
preparaton. Fna checks carred out on the nshed products are usefu n
conrmng that the correct ngredents have been used and that that materas have
been correcty processed. It s however essenta that proper n process contro s
exercsed and that t s adequatey documented to provde reabe evdence that
the correct procedures have been foowed. The need for GMP s recognzed
throughout the word. More than 20 countres have ssued ther own GMP gudenes.
(The essenta components of GMP are summarzed n gure 1.)



Why it is required?
The Good Manufacturng Practces are prescrbed to ensure that:
() Raw materas used n the manufacture of pharmaceutcas are authentc, of
prescrbed quaty and are free from contamnaton.
() The manufacturng process s as has been prescrbed to mantan the standards.
() Adequate quaty contro measures are adopted and
(v) The manufactured drug whch s reeased for sae has the prescrbed quaty.
(v) To acheve the ob|ectves sted above, each cencee sha evove methodoogy
and procedures for foowng the prescrbed process of manufacture of drugs whch
shoud be documented as a manua and kept for reference and nspecton. However,
teachng nsttutons and regstered quaed Vadyas, Sddhas and Hakeems who
prepare medcnes on ther own to dspense to ther patents and not seng such
drugs n the market are exempted from the purvew of G.M.P.

Wr!d Hea!th Or"a#i$ati# %WHO& GMP
WHO denes good manufacturng practce has "that part of quaty assurance
whch assures that products are consstenty produced and controed to the quaty
standards approprate to ther ndented use and as requred by the marketng
authorzaton"

GMP covers a aspects of the manufacturng process: dened manufacturng
processes; crtca manufacturng steps; sutabe premses, storage, transport;
quaed and traned producton and quaty contro personne; adequate aboratory
factes; approved wrtten procedures and nstructons; records to show a steps of
dened procedures have been taken; fu traceabty of a product through batch
rewards and dstrbuton records and systems for reca and nvestgaton of
compants.

GMP RE'UIREMENTS FOR PREMISES AND MATERIALS FOR
PHARMACEUTICAL PRODUCTS
() GENERAL RE'UIREMENTS
()() L*ati# a#d surru#di#"s)+ The factory budng(s) for manufacture of
drugs sha be so stuated and sha have such measures as to avod rsk of
contamnaton from externa envronment ncudng open sewage, dran, pubc
avatory or any factory whch produces dsagreeabe or obnoxous, odour, fumes,
excessve soot, dust, smoke, chemca or boogca emssons.
(),) -ui!di#"s a#d .re/ises)0 The budng(s) used for the factory sha be
desgned, constructed, adapted and mantaned to sut the manufacturng
operatons so as to permt producton of drugs under hygenc condtons. They sha
conform to the condtons ad down n the Factores Act, 1948 (63 of 1948).
The premses used for manufacturng, processng, warehousng, packagng, abeng
and testng purposes sha be -
1. compatbe wth other drug manufacturng operatons that may be carred out
n the same or ad|acent area / secton;
2. adequatey provded wth workng space to aow ordery and ogca
pacement of equpment, materas and movement of personne so as to :
1. avod the rsk of mx-up between dherent categores of drugs or wth
raw materas, ntermedates and n-process matera;
2. avod the possbtes of contamnaton and cross-contamnaton by
provdng sutabe mechansm;
() desgned / constructed / mantaned to prevent entry of nsects, pests, brds,
vermns, and rodents. Interor surface (was, oors, and cengs) sha be smooth
and free from cracks, and permt easy ceanng, pantng and dsnfecton;
(v) ar condtoned, where prescrbed for the operatons and dosage forms under
producton. The producton and dspensng areas sha be we ghted, ehectvey
ventated, wth ar contro factes and may have proper Ar Handng Unts
(wherever appcabe) to mantan condtons ncudng temperature and,wherever
necessary, humdty
as dened for the reevant product. These condtons sha be approprate to the
category of drugs and nature of the operaton. These sha aso be sutabe to the
comforts of the personne workng wth protectve cothng, products handed,
operatons undertaken wthn them n reaton to the externa envronment. These
areas sha be reguary montored for compance wth requred speccatons;
(v) provded wth dranage system, as speced for the varous categores of
products, whch sha be of adequate sze and so desgned as to prevent back- ow
and/or to prevent nsects and rodents enterng the premses. Open channes sha
be avoded n manufacturng areas and, where provded, these sha be shaow to
factate ceanng and dsnfecton;
(v) The was and oors of the areas where manufacture of drugs s carred out sha
be free from cracks and open |onts to avod accumuaton of dust. These sha be
smooth, washabe, coved and sha permt easy and ehectve ceanng and
dsnfecton. The nteror surfaces sha not shed partces. A perodca record of
ceanng and pantng of the premses sha be mantaned.
()1 Water syste/
There sha be vadated system for treatment of water drawn from own or any other
source to render t potabe n accordance wth standards speced by the Bureau of
Indan Standards or Loca Muncpaty, as the case may be, so as to produce Pured
Water conformng to Pharmacopoea speccaton. Pured Water so produced sha
ony be used for a the operatons except washng and ceanng operatons where
potabe water may be used. Water sha be stored n tanks, whch do not adversey
ahect quaty of water and ensure freedom from mcroboogca growth. The tank
sha be ceaned perodcay and records mantaned by the censee n ths behaf.

()2 Dis.sa! 3 4aste
() The dsposa of sewage and emuents (sod, qud and gas) from the manufactory
sha be n conformty wth the requrements of Envronment Pouton Contro Board.
() A bo-medca waste sha be destroyed as per the provsons of the Bo-Medca
Waste (Management and Handng) Rues, 1996.
() Addtona precautons sha be taken for the storage and dsposa of re|ected
drugs. Records sha be mantaned for a dsposa of waste.
(v) Provsons sha be made for the proper and safe storage of waste materas
awatng dsposa. Hazardous, toxc substances and ammabe materas sha be
stored n sutaby desgned and segregated encosed areas n conformty wth
Centra and State Legsatons.
,) WAREHOUSING AREA
1. Adequate areas sha be desgned to aow sumcent and ordery warehousng
of varous categores of materas and products ke startng and packagng
materas, ntermedates, buk and nshed products, products n quarantne,
reeased, re|ected, returned or recaed, machne and equpment spare parts
and change tems.
2. Warehousng areas sha be desgned and adapted to ensure good storage
condtons. They sha be cean, dry and mantaned wthn acceptabe
temperature mts. Where speca storage condtons are requred (e.g.,
temperature, humdty), these sha be provded, montored and recorded.
Storage areas sha have approprate house-keepng and rodent, pests and
vermn contro procedures and records mantaned. Proper racks, bns and
patforms sha be provded for the storage of materas.
3. Recevng and dspatch bays sha protect materas and products from
adverse weather condtons.
4. Where quarantne status s ensured by warehousng n separate earmarked
areas n the same warehouse or store, these areas sha be ceary
demarcated. Any system repacng the physca quarantne, sha gve
equvaent assurance of segregaton. Access to these areas sha be restrcted
to authorzed persons.
5. There sha be a separate sampng area n the warehousng area for actve
raw materas and excpents. If sampng s performed n any other area, t
sha be conducted n such a way as to prevent contamnaton, cross-
contamnaton and mx- up.
6. Segregaton sha be provded for the storage of re|ected, recaed or returned
materas or products. Such areas, materas or products sha be sutaby
marked and secured. Access to these areas and materas sha be restrcted.
7. Hghy hazardous, posonous and exposve materas such as narcotcs,
psychotropc drugs and substances presentng potenta rsks of abuse, re or
exposon sha be stored n safe and secure areas. Adequate re protecton
measures sha be provded n conformty wth the rues of the concerned
cvc authorty.
8. Prnted packagng materas sha be stored n safe, separate and secure
areas.
9. Separate dspensng areas for (Beta)
actum, Sex Hormones and Cyto-toxc substances or any such speca
categores of products sha be provded wth proper suppy of tered ar and
sutabe measures for dust contro to avod contamnaton. Such areas sha
be under dherenta pressure.
10.Sampng and dspensng of stere materas sha be conducted under aseptc
condtons conformng to Grade A, whch can aso be performed n a
dedcated area wthn the manufacturng facty.
11.Reguar checks sha be made to ensure adequate steps are taken aganst
spage, breakage and eakage of contaners.
12.Rodent treatments (pest contro) shoud be done reguary and at east once
n a year and record mantaned.
1) PRODUCTION AREA
1.The producton area sha be desgned to aow the producton preferaby n un-
ow and wth ogca sequence of operatons.
2.In order to avod the rsk of cross-contamnaton, separate dedcated and sef-
contaned factes sha be made avaabe for the producton of senstve
pharmaceutca products ke pencn or boogca preparatons wth ve mcro-
organsms. Separate dedcated factes sha be provded for the manufacture of
contamnaton causng and potent products such as Beta actum, Sex Hormones and
Cyto-toxc substances.
3.Workng and n-process space sha be adequate to permt ordery and ogca
postonng of equpment and materas and movement of personne to avod cross-
contamnaton and to mnmze rsk of omsson or wrong appcaton of any of
manufacturng and contro measures.
4.Ppe-work, eectrca ttngs, ventaton openngs and smar servce nes sha be
desgned, xed and constructed to avod creaton of recesses. Servce nes sha
preferaby be dented by coours and the
nature of the
suppy and drecton of the ow
sha be marked/ndcated.
2) ANCILLAR5 AREAS
1. Rest and refreshment rooms sha be separate from other areas. These areas
sha not ead drecty to the manufacturng and storage areas.
2. Factes for changng, storng cothes and for washng and toet purposes
sha be easy accessbe and adequate for the number of users. Toets,
separate for maes and femaes, sha not be drecty connected wth
producton or storage areas. There sha be wrtten nstructons for ceanng
and dsnfecton for such areas.
3. Mantenance workshops sha be separate and away from producton areas.
Whenever spares, changed parts and toos are stored n the producton area,
these sha be kept n dedcated rooms or ockers. Toos and spare parts for
use n stere areas sha be dsnfected before these are carred nsde the
producton areas.
4. Areas housng anmas sha be soated from other areas. The other
requrements regardng anma houses sha be those as prescrbed n rue
150-C(3) of the Drugs and Cosmetcs Rues, 1945 whch sha be adopted for
producton purposes.
6) 'UALIT5 CONTROL AREA
1.Ouaty Contro Laboratores sha be ndependent of the producton areas.
Separate areas sha be provded each for physco-chemca, boogca,
mcroboogca or rado-sotope anayss. Separate nstrument room wth adequate
area sha be provded for senstve and sophstcated nstruments empoyed for
anayss.
2.Ouaty Contro Laboratores sha be desgned appropratey for the operatons to
be carred out n them. Adequate space sha be provded to avod mx-ups and
cross-contamnaton. Sumcent and sutabe storage space sha be provded for test
sampes, retaned sampes, reference standards, reagents and records.
3.The desgn of the aboratory sha take nto account the sutabty of constructon
materas and ventaton. Separate ar handng unts and other requrements sha
be provded for boogca, mcroboogca and radosotopes testng areas. The
aboratory sha be provded wth reguar suppy of water of approprate quaty for
ceanng and testng purposes.
.4.Ouaty Contro Laboratory sha be dvded nto separate sectons .e. for
chemca, mcroboogca and wherever requred, boogca Testng. These sha
have adequate area for basc nstaaton and for ancary purposes. The
mcroboogy secton sha have arrangements such as arocks and amnar ar ow
work staton, wherever consdered necessary.


7) PERSONNEL
1.The manufacture sha be conducted under the drect supervson of competent
technca stah wth prescrbed quacatons and practca experence n the reevant
dosage form and / or actve pharmaceutca products.
2.The head of the Ouaty Contro Laboratory sha be ndependent of the
manufacturng unt. The testng sha be conducted under the drect supervson of
competent technca stah who sha be whoe tme empoyees of the censee.
3.Personne for Ouaty Assurance and Ouaty Contro operatons sha be sutaby
quaed and experenced.
4.Wrtten dutes of technca and Ouaty Contro personne sha be ad and foowed
strcty.
5.Number of personne empoyed sha be adequate and n drect proporton to the
workoad.
6.The censee sha ensure n accordance wth a wrtten nstructon that a
personne n producton area or nto Ouaty Contro Laboratores sha receve
tranng approprate to the dutes and responsbty assgned to them. They sha be
provded wth
reguar n-servce tranng.
8) HEALTH9 CLOTHING AND SANITATION OF WOR:ERS
7.1.The personne handng Beta-actum antbotcs sha be tested for Pencn
senstvty before empoyment and those handng sex hormones, cytotoxc
substances and other potent drugs sha be perodcay examned for adverse
ehects. These personne shoud be moved out of these sectons
(except n dedcated factes), by rotaton, as a heath safeguard.
7.2. Pror to empoyment, a personne, sha undergo medca examnaton
ncudng eye examnaton, and sha be free from Tubercuoss, skn and other
communcabe or contagous dseases. Thereafter, they shoud be medcay
examned perodcay, at east once a year. Records sha be mantaned thereof.
The censee sha provde the servces of a quaed physcan for assessng the
heath status of personne nvoved n dherent actvtes.
7.3 A persons, pror to and durng empoyment, sha be traned n practces whch
ensure personne hygene. A hgh eve of persona hygene sha be observed by a
those engaged n the manufacturng processes. Instructons to ths ehect sha be
dspayed n change-rooms and other strategc ocatons.
7.4 No person showng9 at any tme9 apparent ness or open esons whch may
adversey ahect the quaty of products, sha be aowed to hande startng
materas, packagng materas, In-process materas, and drug products unt hs
condton s no onger |udged to be a rsk.
7.5 A empoyees sha be nstructed to report about ther ness or abnorma heath
condton to ther mmedate supervsor so that approprate acton can be taken.
7.6 Drect contact sha be avoded between the unprotected hands of personne
and raw materas, ntermedate or nshed9 unpacked products.
7.7 A personne sha wear cean body coverngs approprate to ther dutes. Before
entry nto the manufacturng area, there sha be change rooms separate for each
sex wth adequate factes for persona ceanness such as wash basn wth runnng
water,
cean towes, hand dryers, soaps, dsnfectants etc. The change rooms sha be
provded wth cabnets for the storage of persona beongngs of the personne.
7.8 Smokng, eatng, drnkng, chewng or keepng pants, food, drnk and persona
medcnes sha not be permtted n producton, aboratory, storage and other areas
where they mght adversey nuence the product quaty.
;) MANUFACTURING OPERATIONS AND CONTROLS
8.1. A manufacturng operatons sha be carred out under the supervson of
technca stah approved by the Lcensng Authorty. Each crtca step n the process
reatng to the seecton, weghng and measurng of raw matera addton durng
varous stages sha be performed by traned personne under the drect persona
supervson of approved technca stah.
The contents of a vesses and contaners used n manufacture and storage durng
the varous manufacturng stages sha be conspcuousy abeed wth the name of
the product, batch no., batch sze and stage of manufacture. Each abe shoud be
ntaed and dated by the authorzed
technca stah.
Products not prepared under aseptc condtons are requred to be free from
pathogens ke Salmonella, Escherichia coli, Pyocyaneaetc.
;) ,) Pre*auti#s a"ai#st /i<0u. a#d *rss+*#ta/i#ati# 0
8. 2. 1. The censee sha prevent mx-up and cross- contamnaton of drug matera
and drug product (from envronmenta dust) by proper ar-handng system, pressure
dherenta, segregaton, status abeng and ceanng. Proper records and Standard
Operatng Procedures thereof sha be mantaned.
8. 2. 2. The censee sha ensure processng of senstve drugs ke Beta-Lactum
antbotcs, sex hormones and cycotoxc substances n segregated areas or soated
producton areas wthn the budng wth ndependent ar-handng unt and proper
pressure dherentas. The ehectve segregaton of these areas sha be
demonstrated wth adequate records of mantenance and servces.
8. 2. 3. To prevent mx-ups durng producton stages, matera under- process sha
be conspcuousy abeed to demonstrate ther status. A equpment used for
producton sha be abeed wth ther current status.
8. 2. 4. Packagng nes sha be ndependent and adequatey segregated. It sha be
ensured that a eft-overs of the prevous packagng operatons, ncudng abes,
cartons and caps are ceared before the
cosng hour.
8. 2. 5. Before packagng operatons are begun, steps sha be taken to ensure that
the work area, packagng nes, prntng machnes, and other equpment are cean
and free from any products, materas and spages. The ne cearance sha be
performed accordng to an approprate checkst and recorded.
8. 2. 6. The correct detas of any prntng (for exampe of batch numbers or expry
dates) done separatey or n the course of the packagng sha be re-checked at
reguar ntervas. A prntng and over-prntng sha be authorsed n wrtng.
8. 2. 7. The manufacturng envronment sha be mantaned at the requred eves of
temperature, humdty and ceanness.
8. 2. 8. Authorsed persons sha ensure change-over nto specc unforms before
undertakng any manufacturng operatons ncudng packagng.
8. 2. 9. There sha be segregated encosed areas, secured for recaed or re|ected
matera and for such matera whch are to be re-processed or recovered.

=) SANITATION IN THE MANUFACTURING PREMISES
9. 1. The manufacturng premses sha be ceaned and mantaned n an ordery
manner, so that t s free from accumuated waste, dust, debrs and other smar
matera. A vadated ceanng procedure
sha be mantaned.
9. 2. The manufacturng areas sha not be used for storage of materas, except for
the
matera beng processed. It sha not be used as a genera thoroughfare.
9. 3. A routne santaton program sha be drawn up and observed, whch sha be
propery recorded and whch sha ndcate -
1. specc areas to be ceaned and ceanng ntervas;
2. ceanng procedure to be foowed, ncudng equpment and materas to be
used for ceanng; and
3. personne assgned to and responsbe for the ceanng operaton.
9. 4. The adequacy of the workng and n-process storage space sha permt the
ordery and ogca postonng of equpment and materas so as to mnmse the rsk
of mx-up between dherent pharmaceutca products or ther components to avod
cross-contamnaton, and to mnmse the rsk of omsson or wrong appcaton of
any of the manufacturng or contro steps.
9. 5. Producton areas sha be we t, partcuary where vsua on-ne contros are
carred out.
(>) RAW MATERIALS
10. 1. The censee sha keep an nventory of a raw-materas to be used at any
stage of manufacture of drugs and mantan records as per Schedue U.
10. 2. A ncomng materas sha be quarantned mmedatey after recept or
processng. A materas sha be stored under approprate condtons and n an
ordery fashon to permt batch segregaton and stock rotaton by a 'rst n/rst
expry' - 'rst-out' prncpe. A ncomng materas sha be checked to ensure that
the consgnment corresponds to the order paced.
10. 3. A ncomng materas sha be purchased from approved sources under vad
purchase vouchers. Wherever possbe, raw materas shoud be purchased drecty
from the producers.
10. 4. Authorsed stah apponted by the
censee n ths behaf, whch may ncude personne from the quaty contro
department, sha examne each consgnment on recept and sha check each
contaner for ntegrty of package and sea. Damaged contaners sha be dented,
recorded and segregated.
10. 5. If a snge devery of matera s made up of dherent batches, each batch
sha be consdered as a separate batch for sampng, testng and reease.
10. 6. Raw materas n the storage area sha be appropratey abeed. Labes sha
be ceary marked wth the foowng nformaton :
1. desgnated name of the product and the nterna code reference, where
appcabe, and anaytca reference number;
2. manufacturer's name, address and batch number;
3. the status of the contents (e.g. quarantne, under test, reeased, approved,
re|ected);
4. the manufacturng date, expry date and re-test date.
10. 7. There sha be adequate separate areas for materas "under test", "approved
", and "re|ected" wth arrangements and equpment to aow dry, cean and ordery
pacement of stored materas and products, wherever necessary, under controed
temperature and humdty.
10. 8. Contaners from whch sampes have been drawn sha be dented.
10. 9. Ony raw materas whch have been reeased by the Ouaty Contro
Department and whch are wthn ther shef-fe sha be used. It sha be ensured
that shef-fe of formuaton product sha not exceed wth that of actve raw
materas used.
10. 10. It sha be ensured that a the contaners of raw materas are paced on the
rased patforms/racks and not paced drecty on the oor.
(() E'UIPMENT
11. 1. Equpment sha be ocated, desgned, constructed, adapted and mantaned
to sut the operatons to be carred out. The ayout and desgn of the equpment
sha am to mnmse the rsk of errors and permt ehectve ceanng and
mantenance n order to avod cross-contamnaton, bud-up of dust or drt and, n
genera, any adverse ehect on the quaty of products. Each equpment sha be
provded wth a og book9 wherever necessary.
11. 2. Baances and other measurng equpment of an approprate range, accuracy
and precson sha be avaabe n the raw-matera stores, producton and n-
process contro operatons and these sha be cabrated and checked on a
schedued bass n accordance wth Standard Operatng Procedures and records
mantaned.
11. 3. The parts of the producton equpment that come nto contact wth the
product sha not be reactve, addtve or adsorptve to an extent that woud ahect
the quaty of the product.
11. 4. To avod accdenta contamnaton, wherever possbe, non-toxc/edbe grade
ubrcants sha be used and the equpment sha be mantaned n a way that
ubrcants do not contamnate the products beng produced.
11. 5. Defectve equpment sha be removed from producton and Ouaty Contro
areas or appropratey abeed.
(,) DOCUMENTATION AND RECORDS
Documentaton s an essenta part of the Ouaty assurance system and, as such,
sha be reated to a aspects of Good Manufacturng Practces (GMP). Its am s to
dene the speccatons for a materas, method of manufacture and contro, to
ensure that a personne concerned wth manufacture know the nformaton
necessary to decde whether or not to reease a batch of a drug for sae and to
provde an audt tra that sha permt nvestgaton of the hstory of any suspected
defectve batch.
12.1. Documents desgned, prepared, revewed and controed, wherever appcabe,
sha compy wth these rues.
12. 2. Documents sha be approved, sgned and dated by approprate and
authorzed persons.
12. 3. Documents sha specfy the tte, nature and purpose. They sha be ad out
n an ordery fashon and be easy to check. Reproduced documents sha be cear
and egbe. Documents sha be reguary revewed and kept up to date. Any
ateraton made n the entry of a document sha be sgned and dated.
12. 4. The records sha be made or competed at the tme of each operaton n such
a way that a sgncant actvtes concernng the manufacture of pharmaceutca
products are traceabe. Records and assocated Standard Operatng Procedures
(SOP) sha be retaned for at east one year after the expry date of the nshed
product.
12. 5. Data may be recorded by eectronc data processng systems or other reabe
means, but master formuae and detaed operatng procedures reatng to the
system n use sha aso
be avaabe n a hard copy to factate checkng of the accuracy of the records.
Wherever documentaton s handed by eectronc data processng methods,
authorzed persons sha enter or modfy data n the computer. There sha be record
of changes and deetons. Access sha be restrcted by 'passwords' or other means
and the resut of entry of crtca data sha be ndependenty checked. Batch records
eectroncay stored sha be protected by a sutabe back-up. Durng the perod of
retenton, a reevant data sha be ready avaabe.
(1) LA-ELS AND OTHER PRINTED MATERIALS
Labes are absoutey necessary for dentcaton of the drugs and ther use. The
prntng sha be done n brght coours and n a egbe manner. The abe sha carry
a the prescrbed detas about the product.
13. 1. A contaners and equpment sha bear approprate abes. Dherent coour
coded abes sha be used to ndcate the status of a product (for exampe: under
test, approved, passed, re|ected).
13. 2. To avod chance of mx-up n prnted packagng materas, product eaets,
reatng to dherent products, sha be stored separatey.
13. 3. Pror to reease, a abes for contaners, cartons and boxes and a crcuars,
nserts and eaets sha be examned by the Ouaty Contro Department of the
censee.
13. 4. Pror to packagng and abeng of a gven batch of a drug, t sha be ensured
by the censee that sampes are drawn from the buk and duy tested, approved
and reeased by the quaty contro personne.
13. 5. Records of recept of a abeng and packagng materas sha be mantaned
for each shpment receved ndcatng recept, contro reference numbers and
whether accepted or re|ected. Unused coded and damaged abes and packagng
materas sha be destroyed and recorded.
13.6. The abe or accompanyng document of reference standards and reference
cuture sha ndcate concentraton, ot number, potency, date on whch contaner
was rst opened and storage condtons, where approprate.
(2) 'UALIT5 ASSURANCE
Ths
s a wde rangng concept concernng a matters that ndvduay or coectvey
nuence the quaty of a product. It s the totaty of the arrangements made wth
the ob|ect of ensurng that products are of the quaty requred for ther ntended
use.
14. 1. The system of quaty assurance approprate to the manufacture of
pharmaceutca products sha ensure that:
1. the pharmaceutca products are desgned and deveoped n a way that takes
account of the requrements of Good Manufacturng Practces (herenafter
referred as GMP) and other assocated codes such as those of Good
Laboratory Practces (herenafter referred as GLP) and Good Cnca Practces
(heren after referred as GCP).
2. adequate arrangements are made for manufacture, suppy, and use of the
correct startng and packagng materas.
3. adequate contros on startng materas, ntermedate products, and buk
products and other n-process contros, cabratons, and vadatons are
carred out.
4. the nshed product s correcty processed and checked n accordance wth
estabshed procedures.
5. the pharmaceutca products are not reeased for sae or supped before
authorzed persons have certed that each producton batch has been
produced and controed n accordance wth the requrements of the abe
cam and any other provsons reevant to producton, contro and reease of
pharmaceutca products.


(6) SELF INSPECTION AND 'UALIT5 AUDIT
It may be usefu to consttute a sef nspecton team suppemented wth a quaty
audt procedure for assessment of a or part of a system wth the specc purpose
of mprovng t.
15 1. To evauate the manufacturer's compance wth GMP n a aspects of
producton and quaty contro, concept of sef-nspecton sha be foowed. The
manufacturer sha consttute a team of ndependent, experenced, quaed
persons from wthn or outsde the company, who can audt ob|ectvey the
mpementaton of methodoogy and procedures evoved. The procedure for sef-
nspecton sha be documented ndcatng sef-nspecton resuts, evauaton,
concusons and recommended correctve actons wth ehectve foow up program.
The recommendatons for correctve acton sha be adopted.
15. 2. The program sha be desgned to detect shortcomngs n the mpementaton
of Good Manufacturng Practce and to recommend the necessary correctve actons.
Sef-nspectons sha be performed routney and on specc occasons, ke when
product recas or repeated re|ectons
occur or when an nspecton by the censng authortes s announced. The team
responsbe for sef-nspecton sha consst of personne who can evauate the
mpementaton of Good Manufacturng Practce ob|ectvey; a recommendatons
for correctve acton sha be mpemented.
15. 3. Wrtten nstructons for sef-nspecton sha be drawn up whch sha ncude
the foowng :
1. Premses ncudng personne factes.
2. Mantenance of budngs and equpment.
3. Storage of startng materas and nshed products.
4. Equpment.
5. Producton and n-process contros.
6. Ouaty contro.
7. Documentaton.
8. Santaton and hygene.
9. Vadaton and revadaton programmes.
10.Cabraton of nstruments or measurement systems.
11.Reca procedures.
12.Compants management.
13.Labes contro.
14.Resuts of prevous sef-nspectons and any correctve steps taken.
(7) 'UALIT5 CONTROL S5STEM
Ouaty contro sha be concerned wth sampng, speccatons, testng,
documentaton, reease procedures whch ensure that the necessary and reevant
tests are actuay carred and that the materas are not reeased for use, nor
products reeased for sae or suppy unt ther quaty has been |udged to be
satsfactory. It s not conned to aboratory operatons but sha be nvoved n a
decsons concernng the quaty of the product. It sha be ensured that a quaty
contro arrangements are ehectvey and reaby carred out. The department as a
whoe sha have other dutes such as to estabsh, evauate, vadate and mpement
a Ouaty Contro Procedures and methods.
16. 1. Every manufacturng estabshment sha estabsh ts own quaty contro
aboratory managed by quaed and experenced stah.
16. 2. The area of the quaty contro aboratory may be dvded nto Chemca,
Instrumentaton, Mcroboogca and Boogca testng. Separate provson shoud be
made for testng rado actve matera s used for manufacturng.
16. 3. Adequate area havng the requred storage condtons sha be provded for
keepng reference sampes. The quaty contro department sha evauate, mantan
and store reference sampes.
16. 4. Standard operatng procedures sha be avaabe for sampng, nspectng,
and testng of raw materas, ntermedate, buk nshed products and packng
materas and, wherever necessary, for montorng envronmenta condtons.
16. 5. There sha be authorzed and dated speccatons for a materas, products,
reagents and sovents ncudng test of dentty, content, purty and quaty. These
sha ncude speccatons for water, sovents and reagents used n anayss.
16. 6. No batch of the product sha be reeased for sae or suppy unt t has been
certed by the authorsed person(s) that t s n accordance wth the requrements
of the standards ad down.
16. 7. Reference/retaned sampes from each batch of the products manufactured
sha be mantaned n a quantty whch s at east twce the quantty of the drug
requred to conduct a the tests, except sterty and pyrogen/Bactera Endotoxn
Test performed on the actve matera and the product manufactured. The retaned
product sha be kept n ts na pack or a smuated pack for a perod of three
months after the date of expry.
16. 8. Assessment of records pertanng to nshed products sha ncude a
reevant factors, ncudng the producton condtons, the resuts of nprocess
testng, the manufacturng (ncudng packagng) documentaton, compance wth
the speccaton for the nshed product, and an examnaton of the nshed pack.
Assessment records shoud be sgned by the person ncharged of producton and
countersgned by the authorsed quaty contro personne before a product s
reeased for sae or dstrbuton.
16. 9. Ouaty contro personne sha have access to producton areas for sampng
and nvestgaton9 as approprate.
16. 10. The quaty contro department sha conduct stabty studes of the
products to ensure and assgn ther shef fe at the prescrbed condtons of storage.
A records of such studes sha be mantaned.
16. 11. The n-charge of Ouaty Assurance sha nvestgate a product compants
and records thereof sha be mantaned.
16. 12. A nstruments sha be cabrated and testng procedures vadated before
these are adopted for routne testng. Perodca cabraton of nstrument and
vadaton of procedures shoud be carred out.
16. 13. Each speccatons for raw materas, ntermedates, na products, and
packng materas sha be approved and mantaned by the Ouaty Contro
Department. Perodc revsons of the speccatons sha be carred out whenever
changes are necessary.
16. 14. Pharmacopoeae, reference standards, workng standards, reference spectra,
other reference materas and technca books, as requred, sha be made avaabe
n the Ouaty Contro Laboratory of the censee.

(8) SPECIFICATION
17. 1. For Raw materas and Packagng materas :-
They sha ncude,-
1. the desgnated name and nterna code reference;
2. reference, f any , to a pharmacopoea monograph;
3. quatatve and quanttatve requrements wth acceptance mts;
4. name and address of manufacturer or supper and orgna manufacturer of
the matera;
5. specmen of prnted matera;
6. drectons for sampng and testng or reference to procedures;
7. storage condtons; and
8. maxmum perod of storage before re-testng.
17. 2. For Product Contaners and Cosures -
17. 2. 1. A contaners and cosures ntended for use sha compy wth the
pharmacopoea requrements. Sutabe vadated test methods, sampe szes,
speccatons, ceanng procedure and sterzaton procedure, wherever ndcated,
sha be strcty foowed to ensure that these are not reactve, addtve, adsorptve,
or each to an extent that sgncanty ahects the quaty or purty of the drug. No
second hand or used contaners and cosures sha be used.
17. 2. 2. Whenever bottes are beng used, the wrtten schedue of ceanng sha be
ad down and foowed. Where bottes are not dred after washng, they shoud be
rnsed wth de-onsed water or dsted water, as the case may be.
17. 3. For n-process and buk products.- Speccatons for n-process matera,
ntermedate and buk products sha be avaabe. The speccatons shoud be
authentcated.
17. 4. For Fnshed Products. - Approprate speccatons for nshed products sha
ncude :-
1. the desgnated name of the product and the code reference.
2. the formua or a reference to the formua and the pharmacopoea reference.
3. drectons for sampng and testng or a reference to procedures.
4. a descrpton of the dosage form and package detas.
5. the quatatve and quanttatve requrements, wth the acceptance mts for
reease.
6. the storage condtons and precautons, where appcabe9 and
7. the shef-fe.
17.5
For preparaton of contaners and cosures. - The requrements mentoned n the
Schedue do not ncude requrements of machnery, equpments and premses
requred for preparaton of contaners and cosures for dherent dosage forms and
categores of drugs. The sutabty and adequacy of the machnery, equpment and
premses sha be examned takng nto consderaton the requrements of each
censee n ths respect.
(; MASTER FORMULA RECORDS
There sha be Master Formua records reatng to a manufacturng procedures for
each product and batch sze to be manufactured. These sha be prepared and
endorsed by the competent technca stah .e. head of producton and quaty
contro. The Master Formua sha ncude :-
1. the name of the product together wth product reference code reatng to ts
speccatons.
2. the patent or propretary name of the product aong wth the generc name, a
descrpton of the dosage form, strength, composton of the product and
batch sze.
3. name, quantty, and reference number of a the startng materas to be
used. Menton any substance that may 'dsappear' n the course of
processng.
4. a statement of the expected na yed wth the acceptabe mts, and of
reevant ntermedate yeds, where appcabe.
5. a statement of the processng ocaton and the prncpa equpment to be
used.
6. the methods, or reference to the methods, to be used for preparng the
crtca equpment ncudng ceanng, assembng, cabratng, sterzng.
7. detaed stepwse processng nstructons and the tme taken for each step.
8. the nstructons for n-process contros wth ther mts.
9. the requrements for storage condtons of the products, ncudng the
contaner, abeng and speca storage condtons where appcabe.
10.any speca precautons to be observed.
11.packng detas and specmen abes.
(= PAC:AGING RECORDS
There sha be authorsed
packagng nstructons for each product, pack sze and type. These sha ncude or
have a reference to the foowng : -
1. name of the product.
2. descrpton of the dosage form, strength and composton.
3. the pack sze expressed n terms of the number or doses, weght or voume of
the product n the na contaner.
4. compete st of a the packagng materas requred for a standard batch
sze, ncudng quanttes, szes and types, wth the code or reference number
reatng to the speccatons of each packagng matera.
5. reprocessng of the reevant prnted packagng materas and specmens
ndcatng where batch number and expry date of the product have been
apped.
6. speca precautons to be observed, ncudng a carefu examnaton of the
area and equpment n order to ascertan the ne cearance before the
operatons begn.
7. descrpton of the packagng operaton, ncudng any sgncant subsdary
operatons and equpment to be used.
8. detas of n-process contros wth nstructons for sampng and acceptance.
9. upon competon of the packng and abeng operaton, a reconcaton sha
be made between number of abeng and packagng unts ssued, number of
unts abeed, packed and excess returned or destroyed. Any sgncant or
unusua dscrepancy n the numbers sha be carefuy nvestgated before
reeasng the na batch.
,>) -ATCH PAC:AGING RECORDS
20. 1. A batch packagng record sha be kept for each batch or part batch
processed. It sha be based on the reevant parts of the packagng nstructons, and
the method of preparaton of such records sha be desgned to avod transcrpton
errors.
20. 2. Before any packagng operatons begns, checks sha be made and recorded
that the equpment and the work statons are cear of the prevous products,
documents or materas not requred for the panned packagng operatons, and that
the
equpment s cean and sutabe for use.
,() -ATCH PROCESSING RECORDS
21.1 There sha be Batch Processng Record for each product. It sha be based on
the reevant parts of the currenty approved Master Formua. The method of
preparaton of such records ncuded n the
Master Formua sha be desgned to avod transcrpton errors.
21.2. Before startng of any process nspect a the manufacturng area and ensure
that the equpment and work staton are cear of prevous products. Ths shoud be
documented and recorded.
21.3. Durng processng, the foowng nformaton sha be recorded at the tme
each acton s taken and the record sha be dated and sgned by the person
responsbe for the processng operatons:
( a ) the name of the product,
( b ) the number of the batch beng manufactured,
( c ) dates and tme of commencement, of sgncant ntermedate stages and of
competon of producton,
( d ) ntas of the operator of dherent sgncant steps of producton and where
approprate, of the person who checked each of these operatons,
( e ) the batch number and/or anaytca contro number as we as the quanttes of
each startng matera actuay weghed,
( f ) any reevant processng operaton or event and ma|or equpment used,
( g ) a record of the n-process contros and the ntas of the person(s) carryng
them out, and the resuts obtaned,
(h ) the amount of product obtaned after dherent and crtca stages of
manufacture (yed),
( ) comments or expanatons for sgncant devatons from the expected yed
mts sha be gven,
( | ) notes on speca probems ncudng detas, wth sgned authorzaton, for any
devaton from the master formua,
(k) addton of any recovered or reprocessed matera wth reference to recovery or
reprocessng stages.
,,) STANDARD OPERATING PROCEDURES %SOPS& AND RECORDS9
REGARDING
22. 1. Recept of Materas;
22. 1. 1. There sha be wrtten Standard Operatng Procedures and records for the
recept of each devery of raw, prmary and prnted packagng matera.
22. 1. 2. The records of the recepts sha ncude
(a) contaner number
(b) the date of recept
(c) the manufacturer's and / or supper's name
(d) the manufacturer's batch or reference number
(e) the tota quantty, and number of contaners, quantty n each contaner
receved
(f) the contro reference number assgned after recept
(g) any other reevant comment or nformaton.
22. 1. 3 There sha be wrtten standard operatng procedures for the nterna
abeng, quarantne and storage of startng materas, packagng materas and
other materas, as approprate.
22. 1. 4. There sha be Standard Operatng Procedures avaabe for each
nstrument and equpment and these sha be paced n cose proxmty to the
reated nstrument and equpment.


22. 2. Sampng.-
22. 2. 1. There sha be wrtten Standard Operatng Procedures for sampng, whch
ncude the person(s) authorzed to take the sampes.
22. 2. 2. The sampng nstructons sha ncude:
1. the method of sampng and the sampng pan,
2. the equpment to be used,
3. any precautons to be observed to avod contamnaton of the matera or any
deteroraton n ts quaty,
4. the quantty of sampes to be taken,
5. nstructons for any requred sub-dvson or poong of the sampes,
6. the type of sampe contaner to be used,
7. any specc precautons to be observed, especay n regard to sampng of
stere or hazardous matera.
22. 3. Batch Numberng.-
22. 3. 1. There sha be Standard Operatng Procedures descrbng the detas of the
batch ( ot ) numberng set up wth the ob|ectve of ensurng that each batch of
ntermedate, buk or nshed product s dented wth a specc batch number.
22.3. 2. Batch numberng standard operatng procedures apped to a processng
stage and to the respectve packagng stage sha be same or traceabe to
demonstrate that they beong to one homogenous mx.
22. 3. 3. Batch number aocaton sha be mmedatey recorded n a ogbook or by
eectronc data processng system. The record sha ncude date of aocaton,
product dentty and sze of batch.
22. 4. Testng
22. 4. 1. There sha be wrtten procedures for testng materas and products at
dherent stages of manufacture, descrbng the methods and equpment to be used.
The tests performed sha be recorded.
22. 5. Records of anayss.+
22. 5. 1. The records sha ncude the foowng data.
1. name of the matera or product and the dosage form,
2. batch number, detas of manufacturer and / or supper;
3. references of reevant speccatons and testng procedures,
4. test resuts, ncudng observatons and cacuatons, and reference to any
speccatons ( mts ),
5. dates of testng;
6. ntas of the persons who performed the testng;
7. ntas of the persons who vered the testng and the detaed cacuatons,
8. a statement of reease or re|ecton, and
9. sgnature and date of the desgnated responsbe person.
22. 5. 2. There sha be wrtten standard operatng procedures and the assocated
records of actons taken for:
1. equpment assemby and vadaton;
2. anaytca apparatus and cabraton;
3. mantenance, ceanng and santaton;
4. personne matters ncudng quacaton, tranng, cothng, hygene;
5. envronmenta montorng;
6. pest contro;
7. compants;
8. recas made;
9. returns receved.
,1) REFERENCE SAMPLES
23. 1. Each ot of every actve ngredent, n a quantty sumcent to carry out a the
tests9 except sterty and pyrogens/Bactera Endotoxn Test, sha be retaned for a
perod of 3 months after the date of expry of the ast batch produced from that
actve ngredent.
23. 2. Sampes of nshed formuatons sha be stored n the same or smuated
contaners n whch the drug has been actuay marketed.
,2) REPROCESSING AND RECO?ERIES
24. 1. Where reprocessng s necessary, wrtten procedures sha be estabshed and
approved by the Ouaty Assurance Department that sha specfy the condtons and
mtatons of repeatng chemca reactons. Such re-processng sha be vadated.
24. 2. If the product batch has to be reprocessed, the procedure sha be authorzed
and recorded. An nvestgaton sha be carred out nto the causes necesstatng re
-processng and approprate correctve measures sha be taken for preventon of
recurrence. Re-processed batch sha be sub|ected to stabty evauaton.
24. 3. Recovery of product resdue may be carred out, f permtted, n the master
producton and contro records by ncorporatng t n subsequent batches of the
product.
,6) DISTRI-UTION RECORDS
25. 1. Pror to dstrbuton or dspatch of gven batch of a drug, t sha be ensured
that the batch has been duy tested, approved and reeased by the quaty contro
personne. Pre-dspatch nspecton sha be performed on each consgnment on a
random bass to ensure that ony
the correct goods are dspatched. Detaed nstructons for warehousng and
stockng of Large Voume Parenteras, f stocked, sha be n exstence and sha be
comped wth after the batch s reeased for dstrbuton. Perodc audts of
warehousng practces foowed at dstrbuton centers sha be carred out and
records thereof sha be mantaned. Standard Operatng Procedures sha be
deveoped for warehousng of products.
25. 2. Records for dstrbuton sha be mantaned n a manner
such
that nshed batch of a drug can be traced to the reta eve to factate prompt and
compete reca of the batch, f and when necessary.
,7 ?ALIDATION AND PROCESS ?ALIDATION
26. 1. Vadaton studes sha be an essenta part of Good Manufacturng Practces
and sha be conducted as per the pre-dened protocos. These sha ncude
vadaton of processng, testng and ceanng procedures.
26. 2. A wrtten report summarzng recorded resuts and concusons sha be
prepared, documented and mantaned.
26. 3. Processes and procedures sha be estabshed on the bass of vadaton study
and undergo perodc revadaton to ensure that they reman capabe of achevng
the ntended resuts. Crtca processes sha be vadated, prospectvey or
retrospectvey.
26. 4. When any new master formua or method of preparaton s adopted, steps
sha be taken to demonstrate ts sutabty for routne processng. The dened
process, usng the materas and equpment speced sha be demonstrated to yed
a product consstenty of the
requred quaty.
26. 5. Sgncant changes to the manufacturng process, ncudng any change n
equpment or materas that may ahect product quaty and / or the reproducbty
of the process, sha be vadated.
,7) PRODUCT RECALLS
27. 1. A prompt and ehectve product reca system of defectve products sha be
devsed for tmey nformaton of a concerned stocksts, whoesaers, suppers, up
to the reta eve wthn the shortest perod. The censee may make use of both
prnt and eectronc meda n ths regard.
27. 2. There sha be an estabshed wrtten procedure n the form of Standard
Operatng Procedure for ehectve reca of products dstrbuted by the censee.
Reca operatons sha be capabe of beng ntated prompty so as to ehectvey
reach at the eve of each dstrbuton channe.
27. 3. The dstrbuton records sha be ready made avaabe to the persons
desgnated for recas.
27. 4. The desgnated person sha record a na report ssued9ncudng a
reconcaton between the devered and the recovered quanttes of the products.
27. 5. The ehectveness of the arrangements for recas sha be evauated from
tme to tme.
27. 6. The recaed products sha be stored separatey n a secured segregated area
pendng na decson on them.
,8 COMPLAINTS AND AD?ERSE REACTIONS
28. 1. A compants thereof concernng product quaty sha be carefuy revewed
and recorded accordng to wrtten procedures. Each compant sha be
nvestgated/evauated by the desgnated personne of the company and records of
nvestgaton and remeda acton taken thereof sha be mantaned.
28. 2. Reports of serous adverse drug reactons resutng from the use of a drug
aong wth comments and documents sha be forthwth reported to the concerned
Lcensng Authorty.
28. 3. There sha be wrtten procedures descrbng the acton to be taken, reca to
be made of the defectve product.
,=) SITE MASTER FILE
The censee sha prepare a succnct document n the form of 'Ste Master Fe'
contanng specc and factua Good Manufacturng Practces about the producton
and/or contro of pharmaceutca manufacturng preparatons carred out at the
censed premses. It sha contan the foowng : -
29. 1. General information.-
1. bref nformaton of the rm;
2. pharmaceutca manufacturng actvtes as permtted by the censng
authorty;
3. other manufacturng actvtes, f any, carred out on the premses;
4. type of products censed for manufacture wth owcharts mentonng
procedures and process ow;
5. number of empoyees engaged n the producton, quaty contro, storage and
dstrbuton;
6. Use of outsde scentc, anaytca or other technca assstance n reaton to
manufacture and anayss;
7. short descrpton of the Ouaty Management system of the rm;
8. products detas regstered wth foregn countres.
29. 2. Personnel -
1. organsatona chart showng the arrangement for quaty assurance ncudng
producton and quaty contro;
2. quacaton, experence and responsbtes of key personne;
3. outne for arrangements for basc and n-servce tranng and how the records
are mantaned;
4. heath requrements for persona engaged n producton;
5. personne hygene requrements, ncudng cothng.
29. 3. Premises -
1. smpe pan or descrpton of manufacturng areas drawn to scae;
2. nature of constructon and xtures / ttngs;
3. bref descrpton of ventaton systems. More detas shoud be gven for
crtca areas wth potenta rsk of arborne contamnaton (schematc drawng
of systems). Casscaton of the rooms used for the manufacture of stere
products shoud be mentoned;
4. speca areas for the handng of the hghy toxc, hazardous and senstzng
materas;
5. bref descrpton of water systems (schematc drawngs of systems), ncudng
santaton;
6. descrpton of panned preventve mantenance programs for premses and of
the recordng system.
29. 4. Equipment -
1. bref descrpton of ma|or equpment used n producton and quaty contro
aboratores (a st of equpment requred);
2. descrpton of panned preventve mantenance programs for equpment and
of the recordng system;
3. quacaton and cabraton, ncudng the recordng systems and
arrangements for computersed systems vadaton.
29. 5. Sanitation -
(a) avaabty of wrtten speccatons and procedures for ceanng manufacturng
areas and equpment.
29. 6. Documentation -
1. arrangements for the preparaton, revson and dstrbuton of
2. necessary documentaton for the manufacture;
3. any other documentaton reated to product quaty that s not mentoned
esewhere ( e.g. mcroboogca contros about ar and water )
29. 7. Production -
1. bref descrpton of producton operatons usng, wherever possbe, ow
sheets and charts specfyng mportant parameters;
2. arrangements for the handng of startng materas, packagng materas,
buk and nshed products, ncudng sampng, quarantne, reease and
storage;
3. arrangements for the handng of re|ected materas and products;
4. bref descrpton of genera pocy for process vadaton.
29. 8. Quality control -
1. descrpton of the quaty contro system and of the actvtes of the quaty
contro department. Procedures for the reease of the nshed products.
29. 9. Loan licence manufacture and licensee -
1. descrpton of the way n whch compance of Good Manufacturng Practces
by the oan censee sha be assessed.
29. 10. Distribution, complaints and product recall -
1. arrangements and recordng system for dstrbuton;
2. arrangements for the handng of compants and product recas.
29. 11. Self-Inspection -
(a) short descrpton of the sef-nspecton system ndcatng whether an outsde,
Independent and experenced externa expert was nvoved n evauatng the
manufacturer's compance wth Good Manufacturng Practces n a aspects of
producton.
29.12. Eport of dru!s -
( a ) products exported to dherent countres;
( b ) compants and product reca, f any.
GMP IN THE MANUFACTURING OF PHARMACEUTICALS
STERILE DOSAGE FORMS %PARENTERAL AND OPHTHALMIC&
() Ge#era! 0
Stere products, beng very crtca and senstve n nature, a very hgh degree of
precautons, preventon and preparatons are needed. Dampness, drt and darkness
are to be avoded to ensure aseptc condtons n a areas. There sha be strct
compance n the prescrbed standards especay n the matter of suppy of water,
ar, actve materas and n the mantenance of hygenc envronment.
,) -ui!di#"s A#d Ci@i! WrAs
0
2. 1. The budng sha be but on proper foundaton wth standardsed materas to
avod cracks n crtca areas ke aseptc souton preparaton, ng and seang
rooms.
2. 2. Locaton of servces ke water, steam, gases etc. sha be such that ther
servcng or repar sha not pose any threat to the ntegrty of the facty. Water
nes sha not pose any threat of eakage to aseptc area.
2. 3. The manufacturng areas sha be ceary separated nto support areas (e.g.
washng and component preparaton areas, storage areas etc.), preparaton areas
(e.g. buk manufacturng area, non-aseptc bendng areas etc.) change areas and
aseptc areas. Operatons ke remova of outer cardboard wrappngs of prmary
packagng materas sha be done n the de-cartonng areas whch are segregated
from the washng areas. Wooden paets, ber board drums, cardboard and other
partce sheddng materas sha not be taken nsde the preparaton areas.
2. 4. In aseptc areas -
Was, oors and ceng shoud be mpervous, non-sheddng, non-akng and non-
crackng. Foorng shoud be unbroken and provded wth a cove both at the |uncton
between the wa and the oor as we as the wa and the ceng.
". was sha be at,
and edges and recesses sha be avoded. Wherever other surfaces
|on the wa (e.g. stersers, eectrc sockets, gas ponts etc.) these
sha be ush
wth the was. Was sha be provded wth a cove
at the |ont between
the ceng and oor.
#. ceng sha be sod and |onts sha be seaed. Lght-ttngs and ar-
grs sha be ush wth the was and not hangng from the ceng9 so
as to prevent contamnaton.
$. there sha be no snks and drans n Grade A and Grade B areas;
%. doors sha be made of non-sheddng matera. These may be made
preferaby of Aumnum or Stee matera. Wooden doors sha not be
used. Doors sha open towards the hgher-pressure area so that they
cose automatcay due to ar pressure.
&. Wndows sha be made of smar matera as the
doors, preferaby wth doube pane and sha be ush wth the was. If
re escapes are to be provded, these sha be sutaby fastened to the
was wthout any gaps.
'. the furnture used sha be smooth, washabe and made of staness
stee or any other approprate matera other than wood.
2. 5. The manufacturng and the support areas sha have the same quaty of cv
structure descrbed above for aseptc areas9 except the envronmenta standards
whch may vary n the
crtca areas.
2. 6. Change rooms wth entrance n the form of ar-ocks sha be provded before
entry nto the stere product manufacturng areas and then to the aseptc area.
Separate ext space from the
aseptc areas s advsabe. Change rooms to the
aseptc areas sha be ceary demarcated nto 'back', 'gray' and 'whte rooms' wth
dherent eves of actvty and ar ceanness. The 'back' change room sha be
provded wth a hand-washng snk. The snk and ts dran n the un- cassed (rst)
change rooms may be kept cean a the tme. The specay desgned dran sha be
perodcay montored to avod presence of pathogenc mcro-organsms. Change
room doors sha not be opened smutaneousy. An approprate nter-ockng system
and a vsua and/ or audbe warnng system may be nstaed to prevent the
openng of more than one door at a tme.
2. 7. For communcaton between aseptc areas and non-aseptc areas, ntercom
teephones or speak-phones sha be used. These sha be mnmum n number.
2. 8. Matera transfer between aseptc areas and outsde sha be through sutabe
ar-ocks or pass-boxes. Doors of such ar-ocks and pass-boxes sha have sutabe
nterockng arrangements.
2. 9. Persona wefare areas ke rest rooms, tea room, canteen and toets sha be
outsde and separated from the
stere product manufacturng area.
2.10. Anma houses sha be away from the stere product manufacturng area and
sha not share a common entrance or ar handng system wth the manufacturng
area.
1) Air Ha#d!i#" Syste/ %Ce#tra! Air+C#diti#i#"&
3. 1. Ar Handng Unts for stere product manufacturng areas sha be dherent
from those for other areas. Crtca areas, such as the aseptc ng area, sterzed
components unoadng area and change rooms conformng to Grades B, C and D
respectvey sha have separate Ar Handng Unts. The ter conguraton n the ar
handng system sha be sutaby desgned to acheve the Grade of ar as gven n
Tabe I. Typca operatona actvtes for cean areas are hghghted n Tabe II and
Tabe III.
3. 2. For products whch are ed aseptcay, the ng room sha meet Grade B
condtons at rest unmanned. Ths condton sha aso be obtaned wthn a perod of
about 30 mnutes of the personne eavng the room after competon of operatons.
3. 3. The ng operatons sha take pace under Grade A condtons whch sha be
demonstrated under workng of smuated condtons whch
sha be acheved by provdng Lamnar Ar ow work statons wth sutabe HEPA
ters or soator technoogy.
3. 4. For products, whch are termnay sterzed, the ng room sha meet Grade
C condtons at rest. Ths condton sha be obtanabe wthn a perod of about 30
mnutes of the
personne eavng the room after competon of operatons.
3. 5. Manufacturng and component preparaton areas sha meet Grade C
condtons.
3. 6. After competon of preparaton, washed components and vesses sha be
protected wth Grade C background and f necessary, under Lamnar Ar Fow work
staton.
3. 7. The mnmum ar changes for Grade B and Grade C areas sha not be ess than
20 ar changes per hour n a room wth good ar ow pattern and approprate HEPA
ters. For Grade A Lamnar Ar Fow work statons, the ar ow rates sha be 0.3
meter per second 20 % (for vertca ows) and 0.45 meter per second 20 % (for
horzonta ows).
TABLE I
Ar Borne Partcuate Casscaton For Manufacture Of Stere Products
Grad
e
At rest (b) In Operaton (a)

Maxmum number of permtted partces per cubc metre equa
to or above
0. 5 m 5 mn 0. 5 m 5 m
A 3520 29 3500 29
B (a) 35,200 293 3,52,000 2,930
C (a)

3,52,000 2,930 35,20,000 29,300
D (a)

35,20,000 29,300 Not dened (c) Not dened (c)

(otes )
". In order to reach the *, + and D air !rades, the number of air chan!es
shall 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 /ith
the appropriate 0lters such as 1EP2 for Grades 2, * and +. -he
maimum permitted number of particle 3at rest3 condition shall
approimately 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 87
Grade D /ith +lass "44,444 or 5 '.& or IS6 +lass 9.
#. -he requirement and limit for the area shall depend on the nature of
the
operation carried out
$. -ype of operations to be carried out in the .arious !rades are !i.en in
-able II and -able III as under)
TABLE II
Types of Operatons To Be Carred Out In The Varous Grades For Aseptc
Preparatons
Grad
e
Types of operatons for aseptc preparatons.
A Aseptc preparaton and ng.
B
Background room condtons for actvtes requrng
Grade A.
C Preparaton of souton to be tered.
D Handng of components after washng.


TABLE III
Types of Operatons To Be Carred Out In The Varous Grades For Termnay
Sterzed Products
Grad
e
Types of operatons for termnay sterzed products.
A
Fng of products9 whch
are usuay at rsk.
C
Pacement of ng and seang machnes, preparaton of soutons,
when usuay at rsk. Fng of product when unusuay at rsk.
D
Moudng, bowng (pre-formng) operatons of pastc contaners,
Preparatons of soutons and components for subsequent ng.

2. E#@ir#/e#ta! M#itri#"
4. 1. A envronmenta parameters sted under para 3.1 to 3.10 sha be vered
and estabshed at the tme of nstaaton and thereafter montored at perodc
ntervas. The recommended frequences of perodc montorng sha be as foows:
%. Partcuate montorng n ar - 6 Monthy
&. HEPA ter ntegrty testng ( smoke testng ) - Yeary
'. Ar change rates - 6 Monthy
8. Ar pressure dherentas - Day
9. Temperature and humdty - Day
:. Mcroboogca montorng by sette pates and/or swabs n aseptc
areas - Day, and at decreased frequency n other areas
(ote ) -he abo.e frequencies of monitorin! shall be chan!ed as per the
requirements and load in indi.idual cases.
4. 2. There sha be a wrtten envronmenta montorng program and mcroboogca
resuts sha be recorded. Recommended mts for mcroboogca montorng of
cean areas "n operaton" are as gven n the tabe beow :

TABLE
Recommended Lmts For Mcroboogca Montorng Of Cean Areas "In-operaton"
Grad
e
Ar sampe
Cfu / m
3
Sette pates ( da.
90 mm. Cfu / 2
hrs.
Contact pates (da.
55 mm) cfu per
pate
Gove ponts (ve
ngers) cfu per
gove
A < 1 < 1 < 1 < 1
B 10 5 5 5
C 100 50 25 -
D 500 100 50 -
(otes )
"4.-hese are a.era!e .alues.
"".Indi.idual settle plates may be eposed for not less than t/o hours in
Grade *, + and D areas and for not less than thirty minutes in Grade 2
area.
4. 3. Approprate acton sha be taken mmedatey f the resut of partcuate and
mcroboogca montorng ndcates that the counts exceed the mts. The Standard
Operatng Procedures sha contan correctve acton. After ma|or engneerng
modcaton to the HVAC system of any area, a montorng sha be re-performed
before producton commences.
6) Gar/e#ts
5. 1. Ths secton covers garments requred for use by personne workng ony n
aseptc areas. Outdoor cothng sha not be brought nto the stere areas.
5. 2. The garments sha be made of non-sheddng and tght weave matera. Cotton
garments sha not be used. The garments sha shed vrtuay no bers or
partcuate matter.
5. 3. The cothng and ts quaty sha be adopted to the process and the work pace
and worn n such a way as to protect the product from contamnaton. Garments
sha be snge pece wth fastenngs at cuhs, neck and at egs to ensure cose t.
Trouser egs sha be tucked nsde the cover boots. Sutabe desgn of garments
sha ether ncude a hood (head-cover) or a separate hood whch can be tucked
nsde the over-a. Pockets, peats and bets sha be avoded n garments. Zps (f
any) sha be of Pastc matera. Garments wth damaged zps sha not be used.
5. 4. Ony cean, sterzed and protectve garments sha be used at each work
sesson where aseptc traton and ng operatons are undertaken and at each
work shft for products ntended to be sterzed9 post-ng. The mask and goves
sha be changed at every work sesson n both nstances.
5. 5. Goves sha be made of atex or other sutabe pastc materas and sha be
powder-free. These sha be ong enough to cover wrsts competey and aow the
over-a cuh to be tucked n.
5. 6. The footwear sha be of sutabe pastc or rubber matera and sha be day
ceaned wth a bactercde.
5. 7. Safety gogges or numbered gasses wth sde extensons sha be used nsde
aseptc areas. These sha be santsed by a sutabe method.
5. 8. Garment changng procedure sha be documented and operators traned n
ths aspect. A fu sze mrror sha be provded n the na change room for the
operator to verfy that he s appropratey attred n the garments. Perodc
nspecton of the garments sha be done by responsbe stah.
7) Sa#itati#
6. 1. There sha be wrtten procedures for the santaton of stere processng
factes. Empoyees carryng out santaton of aseptc areas sha be traned
speccay for ths purpose.
6. 2. Dherent santzng agents sha be used n rotaton and the concentratons of
the same sha be as per the recommendatons of the manufacturer. Records of
rotatona use of santzng agents sha be mantaned.
6. 3. Dsted water freshy coected drecty from the dsted water pant or water
mantaned above 70 degree centgrade from the re-crcuaton oop sha be used
for duton of dsnfectants. Aternatey, dsted water stersed by autocavng or
membrane traton sha be used. The duton sha be carred out n the 'whte'
change room.
6. 4. Where acoho or Isopropy acoho s used for duton of dsnfectants for use
as hand sprays, the preparaton of the same sha be done n the buk preparaton
area and the duted souton membrane-tered nto sutabe stere contaners hed
n aseptc area.
6. 5. Duted dsnfectants sha bear the abe 'use before'9based on mcroboogca
estabshment of ther germcda propertes. The soutons sha be adequatey
abeed and documents mantaned.
6. 6. Formadehyde or any other equay ehectve fumgant s recommended for the
fumgaton of aseptc areas or after ma|or cv modcatons. There sha be
Standard Operatng Procedures for ths purpose . Its use for routne purposes sha
be dscouraged and an
equay ehectve surface ceanng regme sha be foowed.
6. 7. Ceanng of stere processng factes sha be undertaken wth ar sucton
devces or wth non-ntng sponges or cothes.
6. 8. Ar partcuate quaty sha be evauated on a reguar bass and records
mantaned.

8) Equi./e#t
7. 1. The speca equpment requred for manufacturng stere products ncudes
component washng machnes, steam stersers, dry heat stersers, membrane
ter assembes, manufacturng vesses, benders, qud ng machnes, powder
ng machnes, seang and abeng machnes, vacuum testng chambers,
nspecton machnes, yophsers, pressure vesses etc. Sutabe and fuy ntegrated
washng-sterzng- ng nes may be provded9dependng upon the type and
voume of actvty.
7. 2. Unt-stersers sha be doube-ended wth sutabe nter-ockng arrangements
between the doors. The ehectveness of the sterzaton process sha be
estabshed ntay by boogca nactvaton studes usng mcroba spore
ndcators and then at east once a year by carryng out therma mappng of the
chamber. Varous sterzaton parameters sha be estabshed based on these
studes and documented. For membrane ters used for traton, approprate ter
ntegrty tests that ensure sterzaton sha be carred out before and after traton.
7. 3. Fng machnes sha be chaenged ntay and then at perodc ntervas by
smuaton tras ncudng stere meda . Standard Operatng Procedures and
acceptance crtera for meda s sha be estabshed, |usted and documented.
Speca smuaton tra procedures sha be deveoped, vadated and documented
for speca products ke ophthamc ontments.
7. 4. The constructon
matera used
for the parts whch are n drect contact wth products and the
manufacturng vesses may be staness stee 316 or Boro-scate gass (f gass
contaners) and the
tubng sha be capabe of beng washed and autocaved.
7. 5. On procurement, nstaaton quacaton of each of the equpment sha be
done by engneers wth the support of producton and quaty assurance personne.
Equpment for crtca processes ke aseptc ng and sterzers sha be sutaby
vadated accordng to a wrtten program before puttng them to use.
7. 6. Standard Operatng Procedures sha be avaabe for each equpment for ts
cabraton and operaton and ceanng. Gauges and other measurng devces
attached to equpment sha be cabrated at sutabe ntervas aganst a wrtten
program. Cabraton status of equpment and gauges sha be adequatey
documented and dspayed.
;)Water a#d Stea/ Syste/s
8. 1. Potabe water meetng mcroboogca speccaton of not more than 500
cfu/m and ndcatng absence of ndvdua pathogenc mcro-
organsms. Escherichia
coli, Salmonella, Staphylococcus aureus and Pseudomonas aeru!inosa per 100 m
sampe sha be used for the preparaton of pured water.
8. 2. Pured water prepared by de-mnerazaton sha meet the mcroboogca
speccaton of not more than 100 cfu per m and ndcate
absence of pathogenc mcro-organsms n 100 m. Pured water sha aso meet IP
speccatons for chemca quaty. Pured water sha be used for hand washng n
change rooms. Contaners, cosures and machne parts may be washed wth potabe
water foowed by sutaby tered pured water. Pured water sha be stored n
staness stee tanks or pastc tanks.
8. 3. Water for In|ecton (herenafter referred as WFI) sha be prepared from potabe
water or pured water meetng the above speccatons by dstaton. Water for
In|ecton sha meet mcroboogca speccaton of not more than 10 cfu per 100
m. WFI sha aso meet IP speccaton for Water for In|ecton and sha have an
endotoxn eve of not more than 0.25 EU / m. Buk soutons of qud parenteras
sha be made n WFI. Fna rnse of product contaners and machne parts sha be
done wth WFI. Dsnfectant soutons for use n aseptc areas sha be prepared n
WFI.
8. 4. Water for In|ecton for the manufacture of qud n|ectabes sha be freshy
coected from the dstaton pant or from a storage or crcuaton oop where the
water has been kept at above 70 degree centgrade. At the pont of coecton, water
may be cooed usng sutabe heat exchanger.
8. 5. Water for non-n|ectabe stere products ke eye drops sha meet IP
speccatons for pured water. In addton, mcroboogca speccaton of not
more than 10 cfu per 100 m and absence of Pseudomonas
aeru!inosa andEnterobacter coli n 100 m sha aso be met.
8. 6. Water for In|ecton sha be stored n steam |acketted staness stee tanks of
sutabe sze and the tanks sha have hydrophobc bactera retenton wth 0.22
mcrons vent ters. The ters sha be sutaby sterzed at perodc ntervas. The
dstrbuton nes for pured water and dsted water sha be of staness stee 316
constructon and sha not shed partces.
8. 7. There sha be a wrtten procedure and program for the santaton of dherent
water systems ncudng storage tanks, dstrbuton nes, pumps and other reated
equpment. Records of santaton sha be mantaned.
8. 8. There sha be wrtten mcroboogca montorng program for dherent types of
water. The resuts sha |ustfy the frequency of sampng and testng. Investgaton
sha be carred out and correctve acton taken n case of devaton from prescrbed
mts.
8. 9. Steam comng n contact wth the product, prmary contaners and other
product contact surfaces sha be stere and pyrogen free. The steam condensate
sha meet mcroboogca speccaton of not more than 10 cfu per 100 m. The
condensate sha aso meet IP speccaton for Water for In|ecton and sha have an
endotoxn eves of not more than 0.25 EU/m. There sha be a sutabe schedue for
the montorng of steam quaty.
=) Ma#u3a*turi#" Pr*ess
9. 1. Manufacture of stere products sha be carred out ony n areas under dened
condtons.
9. 2. Buk raw materas sha be montored for bo-burden perodcay. Bo-burden of
buk souton pror to membrane traton sha be montored perodcay and a mt
of not more than 100 cfu per m s recommended.
9. 3. The tme between the start of the preparaton of the souton and ts
sterzaton or traton through a mcro-organsm retanng ter sha be
mnmsed. There sha be a set maxmum permssbe tme for each product that
takes nto account ts composton and method of storage mentoned n the
Master formua record.
9. 4. Gases comng n contact wth the
stere product sha be tered through two 0.22 mcrons hydrophobc ters
connected n+seres. These ters sha be tested for ntegrty. Gas cynders sha not
be taken nsde aseptc areas.
9. 5. Washed contaners sha be sterzed mmedatey before use. Sterzed
contaners, f not used wthn an estabshed tme, sha be rnsed wth dsted or
tered pured water and re-sterzed.
9. 6. Each ot of nshed product sha be ed n one contnuous operaton. In each
case, where
one batch s ed
n usng more than one operaton, each ot sha be tested separatey for sterty
and hed separatey t sterty test resuts are known.
9. 7. Speca care sha be exercsed whe ng products n powder form so as not
to contamnate the envronment durng transfer of powder to ng machne-hopper.
(>)FORM+FILL+SEAL TECHNOLOG5 OR -LOW9 FILL+SEAL TECHNOLOG5
10. 1. Form-F-Sea unts are specay but automated machnes n whch through
one contnuous operaton, contaners are formed from thermopastc granues, ed
and then seaed. Bow, - sea unts are machnes n whch contaners are
mouded/bown (pre-formed) n separate cean rooms, by non contnuous
operatons.
(ote )
"#.-hese shall be installed in at least Grade + en.ironment.
"$.-hese shall comply /ith the limits as recommended in -able at item
%.#.
10. 2. Form - F - Sea / Bow, F - Sea machnes used for the manufacture of
products for termna sterzaton sha be nstaed n at east Grade C envronment
and the ng zone wthn the machne sha fu Grade A requrements.
(>) 1. Ter/i#a!!y Steri!i$ed Prdu*ts
"%.Preparaton of prmary packagng matera such as gass bottes,
ampoues and
rubber stoppers sha be done n at east Grade D envronment. Where
there s unusua rsk to the product from mcroba contamnaton, the
above operaton sha be done n Grade C envronment. A the
processes used for component preparaton sha be vadated.
"&.Fng of products requrng termna sterzaton sha be done under
Grade A envronment wth a Grade C background.
10. 4. Preparaton of soutons, whch are to be sterzed by traton, sha be done
n Grade C envronment, and f not to be tered, the preparaton of materas and
products sha be n a Grade A envronment wth Grade B n background.
(>) 6) Fi!trati# % Me/Bra#e &
( ) Soutons for Large Voume Parenteras sha be tered through a non-ber
reeasng, sterzng grade cartrdge/membrane ter of nomna pore sze of 0.22
mcrons for aseptc ng whereas 0.45 mcrons porosty sha be used for termnay
sterzed products.
( ) A second traton usng another 0.22 mcrons sterzng grade
cartrdge/membrane ter sha be performed mmedatey pror to ng. Process
speccatons sha ndcate the maxmum tme durng whch a traton system may
be used wth a vew to precudng
mcroba bud-up to eves that may ahect the mcroboogca quaty of the Large
Voume Parenteras.
( ) The ntegrty of the sterzed ter sha be vered and conrmed mmedatey
after use by an approprate method such as Bubbe Pont, Dhusve Fow or Pressure
Hod Test.
(>) 7. Steri!i$ati# % Aut*!a@i#" &
10.6.1. Before any sterzaton process s adopted, ts sutabty for the product and
ts emcacy n achevng the desred sterzng condtons n a parts of each type of
oad pattern to be processed, sha be demonstrated by physca measurements and
by boogca ndcators, where approprate.
10.6.2. A the sterzaton processes sha be appropratey vadated. The vadty of
the process sha be vered at reguar ntervas, but at east annuay. Whenever
sgncant modcatons have been made to the equpment and product, records
sha be mantaned thereof.
10.6.3.The sterzer sha be doube ended to prevent mx-ups.
10.6.4.Perodc bo-burden montorng of products before termna sterzaton sha
be carred out and controed to mts speced for the product n the Master
Formua.
10.6.5.The use of boogca ndcators sha be consdered as an addtona method
for montorng the sterzaton. These sha be stored and used accordng to the
manufacture's nstructons. Ther quaty sha be checked by postve contros. If
boogca ndcators are used, strct precautons sha be taken to avod transferrng
mcroba contamnaton from them.
10.6.6.There sha be cear means of dherentatng 'sterzed' and 'unsterzed'
products. Each basket, tray or other carrer of products or components sha be
ceary abeed wth the name of the matera, ts batch number, and sterzaton
status. Indcators sha be used, where approprate, to ndcate whether a batch (or
sub-batch) has passed through the sterzaton process.
10.6.7.Sterzaton records sha be avaabe for each sterzaton-run and may aso
ncude thermographs and sterzaton montorng strps. They sha be mantaned
as part of the batch reease procedure.
(>) 8. Steri!i$ati# % -y Dry Heat &
10.7.1. Each heat sterzaton cyce sha be recorded on a tme / temperature chart
of a sutabe sze by approprate equpment of the requred accuracy and precson.
The poston of temperature probes used for controng and / or recordng sha be
determned durng the vadaton and, where appcabe, sha aso be checked
aganst a second ndependent temperature probe ocated n the same poston. The
chart sha form a part of the batch record. Contaner mappng may aso be carred
out n the case of Large Voume Parenteras.
10.7.2. Chemca or boogca ndcators may aso be used, but sha not take the
pace of physca vadaton.
10.7.3. Sumcent tme sha be aowed for the oad to reach the requred
temperature before measurement of sterzaton tme commences. Ths tme sha
be separatey
determned for each type of oad to be processed.
10.7.4. After the hgh temperature phase of a heat sterzaton cyce, precautons
sha be taken aganst contamnaton of sterzed oad durng coong. Any coong
ud or gas n contact wth the product sha be sterzed uness t can be shown
that any eakng contaner woud not be approved for use. Ar net and outets sha
be provded wth bactera retanng ters.
10.7.5.The process used for sterzaton by dry heat sha ncude ar-crcuaton
wthn the chamber and the mantenance of a postve pressure to prevent the entry
of non-stere ar. Ar nets and outets shoud be provded wth mcro-organsm
retanng ters. Where ths process of sterzaton by dry heat s aso ntended to
remove pyrogens, chaenge tests usng endotoxns woud be requred as part of the
vadaton process.
(>) ;)
Steri!i$ati# %-y Mist Heat&
10.8.1. Both the temperature and pressure sha be used to montor the process.
Contro nstrumentaton sha normay be ndependent of montorng
nstrumentaton and recordng charts. Where automated contro and montorng
systems are used for these appcatons, these sha be vadated to ensure that
crtca process requrements are met. System and cyce fauts sha be regstered by
the system and observed by the operator. The readng of the ndependent
temperature ndcator sha be routney checked aganst the chart-recorder durng
the sterzaton perod. For sterzers tted wth a dran at the bottom of the
chamber, t may aso be necessary to record the temperature at ths poston
throughout the sterzaton perod. There sha be frequent eak tests done on the
chamber durng the vacuum phase of the cyce.
10.8.2. The tems to be sterzed, other than products n seaed contaners, sha be
wrapped n a matera whch aows remova of ar and penetraton of steam but
whch prevents re-contamnaton after sterzaton. A parts of the oad sha be n
contact wth the sterzng agent at the requred temperature for the requred tme.
10.8.3. No Large Voume Parentera sha be sub|ected to steam sterzaton cyce
unt t has been ed and seaed.
10.8.4. Care sha be taken to ensure that the steam used for sterzaton s of a
sutabe quaty and does not contan addtves at a eve whch coud cause
contamnaton of the product or equpment.
(>) =. C/.!eti# C Fi#a!isati# 3 Steri!e Prdu*ts
10.9.1. A unt operatons and processes n the manufacture of a batch sha have a
mnmum tme speced and the shortest vadated tme sha be used from the
start of a batch to ts utmate reease for dstrbuton.
10.9.2. Contaners sha be cosed by appropratey vadated methods. Contaners
cosed by fuson, e.g. gass or pastc ampoues sha be sub|ected to 100 % ntegrty
testng. Sampes of other contaners sha be checked for ntegrty accordng to
approprate procedures.
10.9.3. Contaners seaed under vacuum sha be tested for requred vacuum
condtons.
10.9.4. Fed contaners of parentera products sha be nspected ndvduay for
extraneous contamnaton or other defects. When nspecton s done vsuay, t sha
be done under sutaby controed condtons of umnaton and background.
Operators dong the nspecton sha pass reguar eye-sght checks wth spectaces,
f worn, and be aowed frequent rest from nspecton. Where other methods of
nspecton are used, the process sha be vadated and the performance of the
equpment checked at sutabe ntervas. Resuts sha be recorded.
((. Prdu*t C#tai#ers A#d *!sures
11. 1. A contaners and cosures ntended for use sha compy wth the
pharmacopoea and other speced requrements. Sutabe sampe szes,
speccatons, test methods, ceanng procedures and sterzaton procedures, sha
be used to assure that contaners, cosures and other component parts of drug
packages are sutabe and are not reactve, addtve, adsorptve or eachabe or
presents the rsk of toxcty to an extent that sgncanty ahects the quaty or
purty of the drug. No second hand or used contaners and cosures sha be used.
11. 2. Pastc granues sha aso compy wth the Pharmacopoea requrements
ncudng physo-chemca and boogca tests.
11. 3. A contaners and cosures sha be rnsed pror to sterzaton wth water for
n|ecton accordng to wrtten procedure.
11. 4. The desgn of cosures, contaners and stoppers sha be such as to make
ceanng, easy and aso to make an artght sea when tted to the bottes.
11. 5. It sha be ensured that contaners and cosures chosen for a partcuar
product are such that when comng nto contact they are not absorbed nto the
product and they do not ahect the product adversey. The cosures and stoppers
shoud be of such quaty substances as not to ahect the quaty of the product and
avod the rsk of toxcty.
11. 6. Whenever gass bottes are used, the wrtten schedue of ceanng sha be
ad down and foowed. Where bottes are not dred after washng, these sha be
nay rnsed wth dsted water or pyrogen free water, as the case may be,
accordng to wrtten procedure.
11. 7. Indvdua contaners of parentera preparatons, ophthamc preparatons
sha be examned aganst back/whte background tted wth dhused ght after
ng so as to ensure freedom from foregn matters.

(() ;
G!ass Btt!es
11.8.1. Shape and desgn of the gass botte sha be ratona and standardzed.
Gass bottes made of USP Type-I and USP Type-II gass sha ony be used. Gass
bottes sha not be reused. Before use, USP Type-II bottes sha be vadated for the
absence of partcuate matter generated over a perod of the shef-fe of the
product and sha be reguary montored after producton9 foowng statstca
sampng methods. USP Type-III gass contaners may be used for non- parentera
stere products such as Otc Soutons.
(() =. P!asti* C#tai#ers
11.9.1. Pre-formed pastc contaners ntended to be used for the packng of Large
Voume Parentera sha be mouded n-house by one-contnuous operaton through
an automatc machne.
11.9.2. Bowng, ng and seang (puggng) operatons sha be conducted n
room(s) conformng to requrements as mentoned n Tabe III of Item 3.10. Entry to
the area where such operatons are undertaken, sha be through a seres of ar
ocks. Bowers sha have an ar suppy whch s tered though 0.22 mcrons ters.
Remova of runners and puggng operatons sha be conducted under a amnar
arow work staton.
(()(>)
RuBBer st..ers
11.10.1. The rubber stoppers used for Large Voume Parenteras sha compy wth
speccatons prescrbed n the current edton of the
Indan Pharmacopoea.
(,. D*u/e#tati#
12. 1. The manufacturng records reatng to manufacture of stere products sha
ndcate the foowng detas : -
"'.Sera number of the Batch Manufacturng Record.
"8.Name of the product.
"9.Reference to Master Formua Record.
":.Batch / Lot number.
#4.Batch / Lot sze.
#".Date of commencement of manufacture and date of competon of
manufacture.
##.Date of manufacture and assgned date of expry.
#$.Date of each step n manufacturng.
#%.Names of a ngredents wth the
grade gven by the quaty contro department.
#&.Ouantty of a ngredents.
#'.Contro reference numbers for a ngredents.
#8.Tme and duraton of bendng, mxng etc. whenever appcabe.
#9.pH of souton whenever appcabe.
#:.Fter ntegrty testng records.
$4.Temperature and humdty records whenever appcabe.
$".Records of pate-counts whenever appcabe.
$#.Resuts of pyrogen and/or bactera endotoxn & toxcty.
$$.Records of weght or voume of drug ed n contaners.
$%.Buk sterty n case of aseptcay ed products.
$&.Leak test records.
$'.Inspecton records.
$8.Sterzaton records ncudng autocave eakage test records, oad
detas, date, duraton , temperature, pressure etc.
$9.Contaner washng records.
$:.Tota number of contaners ed.
%4.Tota numbers of contaners re|ected at each stage.
%".Theoretca yed, permssbe yed, actua yed and varaton thereof.
%#.Carcaton for varaton n yed beyond permssbe yed.
%$.Reference numbers of reevant anaytca reports.
%%.Detas of reprocessng, f any.
%&.Name of a operators carryng out dherent actvtes.
%'.Envronmenta montorng records.
%8.Specmens of prnted packagng matera.
%9.Records of destructon of re|ected contaners and prnted packagng
materas.
%:.Sgnature of the competent technca stah responsbe for manufacture
and testng.
(otes )-
&4.Products shall be released only after complete 0llin! and testin!.
&".;esult of the tests relatin! to sterility, pyro!ens, and
*acterial endotoins shall be maintained in the analytical records.
&#.<alidation details and simulation trial records shall be maintained
separately.
&$.;ecords of en.ironmental monitorin! li=e temperature, humidity,
microbiolo!ical data etc. shall be maintained. ;ecords of periodic
ser.icin! of 1EP2 0lters, sterili,ers and other periodic maintenance of
facilities and equipment carried out shall also be maintained.
&%.Separate facilities shall be pro.ided for 0llin!-cum-sealin! of Small
<olume In>ectables and Lar!e <olume Parenterals.
&&.Separate factes sha be provded for manufacture of Large Voume
parenteras n gass contaners and pastc contaners.

ORAL SOLID DOSAGE FORMS %TABLETS AND CAPSULES&
Note : Good 5anufacturin! Practices for Premises and materials for pharmaceutical
products shall be complied /ith the manufacture of oral Solid Dosa!e ?orms
@-ablets and capsulesA. In addition to these requirements, the follo/in! Speci0c
;equirements shall also be follo/ed, namely) -
2) Ge#era!
1. 1. The processng of dry materas and products creates probems of dust contro
and cross-contamnaton. Speca attenton s, therefore, needed n the desgn,
mantenance and use of premses and equpment n order to overcome these
probems. Wherever requred, encosed dust contro manufacturng systems sha be
empoyed.
1.2. Sutabe envronmenta condtons for the products handed sha be mantaned
by nstaaton of ar-condtonng wherever necessary. Ehectve ar-extracton
systems, wth dscharge ponts stuated to avod contamnaton of other products
and processes sha be provded. Fters sha be nstaed to retan dust and to
protect the factory and oca envronment.
1. 3 Speca care sha be taken to protect aganst subsequent contamnaton of the
product by partces of meta or wood. The use of meta detector s recommended.
Wooden equpment shoud be avoded. Screens, seves, punches and des sha be
examned for wear and tear or for breakage before and after each use.
1. 4. A ngredents for a dry product sha be sfted before use uness the quaty of
the nput matera can be assured. Such sftng sha normay be carred out at
dedcated areas.
1. 5. Where the factes are desgned to provde speca envronmenta condtons
of pressure dherentas between rooms, these condtons sha be reguary
montored and any speccaton resuts brought to the mmedate attenton of the
Producton and Ouaty assurance departments whch sha be mmedatey attended
to.
1. 6. Care sha be taken to guard aganst any matera odgng and remanng
undetected n any processng or packagng equpment. Partcuar care sha be taken
to ensure that any vacuum, compressed ar or ar-extracton nozzes are kept cean
and that there s no evdence of ubrcants eakng nto the product from any part of
the equpments.
6) Si3ti#"9 /i<i#" a#d "ra#u!ati#
2. 1. Uness operated as a cosed system, mxng, sftng and bendng equpments
sha be tted wth dust extractors.
2.2 Resdues from sevng operatons sha be examned perodcay for evdence of
the presence of unwanted materas.
2. 3. Crtca operatng parameters ke tme and temperature for each mxng,
bendng and dryng operaton sha be speced n a Master Formua, montored
durng processng, and recorded n the batch records.
2. 4. Fter bags tted to ud-bed-drer sha not be used for dherent products,
wthout beng washed n-between use. Wth certan hghy potent or senstsng
products, bags specc to one product ony sha be used. Ar enterng the drer sha
be tered. Steps sha be taken to prevent contamnaton of the ste and oca
envronment by dust n the ar eavng the drer due to cose postonng of the ar-
nets and exhaust.
2. 5. Granuaton and coatng soutons sha be made, stored and used n a manner
whch mnmses the rsk of contamnaton or mcroba growth.
7) C/.ressi# %TaB!ets&
3. 1. Each tabet compressng machne sha be provded wth ehectve dust contro
factes to avod cross contamnaton. Uness the same product s beng made on
each machne, or uness the compresson machne tsef provdes ts own encosed
ar controed envronment, the machne sha be nstaed n separate cubces.
3. 2. Sutabe physca, procedura and abeng arrangements sha be made to
prevent mx-up of materas, granues and tabets on compresson machnery.
3. 3. Accurate and cabrated weghng equpment sha be ready avaabe and
used for n-process montorng of tabet weght varaton. Procedures used sha be
capabe of detectng out-of-mts tabets.
3. 4. At the commencement of each compresson run and n case of mutpe
compresson ponts n a compresson machne, sumcent ndvdua tabets sha be
examned at xed ntervas to ensure that a tabet from each compresson staton or
from each compresson pont has been nspected for sutabe pharmacopoea
parameters ke 'appearance', 'weght varaton', 'dsntegraton', 'hardness',
'frabty' and 'thckness'. The resuts sha be recorded as part of the batch
documentaton.
3. 5. Tabets sha be de-dusted, preferaby by automatc devce and sha be
montored for the presence of foregn materas besdes any other defects.
3. 6. Tabets sha be coected nto cean, abeed contaners.
3. 7. Re|ected or dscarded tabets sha be soated n dented contaners and ther
quantty recorded n the Batch Manufacturng Record.
3. 8. In-process contro sha be empoyed to ensure that the products reman wthn
speccaton. Durng compresson, sampes of tabets sha be taken at reguar
ntervas of not greater than 30 mnutes to ensure that they are beng produced n
compance wth speced n-process speccaton. The tabets sha aso be
perodcay checked for addtona parameters such as 'appearance', 'weght
varaton', 'dsntegraton', 'hardness', 'frabty ' and 'thckness' and contamnaton
by ubrcatng o.
8) Cati#" %TaB!ets&
4. 1. Ar supped to coatng pans for dryng purposes sha be tered ar and of
sutabe quaty. The area sha be provded wth sutabe exhaust system and
envronmenta contro (temperature, humdty) measures.
4. 2. Coatng soutons and suspensons sha be made afresh and used n a manner,
whch sha mnmse the rsk of mcroba growth. Ther preparaton and use sha be
documented and recorded.
;) Fi!!i#" 3 Hard Ge!ati# Ca.su!e
Empty capsues shes sha be regarded as 'drug component' and treated
accordngy. They sha be stored under condtons whch sha ensure ther safety
from the ehects of excessve heat and mosture.
=) Pri#ti#" %TaB!ets A#d Ca.su!es&
6. 1. Speca care sha be taken to avod product mx-up durng any prntng of
tabets and capsues. Where dherent products, or dherent batches of the same
product, are prnted smutaneousy, the operatons sha adequatey be segregated.
Edbe grade coours and sutabe prntng nk sha be used for such prntng.
6. 2. After prntng, tabets and capsues sha be approved by Ouaty Contro before
reease for packagng or sae.
(>) Pa*Aa"i#" %Stri. a#d -!ister&
7. 1. Care sha be taken when usng automatc tabet and capsue countng, strp
and bster packagng equpment to ensure that a 'rogue' tabets, capsues or fos
from packagng operaton are removed before a new packagng operaton s
commenced. There sha be an ndependent recorded check of the equpment
before a new batch of tabets or capsues s handed.
7. 2. Uncoated tabets sha be packed on equpment desgned to mnmse the rsk
of cross-contamnaton. Such packagng sha be carred out n an soated area
when potent tabets or Beta-actum contanng tabets are beng packed.
7. 3. The strps comng out of the machne sha be nspected for defects such as
msprnt, cuts on the fo, mssng tabets and mproper seang.
7. 4. Integrty of ndvdua packagng strps and bsters sha be sub|ected to
vacuum test perodcay to ensure eak proofness of each pocket strp
and bster
and records mantaned.
ORAL LI'UIDS %S5RUPS9 ELIDIRS9 EMULSIONS AND SUSPENSIONS&
Note : -he General ;equirements as !i.en in Good 5anufacturin! Practices for
Premises and 5aterials for pharmaceutical products shall be complied /ith the
manufacture of @ Syrups , Eliirs, Emulsions and Suspensions A. In addition to these
requirements, the follo/in! Speci0c ;equirements shall also be follo/ed, namely
(() -ui!di#" A#d Equi./e#t
1. 1. The premses and equpment sha be desgned, constructed and mantaned to
sut the manufacturng of Ora Lquds. The ayout and desgn of the manufacturng
area sha strve to mnmze the rsk of cross- contamnaton and mx-ups.
1. 2. Manufacturng area sha have entry through doube door ar-ock facty. It
sha be made y proof by use of ' y catcher' and / or 'ar curtan'.
1. 3. Dranage sha be of adequate sze and have adequate traps, wthout open
channes and the
desgn sha be such as to prevent back ow. Drans sha be shaow to factate
ceanng and dsnfectng.
1. 4. The producton area sha be ceaned and santsed at the end of every
producton process.
1. 5. Tanks, contaners, ppe work and pumps sha be desgned and nstaed so that
they can be easy ceaned and santzed. Equpment desgn sha be such as to
prevent accumuaton of resdua mcroba growth or cross-contamnaton.
1. 6. Staness Stee or any other approprate matera sha be used for parts of
equpments comng n drect contact wth the products. The use of gass apparatus
sha be mnmum.
1. 7. Arrangements for ceanng of contaners, cosures and droppers sha be made
wth the hep of sutabe machnes/devces equpped wth hgh pressure ar, water
and steam |ets.
1. 8. The furnture used sha be smooth, washabe and made of staness stee.
(,) PuriEed Water
2. 1. The chemca and mcroboogca quaty of pured water used sha be
speced and montored routney. The mcroboogca evauaton sha ncude
testng for absence of pathogens and sha not exceed 100 cfu / m (as per Appendx
12.5 of IP 1996).
2. 2. There sha be a wrtten procedure for operaton and mantenance of the
pured water system. Care sha be taken to avod the rsk of mcroba proferaton
wth approprate methods ke recrcuaton, use of UV treatment, treatment wth
heat and santzng agent. After any chemca santsaton of the water system, a
ushng sha be done to ensure that the
santzng agent has been ehectvey removed.
(1) Ma#u3a*turi#"
3. 1. Manufacturng personne sha wear non-ber sheddng cothng to prevent
contamnaton of the product.
3. 2. Materas key to shed ber ke gunny bags, or wooden paets sha not be
carred nto the area where products or ceaned- contaners are exposed.
3. 3. Care sha be taken to mantan the homogenty of emuson by use of
approprate emuser and suspensons by use of approprate strrer durng ng.
Mxng and ng processes sha be speced and montored. Speca care sha be
taken at the begnnng of the ng process, after stoppage due to any nterrupton
and at the end of the process to ensure that the product s unformy homogenous
durng the ng process.
3. 4. The prmary packagng area sha have an ar suppy whch s tered through 5
mcron ters. The temperature of the area sha not exceed 30 degrees centgrade.
3. 5. When the buk product s not mmedatey packed, the maxmum perod of
storage and storage condtons sha be speced n the Master Formua. The
maxmum perod of storage tme of a product n the buk stage sha be vadated.
EDTERNAL PREPARATIONS %CREAMS9 OINTMENTS9 PASTES9 EMULSIONS9
LOTIONS9 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 the
manufacture of -opical Products i.e. Eternal Preparations @+reams, 6intments,
Pastes, Emulsions, Lotions, Solutions, Dustin! po/ders and identical products used
for eternal applicationsA. In addition to these requirements, the follo/in! Speci0c
;equirements shall also be follo/ed, namely )
1.The entrance to the area where topca products are manufactured sha be
through a sutabe arock. Outsde the arock, nsectocutors sha be nstaed.
2.The ar to ths manufacturng area sha be tered through at east 20 ar ters
and sha be ar-condtoned. The area sha be ventated.
3.The area sha be tted wth an exhaust system of
sutabe capacty to ehectvey remove vapours, fumes, smoke or oatng dust
partces.
4.The
equpment used sha be desgned and mantaned to prevent the product from
beng accdentay contamnated wth any foregn matter or ubrcant.
5.No rags or dusters sha be used n the process of ceanng or dryng the process
equpment or accessores used.
6.Water used n compoundng sha be Pured Water IP.
7.Powders, whenever used, sha be sutaby seved before use.
8.Heatng vehces and a
base ke petroeum |ey sha be done n a separate mxng area n sutabe
staness stee vesses, usng steam, gas, eectrcty, soar energy etc.
9.A separate packng secton may be provded for prmary packagng of the
products.
METERED 0 DOSE INHALERS %MDI&
Nte F
-he General ;equirements as !i.en inf Good 5anufacturin! Practices for premises
and 5aterials for pharmaceutical products shall be complied /ith the manufacture
of 5etered-Dose-Inhalers @5DIA. In addition to these requirements, the follo/in!
Speci0c ;equirements shall also be follo/ed, namely )
(2) Ge#era!
Manufacture of Metered-Dose-Inhaers sha be done under condtons whch sha
ensure mnmum mcroba and partcuate contamnaton. Assurance of the quaty
of components and the buk product s very mportant. Where medcaments are n
suspended state, unformty of suspenson sha be estabshed.
(6) -ui!di#" a#d *i@i! 4rAs
2. 1. The budng sha be ocated on a sod foundaton to reduce rsk of crackng
was and oor due to the
movement of equpment and machnery.
2. 2. A budng surfaces sha be mpervous, smooth and non-sheddng. Foorng
sha be contnuous and provded wth a cover between the oor and the wa as we
as between the wa and the ceng. Ceng sha be sod, contnuous and
proceeded a cone wth the was. Lght ttngs and ar-grs sha be ush wth the
ceng. A servce nes requrng mantenance sha be erected n such a manner
that these are accessbe from outsde the producton area.
2. 3. The manufacturng area sha be segregated nto change rooms for personne,
contaner preparaton area, buk preparaton and ng area, quarantne area and
spray testng and packng areas.
2. 4. Secondary change rooms sha be provded for operators to change from
factory cothng to speca departmenta cothng before enterng the manufacturng
and ng area.
2. 5. Separate area sha be provded for de-cartonng of components before they
are ar washed.
2. 6. The propeants used for manufacture sha be devered to the manufacturng
area dstrbuton system by terng them through 2 mcron ters. The buk
contaners of propeants sha be stored, sutaby dented, away from the
manufacturng factes.
(7) E#@ir#/e#ta! C#diti#s
3. 1. Where products or cean components are exposed, the area sha be supped
wth tered ar of Grade C.
3. 2. The requrements of temperature and humdty n the manufacturng area sha
be decded dependng on the type of product and propeants handed n the facty.
Other support areas sha have comfort eves of temperature and humdty.
3. 3. There sha be a dherence n room pressure between the manufacturng area
and the support areas and the dherenta pressure sha be not ess than 15 Pascas,
(0.06 nches or 1.5 mm Water gauge).
3. 4. There sha be a wrtten schedue for the montorng of envronmenta
condtons. Temperature and humdty sha be montored day.
(8) Gar/e#ts
4. 1. Personne n the manufacturng and ng secton sha wear sutabe snge-
pece-garment made out of non-sheddng, tght weave matera. Personne n
support areas sha wear cean factory unforms.
4. 2. Goves made of sutabe matera havng no nteracton wth the propeants
sha be used by the operators n the manufacturng and ng areas. Preferaby,
dsposabe goves sha be used.
4. 3. Sutabe department+specc personne protectve equpment ke footwear and
safety gasses sha be used wherever hazard exsts.
(;) Sa#itati#
5. 1. There sha be wrtten procedures for the santaton of the MDI manufacturng
facty. Speca care shoud be taken to hande resdues and rnses of propeants.
5. 2. Use of water for ceanng sha be restrcted and controed. Routney used
dsnfectants are sutabe for santsng the dherent areas. Records of santaton
sha be mantaned.
(=) Equi./e#t
6. 1. Manufacturng equpment sha be of cosed system. The vesses and suppy
nes sha be of staness stee.
6. 2. Sutabe check weghts, spray testng machnes and abeng machnes sha be
provded n the department.
6. 3. A the equpment sha be sutaby cabrated and ther performance vadated
on recept and thereafter perodcay.
,>) Ma#u3a*ture
7. 1. There sha be an approved master formua records for the manufacture of
metered dose nhaers. A propeants, quds and gases sha be tered through 2
mcron ters to remove partces.
7. 2. The prmary packng matera sha be appropratey ceaned by compressed ar
sutaby tered through 0.2 mcron ter. The humdty of the compressed ar sha
be controed as appcabe.
7. 3. The vaves sha be carefuy handed and after de-cartonng, these sha be
kept n cean9 cosed contaners n the ng room.
7. 4. For suspensons, the buk sha be kept strred contnuousy.
7. 5. In-process contros sha ncude perodca checkng of weght of buk
formuaton ed n the contaners. In a two-shot-ng process (qud ng
foowed by gaseous ng), t sha be ensured that 100 % check on
weght s carred out.
7. 6. Fed contaners sha be quarantned for a
sutabe perod estabshed by the manufacturer to detect eakng contaners pror to
testng, abeng and packng.
,() D*u/e#tati#
8. 1. In addton to the routne good manufacturng practces documentaton of
manufacturng records sha be show the foowng addtona nformaton:-
( 1 ) Temperature and humdty n the manufacturng area.
( 2 ) Perodc ed weghts of the formuaton.
( 3 ) Records of re|ectons durng on ne check weghng.
( 4 ) Records of re|ecton durng spray testng.

CONCLUSION
The quaty and purty of the pharmaceutca product depends on the Condton
mantaned durng the manufacturng process. The Good Manufacturng
Process(GMP) concept strcty adhere to strngent speccatons foowed durng the
manufacturng process. Ths assure the quaty of the na product. Hence GMP s
very essenta to provde quaty products and thereby preventng the market entry
for countert drug.



REFERENCE

". The prncpa rues were pubshed n the omca gazette vde
notcaton No. F.28-10/45-H(1) dated 21
st
December 1945 and ast
amended vde GSR 700(E) dated 28-09-2001
#. The drug and cosmetc rues, 1945, as amended upto 01-05-1979 s
contaned n the pubcaton of the mnstry of heath and famy
wefare (department of heath) contanng the drug and cosmetcs act
1940 (PDGHS-61).
$. Goba programme for vaccnes suppy and quaty wrtten by Gan
Chaoner - Larsson, Roger Anderson and Ank Egan.
%. www.usfda.com
&. A pan for tota quaty contro by P.P. Sharma
'. Companon voume to a HANDBOOK OF DRUG LAWS by M.L. Mehra
8. www.gmp.com