Good Manufacturing Practice: Active pharmaceutical ingredient (API) FAQs

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EMEA: Good Manufa turing Pra ti e ! "uestions and answers General Phar#a euti al $oun il %he Medi ines for Hu#an &se ($lini al %rials) Regulations '((): *+ '((),-(.%he Medi ines for Hu#an &se (Manufa turing/ 0holesale 1ealing and Mis ellaneous A#end#ents) Regulations '((2 ! *+ '((2,'345 %he Medi ines for Hu#an &se (Mar6eting Authorisations Et 7) Regulations -55) ! *+ -55),.-))

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-7 +f an AP+ #anufa turer is already supplying a nu#9er of AP+s to a o#pany and they have 9een audited previously to onfir# o#plian e with GMP/ is it ne essary to perfor# another audit if a new AP+ is to 9e sour ed fro# the#; '7 1o AP+ audits have to 9e produ t spe ifi if a nu#9er of AP+s fro# one #anufa turer are used

in the sa#e dosage for#s; .7 Are there any plans to inspe t all AP+ #anufa turers 9y European &nion (E&) Regulatory Authorities; )7 0hat an a o#pany do if an AP+ #anufa turer refuses to sign a te hni al agree#ent; 2a7 A o#pany has an esta9lished produ t whi h re<uires a variation to 9e su9#itted for a parti ular hange7 As part of the hange the o#pany has to su9#it a "P de laration for o#plian e of the AP+ #anufa turer with GMP/ however the AP+ #anufa turer is not #eeting GMP standards7 0hat should the o#pany do; 297 +f the s enario in part a of the <uestion was not for an atypi al a tive 9ut an esta9lished AP+ whi h was not found to 9e in o#plian e with +$H"3A/ does this #ean the "P annot ertify 9at hes #ade with AP+ fro# this site; =7 8or natural and se#i!syntheti AP+s/ how far 9a 6 should you audit for o#plian e with GMP; 37 *o#e e: ipients are o#ing under the sa#e e:pe tations for GMP o#plian e as AP+s7 0hat are the ti#es ales for guidelines; 47 $an a GMP ertifi ate issued 9y an EEA $o#petent Authority/ MRA partners or other re ognised authority 9e used in lieu of an audit 9y a #anufa turing authorisation holder to onfir# GMP $o#plian e of an a tive su9stan e #anufa turer , supplier; -7 +f an AP+ #anufa turer is already supplying a nu#9er of AP+s to a o#pany and they have 9een audited previously to onfir# o#plian e with GMP/ is it ne essary to perfor# another audit if a new AP+ is to 9e sour ed fro# the#; +t #ay not 9e ne essary to re!audit 9ut this will depend upon the e:a t ir u#stan es7 %here should 9e a do u#ented review and ris6 assess#ent to >ustify re eiving the new AP+ fro# the urrent #anufa turer7 %he o#pany?s ongoing audit progra##e should ensure the new AP+ is overed during the ne:t audit7 @Ba 6 to topA '7 1o AP+ audits have to 9e produ t spe ifi if a nu#9er of AP+s fro# one #anufa turer are used in the sa#e dosage for#s; AP+ audits do not have to 9e produ t spe ifi 7 Bou need to onsider what dosage for#s the AP+s are 9eing used in7 %he fo us should 9e on GMP o#plian e7 $hangeovers/ leaning and leaning validation should also 9e reviewed7 Ensure that AP+s are o#ing fro# fa ilities that you have a tually audited7 @Ba 6 to topA .7 Are there any plans to inspe t all AP+ #anufa turers 9y European &nion (E&) Regulatory Authorities; %he E$ proposals to o#9at ounterfeits #entions AP+ #anufa turers/ this is urrently awaiting onsultation feed9a 67 *o#e E& Regulatory Authorities and the European 1ire torate for the "uality of Medi ines C Health$are (E1"M) perfor# audits of AP+ #anufa turers whi h are re orded on the European &nion 1rug Regulatory Authorities (E&1RA) data9ase7 %here is urrently a pilot progra##e 9etween the E&/ the 8ood and 1rug Ad#inistration (81A) and the %herapeuti Goods Ad#inistration (%GA) to share inspe tion out o#es/ fo using on AP+

#anufa turers7 +$H"3 is the internationally re ognised standard used7 +nspe tion findings and reports are shared and so#e >oint inspe tions are 9eing perfor#ed7 *ee European Medi ines Agen y (EMAD we9site for #ore details7 %here is the possi9ility this progra##e will in lude #anufa turing sites in the future7 @Ba 6 to topA )7 0hat an a o#pany do if an AP+ #anufa turer refuses to sign a te hni al agree#ent; %e hni al agree#ents are i#portant to ensure ea h party understands its responsi9ilities/ parti ularly surrounding #anage#ent of hanges7 +f an AP+ #anufa turer refuses to sign an agree#ent/ then an alternate supplier should 9e found7 @Ba 6 to topA 2a7 A o#pany has an esta9lished produ t whi h re<uires a variation to 9e su9#itted for a parti ular hange7 As part of the hange the o#pany has to su9#it a "P de laration for o#plian e of the AP+ #anufa turer with GMP/ however the AP+ #anufa turer is not #eeting GMP standards7 0hat should the o#pany do; +f the AP+ is an atypi al a tive (eg honey or gly erine and phar#a euti al 9usiness is s#all volu#e of sales) then the e:pe tations are that there should 9e a lear spe ifi ation/ the site should have 9een audited/ hanges should 9e ontrolled/ appropriate he 6s should 9e #ade on in o#ing goods7 Ea h atypi al a tive s enario should 9e assessed on a ase 9y ase 9asis7 @Ba 6 to topA 297 +f the s enario in part a of the <uestion was not for an atypi al a tive 9ut an esta9lished AP+ whi h was not found to 9e in o#plian e with +$H"3A/ does this #ean the "P annot ertify 9at hes #ade with AP+ fro# this site; %he defi ien ies are 6nown at the AP+ site and there are plans to address the issues7 %he "P should esta9lish e:a tly what is 9eing done to address the issues and 9uild up a ase to >ustify what they are doing7 0or6 with the #anufa turer to i#prove o#plian e7 1o u#ent the situationE assess the ris6s and the a tion plan with the o#pany7 $onventional AP+ #anufa turers should 9e #ore willing to o#ply than atypi al a tive #anufa turers as the phar#a euti al industry is their #ain 9usiness7 +f serious defi ien ies are found onsider pu9li health i#pli ations7 %he MHRA should 9e infor#ed in these ir u#stan es and a Ffor ause? inspe tion of the #anufa turer #ay 9e initiated7 &lti#ately if a site is not o#pliant with GMP then it should not 9e used and a "P should not ertify it as su h7 @Ba 6 to topA =7 8or natural and se#i!syntheti AP+s/ how far 9a 6 should you audit for o#plian e with GMP;

Guidan e on esta9lishing the point at whi h produ tion of the AP+ 9egins is outlined in -7' and %a9le - of Part ++ of the Guide7 A ris6 assess#ent should 9e perfor#ed to identify potential pro9le#s eg supplier history/ pro ess ontrol/ variation in starting #aterials/ how diffi ult these are to ontrol and to identify how far 9a 6 in the past there is the potential for pro9le#s that are unli6ely to 9e re#oved or dete ted during later pro esses7 $onsideration should also 9e given to the revisions of Anne: ' of the Guide and the learning points fro# the re ent Heparin onta#ination issue/ where a low #ole ular weight Heparin used widely in Europe ontained low levels of onta#inant7 @Ba 6 to topA 37 *o#e e: ipients are o#ing under the sa#e e:pe tations for GMP o#plian e as AP+s7 0hat are the ti#es ales for guidelines; %he E$ in onsultation with industry representatives developed a <uestionnaire and regulatory i#pa t assess#ent7 %his was ir ulated to e: ipient #anufa turers and users and the output has 9een analysed and re o##endations have 9een put forward7 0e await further develop#ents7 %he list of F ertain? e: ipients is still to 9e onfir#ed 9y the E$7 %he MHRA onsiders guidan e su h as that pu9lished 9y the Phar#a euti al "uality Group (P"G) and %he +nternational Phar#a euti al E: ipients $oun il Europe (+PE$) provides a useful ontri9ution to supply hain #anage#ent7 @Ba 6 to topA 47 $an a GMP ertifi ate issued 9y an EEA $o#petent Authority/ MRA partners or other re ognised authority 9e used in lieu of an audit 9y a #anufa turing authorisation holder to onfir# GMP $o#plian e of an a tive su9stan e #anufa turer , supplier; Arti le )=(f) of 1ire tive '((-,4.,E$ as a#ended re<uires the holder of a #anufa turing authorisation to use as starting #aterials only a tive su9stan es whi h have 9een #anufa tured in a ordan e with the detailed guidelines on good #anufa turing pra ti e for starting #aterials7 $o#plian e with this o9ligation should 9e gained through audits of the a tive su9stan e suppliers 9y the #anufa turing authorisation holder the#selves or a third party a ting on their 9ehalf7 GMP ertifi ates issued 9y EEA/ MRA partners or other re ognised authorities annot fulfill this statutory o9ligation or the re<uire#ents of se tion 27'2 of the GMP Guide7 GMP ertifi ates an however provide useful infor#ation to #anufa turing authorisation holders and #ay 9e used together with other supporting infor#ation in a ris6!9ased approa h 9y the #anufa turer in esta9lishing priorities for its own audit progra##e of a tive su9stan e suppliers7 @Ba 6 to topA