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CHAPTER 5 PRODUCTION
Principle
Pr oducti on oper ati ons must fol l ow cl ear l y defi ned pr ocedur es; they must compl y wi th the
pr i nci pl es of Good Manufactur i ng Pr acti ce i n or der to obtai n pr oducts of the r equi si te
qual i ty and be i n accor dance wi th the r el evant manufactur i ng and mar keti ng
authori sati ons.
General
5.1 Producti on shoul d be performed and supervi sed by competent peopl e.
5.2 Al l handl i ng of materi al s and products, such as recei pt and quaranti ne, sampl i ng, storage,
l abel l i ng, di spensi ng, processi ng, packagi ng and di stri buti on shoul d be done i n accordance
wi th wri tten procedures or i nstructi ons and, where necessary, recorded.
5.3 Al l i ncomi ng mater i al s shoul d be checked to ensur e that the consi gnment cor r esponds to
the order. Contai ners shoul d be cl eaned where necessary and l abel l ed wi th the prescri bed
data.
5.4 Damage to contai ners and any other probl em whi ch mi ght adversel y affect the qual i ty of a
materi al shoul d be i nvesti gated, recorded and reported to the Qual i ty Control Department.
5.5 I ncomi ng mater i al s and fi ni shed pr oducts shoul d be physi cal l y or admi ni str ati vel y
quaranti ned i mmedi atel y after recei pt or processi ng, unti l they have been rel eased for use
or di stri buti on.
5.6 I ntermedi ate and bul k products purchased as such shoul d be handl ed on recei pt as though
they were starti ng materi al s.
5.7 Al l mater i al s and pr oducts shoul d be stor ed under the appr opr i ate condi ti ons establ i shed
by the manufactur er and i n an or der l y fashi on to per mi t batch segr egati on and stock
rotati on.
5.8 Checks on yi el ds, and r econci l i ati on of quanti ti es, shoul d be car r i ed out as necessar y to
ensure that there are no di screpanci es outsi de acceptabl e l i mi ts.
5.9 Operati ons on di fferent products shoul d not be carri ed out si mul taneousl y or consecuti vel y
i n the same room unl ess there i s no ri sk of mi x-up or cross-contami nati on.
5.10 At every stage of processi ng, products and materi al s shoul d be protected from mi crobi al and
other contami nati on.
5.11 When wor ki ng wi th dr y mater i al s and pr oducts, speci al pr ecauti ons shoul d be taken to
prevent the generati on and di ssemi nati on of dust. Thi s appl i es parti cul arl y to the handl i ng
of hi ghl y acti ve or sensi ti si ng materi al s.
5.12 At al l ti mes dur i ng pr ocessi ng, al l mater i al s, bul k contai ner s, major i tems of equi pment
and wher e appr opr i ate r ooms used shoul d be l abel l ed or other wi se i denti fi ed wi th an
i ndi cati on of the pr oduct or mater i al bei ng pr ocessed, i ts str ength (wher e appl i cabl e) and
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I Chapter 5 Production ___________________________________________________
batch number . Wher e appl i cabl e, thi s i ndi cati on shoul d al so menti on the stage of
producti on.
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___________________________________________________Chapter 5 Production I
5.13 Label s appl i ed to contai ners, equi pment or premi ses shoul d be cl ear, unambi guous and i n
the companys agreed format. I t i s often hel pful i n addi ti on to the wordi ng on the l abel s to
use col ours to i ndi cate status (for exampl e, quaranti ned, accepted, rejected, cl ean, ...).
5.14 Checks shoul d be car r i ed out to ensur e that pi pel i nes and other pi eces of equi pment used
for the tr anspor tati on of pr oducts fr om one ar ea to another ar e connected i n a cor r ect
manner.
5.15 Any devi ati on fr om i nstr ucti ons or pr ocedur es shoul d be avoi ded as far as possi bl e. I f a
devi ati on occur s, i t shoul d be appr oved i n wr i ti ng by a competent per son, wi th the
i nvol vement of the Qual i ty Control Department when appropri ate.
5.16 Access to producti on premi ses shoul d be restri cted to authori sed personnel .
5.17 Nor mal l y, the pr oducti on of non-medi ci nal pr oducts shoul d be avoi ded i n ar eas and wi th
the equi pment desti ned for the producti on of medi ci nal products.
Prevention of cross-contamination in production
5.18 Contami nati on of a starti ng materi al or of a product by another materi al or product must
be avoi ded. Thi s ri sk of acci dental cross-contami nati on ari ses from the uncontrol l ed rel ease
of dust, gases, vapours, sprays or organi sms from materi al s and products i n process, from
r esi dues on equi pment, and fr om oper ator s cl othi ng. The si gni fi cance of thi s r i sk var i es
wi th the type of contami nant and of pr oduct bei ng contami nated. Amongst the most
hazar dous contami nants ar e hi ghl y sensi ti si ng mater i al s, bi ol ogi cal pr epar ati ons
contai ni ng l i vi ng or gani sms, cer tai n hor mones, cytotoxi cs, and other hi ghl y acti ve
mater i al s. Pr oducts i n whi ch contami nati on i s l i kel y to be most si gni fi cant ar e those
admi ni stered by i njecti on, those gi ven i n l arge doses and/or over a l ong ti me.
5.19 Cr oss-contami nati on shoul d be avoi ded by appr opr i ate techni cal or or gani sati onal
measures, for exampl e:
a) pr oducti on i n segr egated ar eas (r equi r ed for pr oducts such as peni ci l l i ns, l i ve
vacci nes, l i ve bacter i al pr epar ati ons and some other bi ol ogi cal s), or by campai gn
(separati on i n ti me) fol l owed by appropri ate cl eani ng;
b) provi di ng appropri ate ai r-l ocks and ai r extracti on;
c) mi ni mi si ng the ri sk of contami nati on caused by reci rcul ati on or re-entry of untreated
or i nsuffi ci entl y treated ai r;
d) keepi ng pr otecti ve cl othi ng i nsi de ar eas wher e pr oducts wi th speci al r i sk of cr oss-
contami nati on are processed;
e) usi ng cl eani ng and decontami nati on procedures of known effecti veness, as i neffecti ve
cl eani ng of equi pment i s a common source of cross-contami nati on;
f) usi ng cl osed systems of producti on;
g) testi ng for resi dues and use of cl eani ng status l abel s on equi pment.
5.20 Measur es to pr event cr oss-contami nati on and thei r effecti veness shoul d be checked
peri odi cal l y accordi ng to set procedures.
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I Chapter 5 Production ___________________________________________________
Validation
5.21 Val i dati on studi es shoul d r ei nfor ce Good Manufactur i ng Pr acti ce and be conducted i n
accordance wi th defi ned procedures. Resul ts and concl usi ons shoul d be recorded.
5.22 When any new manufacturi ng formul a or method of preparati on i s adopted, steps shoul d be
taken to demonstr ate i ts sui tabi l i ty for r outi ne pr ocessi ng. The defi ned pr ocess, usi ng the
mater i al s and equi pment speci fi ed, shoul d be shown to yi el d a pr oduct consi stentl y of the
requi red qual i ty.
5.23 Si gni fi cant amendments to the manufacturi ng process, i ncl udi ng any change i n equi pment
or mater i al s, whi ch may affect pr oduct qual i ty and/or the r epr oduci bi l i ty of the pr ocess
shoul d be val i dated.
5.24 Processes and procedures shoul d undergo peri odi c cri ti cal re-val i dati on to ensure that they
remai n capabl e of achi evi ng the i ntended resul ts.
Starting materials
5.25 The pur chase of star ti ng mater i al s i s an i mpor tant oper ati on whi ch shoul d i nvol ve staff
who have a parti cul ar and thorough knowl edge of the suppl i ers.
5.26 Star ti ng mater i al s shoul d onl y be pur chased fr om appr oved suppl i er s named i n the
r el evant speci fi cati on and, wher e possi bl e, di r ectl y fr om the pr oducer . I t i s r ecommended
that the speci fi cati ons establ i shed by the manufactur er for the star ti ng mater i al s be
di scussed wi th the suppl i ers. I t i s of benefi t that al l aspects of the producti on and control of
the star ti ng mater i al i n questi on, i ncl udi ng handl i ng, l abel l i ng and packagi ng
r equi r ements, as wel l as compl ai nts and r ejecti on pr ocedur es ar e di scussed wi th the
manufacturer and the suppl i er.
5.27 For each del i ver y, the contai ner s shoul d be checked for i ntegr i ty of package and seal and
for correspondence between the del i very note and the suppl i ers l abel s.
5.28 I f one materi al del i very i s made up of di fferent batches, each batch must be consi dered as
separate for sampl i ng, testi ng and rel ease.
5.29 Star ti ng mater i al s i n the stor age ar ea shoul d be appr opr i atel y l abel l ed (see Chapter 5,
i tem13). Label s shoul d bear at l east the fol l owi ng i nformati on:
the desi gnated name of the product and the i nternal code reference where appl i cabl e;
a batch number gi ven at recei pt;
wher e appr opr i ate, the status of the contents (e.g. i n quar anti ne, on test, r el eased,
rejected);
where appropri ate, an expi ry date or a date beyond whi ch retesti ng i s necessary.
When ful l y computer i sed stor age systems ar e used, al l the above i nfor mati on need not
necessari l y be i n a l egi bl e form on the l abel .
5.30 There shoul d be appropri ate procedures or measures to assure the i denti ty of the contents
of each contai ner of star ti ng mater i al . Bul k contai ner s fr om whi ch sampl es have been
drawn shoul d be i denti fi ed (see Chapter 6, i tem 13).
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___________________________________________________Chapter 5 Production I
5.31 Onl y starti ng materi al s whi ch have been rel eased by the Qual i ty Control Department and
whi ch are wi thi n thei r shel f l i fe shoul d be used.
5.32 Star ti ng mater i al s shoul d onl y be di spensed by desi gnated per sons, fol l owi ng a wr i tten
pr ocedur e, to ensur e that the cor r ect mater i al s ar e accur atel y wei ghed or measur ed i nto
cl ean and properl y l abel l ed contai ners.
5.33 Each di spensed materi al and i ts wei ght or vol ume shoul d be i ndependentl y checked and the
check recorded.
5.34 Mater i al s di spensed for each batch shoul d be kept together and conspi cuousl y l abel l ed as
such.
Processing operations: intermediate and bulk products
5.35 Befor e any pr ocessi ng oper ati on i s star ted, steps shoul d be taken to ensur e that the wor k
ar ea and equi pment ar e cl ean and fr ee fr om any star ti ng mater i al s, pr oducts, pr oduct
resi dues or documents not requi red for the current operati on.
5.36 I ntermedi ate and bul k products shoul d be kept under appropri ate condi ti ons.
5.37 Cri ti cal processes shoul d be val i dated (see "VALI DATI ON" i n thi s Chapter).
5.38 Any necessar y i n-pr ocess contr ol s and envi r onmental contr ol s shoul d be car r i ed out and
recorded.
5.39 Any si gni fi cant devi ati on from the expected yi el d shoul d be recorded and i nvesti gated.
Packaging materials
5.40 The pur chase, handl i ng and contr ol of pr i mar y and pr i nted packagi ng mater i al s shal l be
accorded attenti on si mi l ar to that gi ven to starti ng materi al s.
5.41 Par ti cul ar attenti on shoul d be pai d to pr i nted mater i al s. They shoul d be stor ed i n
adequatel y secure condi ti ons such as to excl ude unauthori sed access. Cut l abel s and other
l oose pri nted materi al s shoul d be stored and transported i n separate cl osed contai ners so as
to avoi d mi x-ups. Packagi ng mater i al s shoul d be i ssued for use onl y by author i sed
personnel fol l owi ng an approved and documented procedure.
5.42 Each del i very or batch of pri nted or pri mary packagi ng materi al shoul d be gi ven a speci fi c
reference number or i denti fi cati on mark.
5.43 Outdated or obsol ete pri mary packagi ng materi al or pri nted packagi ng materi al shoul d be
destroyed and thi s di sposal recorded.
Packaging operations
5.44 When setti ng up a programme for the packagi ng operati ons, parti cul ar attenti on shoul d be
gi ven to mi ni mi si ng the r i sk of cr oss-contami nati on, mi x-ups or substi tuti ons. Di ffer ent
products shoul d not be packaged i n cl ose proxi mi ty unl ess there i s physi cal segregati on.
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I Chapter 5 Production ___________________________________________________
5.45 Before packagi ng operati ons are begun, steps shoul d be taken to ensure that the work area,
packagi ng l i nes, pr i nti ng machi nes and other equi pment ar e cl ean and fr ee fr om any
products, materi al s or documents previ ousl y used, i f these are not requi red for the current
operati on. The l i ne-cl earance shoul d be performed accordi ng to an appropri ate check-l i st.
5.46 The name and batch number of the pr oduct bei ng handl ed shoul d be di spl ayed at each
packagi ng stati on or l i ne.
5.47 Al l pr oducts and packagi ng mater i al s to be used shoul d be checked on del i ver y to the
packagi ng depar tment for quanti ty, i denti ty and confor mi ty wi th the Packagi ng
I nstructi ons.
5.48 Contai ner s for fi l l i ng shoul d be cl ean befor e fi l l i ng. Attenti on shoul d be gi ven to avoi di ng
and removi ng any contami nants such as gl ass fragments and metal parti cl es.
5.49 Normal l y, fi l l i ng and seal i ng shoul d be fol l owed as qui ckl y as possi bl e by l abel l i ng. I f i t i s
not the case, appr opr i ate pr ocedur es shoul d be appl i ed to ensur e that no mi x-ups or
mi sl abel l i ng can occur.
5.50 The correct performance of any pri nti ng operati on (for exampl e code numbers, expi ry dates)
to be done separ atel y or i n the cour se of the packagi ng shoul d be checked and r ecor ded.
Attenti on shoul d be pai d to pr i nti ng by hand whi ch shoul d be r e-checked at r egul ar
i nterval s.
5.51 Speci al car e shoul d be taken when usi ng cut-l abel s and when over -pr i nti ng i s car r i ed out
off-l i ne. Rol l -feed l abel s are normal l y preferabl e to cut-l abel s, i n hel pi ng to avoi d mi x-ups.
5.52 Checks shoul d be made to ensure that any el ectroni c code readers, l abel counters or si mi l ar
devi ces are operati ng correctl y.
5.53 Pri nted and embossed i nformati on on packagi ng materi al s shoul d be di sti nct and resi stant
to fadi ng or erasi ng.
5.54 On-l i ne contr ol of the pr oduct dur i ng packagi ng shoul d i ncl ude at l east checki ng the
fol l owi ng:
a) general appearance of the packages;
b) whether the packages are compl ete;
c) whether the correct products and packagi ng materi al s are used;
d) whether any over-pri nti ng i s correct;
e) correct functi oni ng of l i ne moni tors.
Sampl es taken away from the packagi ng l i ne shoul d not be returned.
5.55 Pr oducts whi ch have been i nvol ved i n an unusual event shoul d onl y be r ei ntr oduced i nto
the pr ocess after speci al i nspecti on, i nvesti gati on and appr oval by author i sed per sonnel .
Detai l ed record shoul d be kept of thi s operati on.
5.56 Any si gni fi cant or unusual di screpancy observed duri ng reconci l i ati on of the amount of bul k
pr oduct and pr i nted packagi ng mater i al s and the number of uni ts pr oduced shoul d be
i nvesti gated and sati sfactori l y accounted for before rel ease.
5.57 Upon compl eti on of a packagi ng oper ati on, any unused batch-coded packagi ng mater i al s
shoul d be destr oyed and the destr ucti on r ecor ded. A documented pr ocedur e shoul d be
fol l owed i f uncoded pri nted materi al s are returned to stock.
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___________________________________________________Chapter 5 Production I
Finished products
5.58 Fi ni shed pr oducts shoul d be hel d i n quar anti ne unti l thei r fi nal r el ease under condi ti ons
establ i shed by the manufacturer.
5.59 The eval uati on of fi ni shed products and documentati on whi ch i s necessary before rel ease of
product for sal e are descri bed i n Chapter6 (Qual i ty Control ).
5.60 After r el ease, fi ni shed pr oducts shoul d be stor ed as usabl e stock under condi ti ons
establ i shed by the manufacturer.
Rejected, recovered and returned materials
5.61 Rejected materi al s and products shoul d be cl earl y marked as such and stored separatel y i n
r estr i cted ar eas. They shoul d ei ther be r etur ned to the suppl i er s or , wher e appr opr i ate,
r epr ocessed or destr oyed. Whatever acti on i s taken shoul d be appr oved and r ecor ded by
authori sed personnel .
5.62 The r epr ocessi ng of r ejected pr oducts shoul d be excepti onal . I t i s onl y per mi tted i f the
qual i ty of the fi nal product i s not affected, i f the speci fi cati ons are met and i f i t i s done i n
accordance wi th a defi ned and authori sed procedure after eval uati on of the ri sks i nvol ved.
Record shoul d be kept of the reprocessi ng.
5.63 The r ecover y of al l or par t of ear l i er batches whi ch confor m to the r equi r ed qual i ty by
i ncorporati on i nto a batch of the same product at a defi ned stage of manufacture shoul d be
author i sed befor ehand. Thi s r ecover y shoul d be car r i ed out i n accor dance wi th a defi ned
procedure after eval uati on of the ri sks i nvol ved, i ncl udi ng any possi bl e effect on shel f l i fe.
The recovery shoul d be recorded.
5.64 The need for addi ti onal testi ng of any fi ni shed product whi ch has been reprocessed, or i nto
whi ch a r ecover ed pr oduct has been i ncor por ated, shoul d be consi der ed by the Qual i ty
Control Department.
5.65 Pr oducts r etur ned fr om the mar ket and whi ch have l eft the contr ol of the manufactur er
shoul d be destr oyed unl ess wi thout doubt thei r qual i ty i s sati sfactor y; they may be
consi der ed for r e-sal e, r e-l abel l i ng or r ecover y i n a subsequent batch onl y after they have
been cr i ti cal l y assessed by the Qual i ty Contr ol Depar tment i n accor dance wi th a wr i tten
pr ocedur e. The natur e of the pr oduct, any speci al stor age condi ti ons i t r equi r es, i ts
condi ti on and hi stor y, and the ti me el apsed si nce i t was i ssued shoul d al l be taken i nto
account i n thi s assessment. Wher e any doubt ar i ses over the qual i ty of the pr oduct, i t
shoul d not be consi der ed sui tabl e for r e-i ssue or r e-use, al though basi c chemi cal r e-
pr ocessi ng to r ecover acti ve i ngr edi ent may be possi bl e. Any acti on taken shoul d be
appropri atel y recorded.