1.1.1.5.
Is there a 2P related recalls from the maret in last 3 years"
1.1.2. 1.1. 1.1.3. 3.1. 1.
Premises Are Are ther theree any any sour source cess of envi enviro ronm nmen enta tall cont contam amin inat atio ion n in the the area area sur surro roun undi ding ng the the building" 1.1. 1.1.3. 3.3. 3. If 456 45674$ are are prot proteectiv ctivee me measur asures es unde undert rta aeen" 1.1. 1.1.3. 3.'. '. Are the there app apprrove oved and and up to date date lay layout outs for for the the are area" a" 1.1.3. (. (. Are to toilets lo lo ca cated be before ch change ro rooms" 1.1. 1.1.3. 3.8. 8. Are Are the there re phys physic ical ally ly sep separ arat ated ed area areass for for each each prod produc ucti tion on ste step" p" Is the flo) of personnel and materials sho)n such that they are unidirectional0 prevent 1.1.2.6. product contamination 0mi/ up" 1.1.3.9 1.1.3.9.. Is there there a dist distinc inctt and sepa separa rate te area area for for )ashi )ashing ng 1.1.3. . . Do th e f lo lo) of cleaned e#uipment through th e ) as ashin g r oo oo m d on on;t allo) re contamination" 1.1. 1.1.3.< 3.<.. Is ther theree pac paca agi ging ng are areaa com compl plet etel ely y phy physi sica call lly y sepa separa rate ted d fro from m proc proces essi sing ng area area"" 1.1. 1.1.3. 3.1= 1=.. Are drai draine ned d e#u e#uip ippe ped d to to pre preve vent nt bac bac fl flo)" o)" 1.1. 1.1.3.1 3.11. 1. Are Are the the vis visib ible le elec electr tric ical al ins insta tall llat atio ions ns mai maint ntai aine ned d in good good cond condit itio ion" n" Does the company comply )ith the national legislation on fire control and prevention" 1.1.2.12. 1.1. 1.1.3. 3.1' 1'.. Is )ast )astee trea treatm tmen entt prog progra ram m cov cover erin ing g the the enti entire re fact factor ory" y" 1.1. 1.1.3.1 3.1(. (. Is the there re a spe speci cial al lig light htin ing g syst system em in in the the samp sampli ling ng$$ )eig )eighi hing ng$$ proc proces essi sing ng are areaa in cas casee those photosensitive ra) materials are being h andled" 1.1.3. Ancillary area 1.1. 1.1.'.1 '.1.. Are Are ther theree 7>P; 7>P;ss for for )as )ashi hing ng uni unifo form rmss sepa separa rate tely ly dep depen endi ding ng on on the the typ typee of area area ,ste ,steri rile le$$ non sterile$ maintenance$ special products" Is there a laundry area for uniforms )hich is separate from production areas" 1.1.3.2. 1.1. 1.1.'. '.'. '. If an outs outsiide laun laundr dry y fac facilit ility y is used used$$ are are pers person onne nell and and the the per person son resp respon onsi sibl blee instructed about the corresponding 7>P" 1.1. 1.1.'.( '.(.. Is this this outs outsid idee laun laundr dry y fac facil ilit ity y per perio iodi dica call lly y aud audit ited ed 0 the the audi auditt rec recor orde ded" d" 1.1. 1.1.'. '.8. 8. Is the therre a pure pure ste steam gene genera rato torr$ if nec necessa essary ry"" 1.1. 1.1.'. '.?. ?. Is ther theree a comp compre ress ssed ed air air gen gener erat ator or free free of oil$ oil$ if nece necess ssar ary" y" Is there an electricity generator for the maintenance of critical systems and processes to 1.1.3.7. be used in case of problems )ith the electricity electricity supply occur" 1.1. 1.1.'. '.. . I7 it it conn connec ecte ted d to cri criti tica call e#ui e#uipm pmen entt as aut autoc ocla lave ve$$ lyop lyophi hili li&e &err @etc @etc"" 1.1. 1.1.'.< '.<.. Do its its per perfo form rman ance ce test tested ed 0th 0thee tim timee it star starts ts )or )or afte afterr elec electr tric icit ity y drop drop is is suit suitab able le"" 2
1.1.1.5.
Is there a 2P related recalls from the maret in last 3 years"
1.1.2. 1.1. 1.1.3. 3.1. 1.
Premises Are Are ther theree any any sour source cess of envi enviro ronm nmen enta tall cont contam amin inat atio ion n in the the area area sur surro roun undi ding ng the the building" 1.1. 1.1.3. 3.3. 3. If 456 45674$ are are prot proteectiv ctivee me measur asures es unde undert rta aeen" 1.1. 1.1.3. 3.'. '. Are the there app apprrove oved and and up to date date lay layout outs for for the the are area" a" 1.1.3. (. (. Are to toilets lo lo ca cated be before ch change ro rooms" 1.1. 1.1.3. 3.8. 8. Are Are the there re phys physic ical ally ly sep separ arat ated ed area areass for for each each prod produc ucti tion on ste step" p" Is the flo) of personnel and materials sho)n such that they are unidirectional0 prevent 1.1.2.6. product contamination 0mi/ up" 1.1.3.9 1.1.3.9.. Is there there a dist distinc inctt and sepa separa rate te area area for for )ashi )ashing ng 1.1.3. . . Do th e f lo lo) of cleaned e#uipment through th e ) as ashin g r oo oo m d on on;t allo) re contamination" 1.1. 1.1.3.< 3.<.. Is ther theree pac paca agi ging ng are areaa com compl plet etel ely y phy physi sica call lly y sepa separa rate ted d fro from m proc proces essi sing ng area area"" 1.1. 1.1.3. 3.1= 1=.. Are drai draine ned d e#u e#uip ippe ped d to to pre preve vent nt bac bac fl flo)" o)" 1.1. 1.1.3.1 3.11. 1. Are Are the the vis visib ible le elec electr tric ical al ins insta tall llat atio ions ns mai maint ntai aine ned d in good good cond condit itio ion" n" Does the company comply )ith the national legislation on fire control and prevention" 1.1.2.12. 1.1. 1.1.3. 3.1' 1'.. Is )ast )astee trea treatm tmen entt prog progra ram m cov cover erin ing g the the enti entire re fact factor ory" y" 1.1. 1.1.3.1 3.1(. (. Is the there re a spe speci cial al lig light htin ing g syst system em in in the the samp sampli ling ng$$ )eig )eighi hing ng$$ proc proces essi sing ng are areaa in cas casee those photosensitive ra) materials are being h andled" 1.1.3. Ancillary area 1.1. 1.1.'.1 '.1.. Are Are ther theree 7>P; 7>P;ss for for )as )ashi hing ng uni unifo form rmss sepa separa rate tely ly dep depen endi ding ng on on the the typ typee of area area ,ste ,steri rile le$$ non sterile$ maintenance$ special products" Is there a laundry area for uniforms )hich is separate from production areas" 1.1.3.2. 1.1. 1.1.'. '.'. '. If an outs outsiide laun laundr dry y fac facilit ility y is used used$$ are are pers person onne nell and and the the per person son resp respon onsi sibl blee instructed about the corresponding 7>P" 1.1. 1.1.'.( '.(.. Is this this outs outsid idee laun laundr dry y fac facil ilit ity y per perio iodi dica call lly y aud audit ited ed 0 the the audi auditt rec recor orde ded" d" 1.1. 1.1.'. '.8. 8. Is the therre a pure pure ste steam gene genera rato torr$ if nec necessa essary ry"" 1.1. 1.1.'. '.?. ?. Is ther theree a comp compre ress ssed ed air air gen gener erat ator or free free of oil$ oil$ if nece necess ssar ary" y" Is there an electricity generator for the maintenance of critical systems and processes to 1.1.3.7. be used in case of problems )ith the electricity electricity supply occur" 1.1. 1.1.'. '.. . I7 it it conn connec ecte ted d to cri criti tica call e#ui e#uipm pmen entt as aut autoc ocla lave ve$$ lyop lyophi hili li&e &err @etc @etc"" 1.1. 1.1.'.< '.<.. Do its its per perfo form rman ance ce test tested ed 0th 0thee tim timee it star starts ts )or )or afte afterr elec electr tric icit ity y drop drop is is suit suitab able le"" 2
1.2. VALIDAI!N ALIDAI!N 1.2.1. 1.3.1.1. 1.3. 1.3.1.3 1.3..
General aspects" Is th there a validation ma master pl plan" Is the there re a vali valida dati tion on and and re* re*va vali lida dati tion on pro progr gram am$$ and and unde underr the the res respo pons nsib ibil ilit ity y of #ual #ualit ity y assurance for approval and follo)*up of its activities" 1.3. 1.3.1. 1.'. '. Are criti riticcally lly im import portaant proc proces esse sess va valida lidate ted" d" 1.3. 1.3.1. 1.(. (. Are the the val validat idatiions ons per perfo forrmed med and and docu docum mente nted" 1.3. 1.3.1.8 1.8.. Is ever every y imp impor orta tant nt mod modif ific icat atio ion n to the the man manuf ufac actu turi ring ng pro proce cess ss val valid idat ated ed$$ incl includ udin ing g any any change in e#uipment$ manufacturing area$ materials$ changes in ra) materials$ pacing materials$ changes in critical support systems processes and methods that may affect the #uality of the product or reproducibility of the process" 1.3. 1.3.1.? 1.?.. In case case elec electr troni onicc dat dataa pro proce cessi ssing ng syst system emss are are used used$$ are are thes thesee val valid idat ated ed"" 1.3. 1.3.1. 1.9. 9. If the the sy syste stem aut autom omat ateed is is a saf safety ety ba bac*u c*up p ep eptt" 1.3. 1.3.1. 1.. . Are safe safety ty pass pass)o )orrds use used for syst system em acce ccess" ss" 1.3. 1.3.1. 1.<. <. Are Are the these se pass pass)o )ord rdss onl only y assi assign gned ed to auth author ori& i&ee per perso sonn nnel el"" Are the validation studies performed according to pre*defined protocols 0there is a 1.2.1.10. report" 1.3. 1.3.1.1 1.11. 1. Are Are tren trend d anal analys yses es per perfo form rmed ed to to asse assess ss the the nee need d to re* re*va vali lida date te in in orde orderr to ass assur uree the the processes and procedures continued to obtain the desired desired results" 1.2.2. #LEANING Is a validation performed to confirm maor0 minor cleaning effectiveness" 1.2.2.1. 1.3. 1.3.3.3 3.3.. Is the the #ual #ualit ity y of the the )at )ater er used used in the the fin final al rin rinse se of of the the sam samee #ual #ualit ity y of the the )at )ater er used used in in production" 1.3. 1.3.3. 3.'. '. Does Does the the Ba Balida lidati tion on Prot Protoc ocol ol incl includ udee Clea Cleani ning ng 7>P; 7>P;ss to be use used0 d0 cle clear arly ly defi define ned d sampling points" 1.3. 1.3.3. 3.(. (. Is the the )or )or of the the >pe >pera rati ting ng Pers Person onne nell eff effec ecti tive vely ly supe superv rvis ised ed"" 1.3. 1.3.3. 3.8. 8. ave ave acce accept ptan ance ce limi limits ts been been set set acco accord rdin ing g )ors )orstt case case"" 1.3.3. ?. ?. Are de detergen t residu es es )i )ithin li limits" 1.3.3.9. Are there Balidation !e !ecords" 1.3. 1.3.3. 3... Is the the in inal al Balida lidati tion on !ep !epor ortt is suppo support rted ed by by the the signa signatu ture re of of all all tho those se inv invol olve ved$ d$ the the verification by Production and the signature of Euality Assurance" 1.3. $AER $AER %&%E' 1.3.1. 6N6!A+ 3
1.'.1.1.
Is the source of )ater used in the company allo)ing suitable continuous supply"
1.'.1.3.
Are the system schematics sho)n"
1.'.1.'.
Does the company have potable$ purified )ater tans"
1.'.1.(.
Is the cleaning and disinfecting record for cistern ,if present 0 potable )ater tans documented$ is it maintained in good condition"
1.'.1.8.
Does the procedure include a ustifiable fre#uency and sampling points"
1.'.1.?.
Is there a 7>P for sampling of all types of produced )ater"
1.'.1.9. Are physicochemical0 microbiological tests0$ ,endoto/in for FI tests of all types of produced )ater recorded0analysis established by current editions of official pharmacopoeias" 1.'.1..
Does it include identification of pathogenic micro organism"
1.'.1.<.
Are the sampling points rotated to cover all points adacent to treatment stages in the station 0 all point of use"
1.'.1.1=.
Is the fre#uency of sampling ustifiable 0validated"
1.'.1.11.
Is the action limit of purified )ater is no more than 1== cfu - m+0 1= cfu - 1==m+ for FI"
1.'.1.13.
Fhen the action limit is e/ceeded$ is an investigation al)ays undertaen to ensure #uality of the batches of product made )ith that )ater according >>7 plan"
1.'.1.1'.
Is the documentation sho)n"
1.'.1.1(.
Is there a preventive maintenance program that includes the )ater system"
1.'.1.18.
Is there an automatic system to prevent use of the )aterG if it is out of specifications if not is there another system"
1.'.1.1?.
If there is an automatic system$ is this checed to verify that it is functioning properly"
4
1.'.1.19.
Are gauges in the station calibrated"
1.'.1.1.
Is there a record for monitoring pressure difference"
1.'.1.1<.
Are there dead legs in the )ater system"
1.'.1.3=.
Is there a trend analysis"
1.3.2.
P(RI)IED $AER
1.'.3.1.
Is the system used to obtain purified )ater satisfiable"
1.'.3.3.
Are there )ritten procedures for the operation of the system"
1.'.3.'.
Is there a tan for purified )ater storageG is it of sanitary type material"
1.'.3. (.
Is it h aving a hydrophob ic vent filter"
1.'.3.8.
Are records periodic integrity tests ept"
1.'.3. ?.
If pu rified )ater ept circulating"
1.'.3.9.
Are the pipes and valves used to distribute purified )ater made of sanitary material"
1.'.3..
Is there a record for the sanitation of purified )ater storage and distribution system"
1.'.3.<.
In case of using u.v lamp is there a record of its )oring hours"
1.'.3.1=.
In the case of chemical sanitation$ or o&one treatment are there record"
1.'.3.11.
In the case that filters e/ist$ are there filter sanitation records"
1.'.3.13.
Are the filter replacement records sho)n"
1.'.3.1'.
If the )ater that feeds the system is chlorinated$ is there a system to remove the chlorine" 5
residues testing
1.'.3.1(.
In case of presence of carbon filter is there a record of saniti&ation of it )ith validated fre#uency"
1.'.3.18.
In case ionic e/change resins used$ is there a 7>P that considers the criteria to follo) for the regeneration of resins and the fre#uency of regeneration"
1.'.3.1?.
Are records ept"
1.'.3.19.
If a reverse osmosis system is used$ is there a record for system saniti&ation )ith satisfiable fre#uency"
1.'.3.1.
In case that chemical sani&atation is undertaen$ are saniti&ing agent residues investigated0 Are records ept"
1.3.3.
$AER )!R IN*E#I!N
1.'.'.1.
Is distillation system is used to get Fater for Inection"
1.'.'.3.
Is there a storage tan for the Fater used for inection"
1.'.'. '.
Is the tan made of sanitary material"
1.'.'.(.
Does it have a hydrophobic vent absolute filter"
1.'.'.8.
Are periodic integrity tests records ept"
1.'.'.?.
Are pipes used in the distribution of Fater for Inection up to the point of use"
1.'.'. 9.
Are pipes made of sanitary material"
1.'.'..
If there any type of heat e/changer are there guarantees that the heat e/changer is not a source of contamination"
1.'.'.<.
Is the )ater maintained circulating at 9=*= HC"
1.'.'.1=.
Is there a system to guarantee that temp maintained 9=*=HC"
6
1.3.+.
1.'.(.1.
VALIDAI!N"
ave the )ater system installation been #ualified" Is a protocol and report been produced"
1.'.(.3.
Is pipes 0tans been passivated"
1.'.(.'.
ave the system operation #ualification been produced" is protocol and report been produced"
1.'.(.(.
Are there daily sampling records for every pretreatment 0treatment point and usage point for a period of 3 to ( )ees in phase one validation"
1.'.(.8.
Are there daily sampling records for every pretreatment0treatment point and usage point for a period of ( to 8 )ees after Phase 1 for phase t)o validation"
1.'.(.?.
Are the reports summari&ing the results of phases 1 and 3 of the validation available"
1.'.(.9.
Are the )eely sampling records available of every usage point for a one*year period continuously in phase three validation"
1.'.(..
Is the validation summary report for phase three validation available" Is the result of these records sho) the system is under control"
1.'.(.<.
Is 7ampling point rotation program included in the performance #ualification protocol0 report"
1.'.(.1=.
Is Physical*chemical and microbiological analysis programme 0system release parameter produced in it"
1.'.(.11.
Are the cleaning and sanitation procedures and fre#uencies been defined in it"
1.'.(.13.
Are 7>Ps have been initiated during the validation phase"
1.'.(.1'.
Is any deviation from the designed criteria in #ualifications 0validation investigated 0action is taen0invetigation recorded in the report"
1.+. %!RAGE AREA 7
1.+.1. 1.(.1.1. 1.(.1.3. 1.(.1. '. 1.(.1.(. 1.(.1.8. 1.(.1.?.
1.(.1.9. 1.(.1.. 1.(.1.<. 1.+.2.
1.(.3.1. 1.(.3.3. 1.(.3.'. 1.(.3.(. 1.(.3.8. 1.(.3.?. 1.(.3.9. 1.(.3.. 1.(.3.<. 1.(.3.1=. 1.(.3.11. 1.(.3.13. 1.(.3.1'. 1.(.3.1(.
%amplin, area Is there a physically separated area for sampling" Does the sampling area have sanitary finishes" Do es the sampling area has +A unit " Does it have change room" Is there a 7>P for the cleaning of the sampling area" Is there a place to eep the sampling utensils in an orderly fashion to protect it from contamination" Is there a )ashing area$ )hich is separated$ for the sampling utensils" Incase no )ashing room for sampling areaG is there a 7>P for the handlig0storage of those sampling utensils to their )ashing area" Is there a 7>P for the incoming of ra) materials to sample and their transfer to the #uarantine area after sampling" $ei,-in, Area
Is there a physically separated )eighing area" Is there a 7>P for the cleaning of the )eighing area" Are t he area have +A unit" Is there an area for the cleaning and sanitation of the containers" Is there a ventilation system in the room )ith pressure differentials$ and the ra) materials handled )ith controlled temperature$ humidity$ and air filtration$ if re#uired" Does it have change room" If orders )hich are already dispensed are not transferred to the plant immediately$ is there a place or system that prevents mi/*ups" Is there a 7>P for cleaning the tools-utensils 0 containers used in )eighing and-or measuring" Is there an area for )ashing the tools-utensils 0 containers used in )eighing and-or measuring" Are these tools-utensils0 containers ept clean and labeled in a safe place" Are the scales calibrated periodically$ is there arecord" Are there records that scales checed on a defined scheduled basis" Is protective e#uipment used )hen necessary" Are the materials$ after being )eighed or measured$ immediately labeled in order to 8
1.(.3.18.
1.(.3.1?. 1.+.3. 1.(.'.1. 1.(.'.3. 1.(.'.'. 1.(.'.(. 1.(.'.8.
1.(.'.?. 1.(.'.9. 1.(.'.. 1.(.'.<. 1.(.'.1=. 1.(.'.11. 1.(.'.13. 1.(.'.1'. 1.(.'.1(. 1.(.'.18. 1.(.'.1?. 1.(.'.19. 1.(.'.1.
prevent mi/*ups" >n the label$ does it state: Name or code and batch of the item $ Name or code of the product to )hich the item is destined $ Product atch number$ Euantity that )as )eighed or measured$ 7ignature and date of the )orer )ho carried out the operation $ 7ignature and date of )eight verification" Is there a 7>P that describes all the operations of this sector-area" $are-ouse Is there a receiving area" Is the receipt of materials documented and recorded" Is a visual inspection done at receipt$ to verify damages or integrity of seal and containers$ )hich could affect product #uality" Is each received container labeled upon receipt0 label attached to the container body and not to its removable parts" Does the label contain the follo)ing information: Item name and code 7upplier name 7upplier%s lot number $ Total Number of 2anufacture date $ 6/piry date $ Internal lot number $ 7pecial storage conditions $ Test Date $ !etest date " Are the premises of ade#uate si&e according to the needs of the company" Is the #uarantine0 release area properly identified" Do the storage environmental conditions ,including lighting$ temperature and humidity comply )ith the established storage re#uirements" Are there records for the temperature$ humidity" Are there temperature records for the cold room if present" Is there an alert system to indicate deviations from the established temperature in the cold room" Is there a 7>P to handle such deviations" Are necessary precautions undertaen for the pacaging of finished products that re#uire cold chain" Are the scales calibrated0 checed on a scheduled basis" Are there areas physically separated or systems in place to prevent mi/*ups of different materials and products" Are there procedures for all the operations of this area receipt of goods$ movement of containers$ load conditions$ dispatches$ etc" Is there 7toc control system of materials and products" Are the I> -6> follo)ed for the use of starting materials" 9
1.(.'.1<.
efore release by #uality control$ are all items and finished products properly identified as such and maintained in #uarantine$ either physically or by a system" 1.(.'.3=. Are reected materials properly identified and stored separately in restricted areas" 1.(.'.31. Is there procedure for materials destruction" 1.(.'.33. Are shelves and-or platforms separated from floors and )alls to allo) cleaning" 1.(.'.3'. Is there a 7>P0record for cleaning )are house" 1.(.'.3(. Are pacages and containers )ith items ,drums$ $ bo/es$ etc. ade#uately closed" 1.(.'.38. Is there an area )hich is secure or )ith restricted access )hich is used to store labels" 1.(.'.3?. Are all outdated printed materials destroyed" 1.(.'.39. Fithin the storage room$ are there distinct areas )hich are physically separated and )ith restricted access for psychotropic and narcotic substances" 1.(.'.3. Is there a 7>P dealing )ith spills of corrosive or to/ic and active substances" 1.(.'.3<. Are there areas specific for the storage of flammable and e/plosive Products $is its temperature 0humidity record comply )ith the stated on the drums" 1.(.'.'=. Is there an area for inished Product !elease" Is there a suitable fire fighting system )ith record of regular chec on it" 1.4.3.31. 1.+.+. Roent / pest control 1.(.(. 1. Is there co ntrol for rodent 0 insects" 1.(.(.3. Is there a map0 monitoring record for the rodent and pest control" 1.4.5. Returne0 Recall Prouct 1.(.8.1. Is there an area that is physically separated and has restricted access for the storage of returned or recalled products until their fate is determined" 1.(.8.3. Are the products properly identified as such" 1.(.8.'. Are all actions and decision taen recorded" 1.. D!#('ENAI!N 1..1. 'aster formula 1.8.1.1. Is there an updated master formula for each product and si&e of lot to be manufactured" Do the Technical Director and-or Euality Control-Assurance Director authori&e all master formulas" 1.8.1.3. If it is necessary to modify the master formula$ are there )ritten procedures on ho) to do this" 1.8.1.'. Is authori&ation from the ealth Authority e/pected before undertaing the change" 1.8.1.(. Do all products have a master formula containing Product name$ code and product 10
1.8.1.8. 1.8.1.?. 1.8.1.9. 1.8.1.. 1.8.1.<. 1.8.1.1=.
1.8.1.11.
1.8.1.13.
1.8.1.1'.
1.8.1.1(. 1.8.1.18.
1.8.1.1?. 1..2. 1.8.3.1. 1.8.3.3.
number" Do all products have a master formula containing Description of pharmaceutical dosage form$ concentration and-or strength of the active ingredients$ Product shelf life" Do all products have a master formula containing Theoretical intermediate yield and theoretical final yields )ith their correspondent limits" Indication of the areas in )hich each one of the process steps occur and e#uipment used" Do all products have a master formula containing Names and signatures of the #ualified people involved in the issuance$ revie)$ and approval ,at least t)o" Do all products have a master formula containing detailed instructions of the steps to follo) for each stage of the process" Do all products have a master formula containing Instructions concerning controls during the process$ of intermediate products and operational variations$ indicating specifications" Do all products have a master formula containing In the master formula$ are there references to the 7>Ps related to different stages of manufacturing$ e#uipment operation$ etc. )hen they correspond" Do all products have a master formula containing 7pecial precautions that should be taen during the different stages of the process due to the characteristics of the starting materials handled and e#uipment" Do all products have a master formula containing The standards for the storage of the intermediate or buls$ including the container$ the labeling and any other storage condition )hen the product re#uires it" Do all products have a master formula containing ormula revie) date" Do all products have a master formula containing orms for record eeping of product specifications during manufacture process ,)eight$ hardness$ friability$ closure of capsules$ disintegration$ viscosity$ etc. performed by production and #uality control" Is a production order issued for each batch of processed product" atc- process recor Does the batch process record contain the Product name$ Issue date$ atch number$ 6/piry date of finished product" Does the batch process record contain the list of ra) materials involved ,including the ones that are used up during processing )ith their code numbers$ lot$ and-or analysis$ theoretical and real #uantities utili&ed for each of them" 11
1.8.3.'. 1.8.3.(. 1.8.3.8. 1.8.3.?. 1.8.3.9. 1.8.3..
1.8.3.<. 1.8.3.1=. 1.8.3.11. 1.8.3.13. 1.8.3.1'. 1.8.3.1(. 1.8.3.18. 1.8.3.1?. 1.5.2.17. 1.5.2.18.
1 ..3. 1.8.'.1. 1.8.'.3. 1.8.'.'.
1.8.'.(. 1.8.'.8.
If it is necessary to adust the concentration of ra) materials$ is the modification signed by a #ualified person" Are the labels of the ra) materials separated$ attached" Is the detailed description of each one of the steps included in the processed lot record" Are the areas and e#uipment-lines released recorded" Is the date$ the starting and ending time of every step recorded" Are the values of operational deviations to be controlled during process ,6/.: temperature$ p$ times$ agitation speeds$ etc. recorded and the acceptance limit indicated" If there are process deviations )ith regard to the master formula$ are they recorded" Fhenever there is an IPC in some step of the process$ are they recorded" Are the real yields of the intermediate and end stage recorded" Are the yields )ithin the acceptable limits" In case of a deviation$ is the cause of the deviation investigated according to the 7>P 0 the findings documented" Are the signatures- initials of the people )ho carry out the different operations and of those )ho supervise them recorded" It is verified that the data that should appear on the batch process record are completed at the time in )hich each action is undertaen during the process" Are reprocessing and re)oring previously authori&ed by Control-Euality Assurance 0 done in accordance )ith a 7>P" After the manufacture process is ended$ is all the documentation that is part of the batch record$ including the certificate of analysis of the inished Product$ filed" Is the file maintained for at least one year after the 6/piry date of the lot" atc- pa ca,in, recor Is a pacaging order for every batch or part batch processed issued" Is the release of areas and e#uipment- lines recorded" Does the batch pacaging record contain the name of the product$ the batch number$ the e/piry date of the finished product and the #uantity of bul product to be paced$ as )ell as the batch number and the planned #uantity of the finished product that )ill be obtained$ the #uantity actually obtained$ and the reconciliation" Does the batch pacaging record contain the date ,s and time,s of the pacaging operations" Does the batch pacaging record contain the initials of the operators of each one of the 12
1.8.'.?.
1.8.'.9. 1.8.'..
1.8.'.<.
1.8.'.1=.
1.8.'.11.
1.8.'.13. 1.8.'.1'. 1 ..+. 1.8.(.1.
1.8.(.3. 1.8.(. '. 1.8.(.(. 1.8.(.8. 1.8.(. ?. 1.8.(.9. 1.8.(..
different steps" Does the batch pacaging record contain the controls undertaen )ith the outcome of verifying the identity and conforming to the pacaging instructions$ including the results of the inprocess controls" Does the batch pacaging record contain Details of the pacaging operations carried out$ including references to e#uipment and the pacaging lines used$ cleaning records" Does the batch pacaging record contain if necessary$ the instructions for eeping the product unpacaged or a record of returning product that has not been pacaged to the storage areas" Does the batch pacaging record contain )henever possible$ samples of the printed pacaging materials used$ including samples bearing the batch number$ e/piry date signed" Does the batch pacaging record contain Notes on any special problems$ including details of any deviation from the pacaging instructions$ )ith )ritten authori&ation by the #ualified person responsible" Does the batch pacaging record contain the #uantities and reference numbers or identification of all the printed pacaging materials and bul product issued$ used$ destroyed or returned to stoc and the #uantities of product obtained to permit an ade#uate reconciliation" Are the reprocessing and re)oring of products controlled in a 7>P for deviations" After the pacaging process is ended$ is all the documentation that is part of the batch pacaging record$ including the analytical protocol of the inished Product$ filed" General ocumenta tion or each procedure$ are the purpose$ scope$ references$ issuing0 effective date and responsibilities clearly defined" Is there the detailed and precise description$ in order of the routine operations" Are the procedures available$ current" Are the signatures of the personnel that issue$ revie)$ and approve the document indicated" Are the records indicated )ithin the procedures available" Do es th e u se of correction fluid o r e raser remain clearly proh ibited in the documentation" If there are amendments-changes$ are the date and signature recorded" Is there a 7>P for the handling of changes and deviations" 13
1.4. N!N5%ERILE PR!D(#% 1.4.1. 1.?.1.1. 1.?.1. 3. 1.?.1.'. 1.?.1.(. 1.6.1.5.
1.?.1.?. 1.?.1.9. 1.?.1.. 1.?.1.<. 1.?.1.1=. 1.?.1.11. 1.?.1.13. 1.?.1.1'. 1.?.1.1(. 1.4.2. 1.?.3.1.
1.?.3.3. 1.?.3.'. 1.?.3.(. 1.?.3.8. 1.?.3.?. 1.?.3.9.
Area" Are there ade#uate changing stages before entering the areas" Is there )ritten instruction )ith that" Are changing rooms having the same class as the area they lead to" Are the change rooms designed )ith air locs" Is a bench of sanitary conditions available6 Is the area for )ashing )ith a supply of purified )ater 0filtered air" Is a validity period established for cleaned obects" Are personnel responsible for clean toilets 0there tools different from )ho clean manufacturing area" Are there gauges to detect pressure differentials" Is there a record" Are the )alls$ floors and ceiling surfaces smooth and easy to clean" Are fi/ed pipes identified and do they indicate the direction of flo)$ )henever necessary" If ra) materials or the handled products )hich re#uire it$ are the temperature and relative humidity measured and recorded" Is the IPC room )ith calibrated needed instruments" Is the area cleaned$ as per established !e#uirements in the cleaning 7>P" Is it documented" E7uipment Are the materials used in the construction of the e#uipment$ non reactive )ith the active ingredients handled" Are the labels adhered to the containers$ e#uipment$ and other au/iliary elements of production and areas unambiguous 0indicate its condition" Are the records of use and maintenance of e#uipment ept" Are the instruments correctly labeled indicating the validity of calibration" Is the e#uipment not in use identified as such and removed from the production areas according to the 7>P" Are all the containers$ e#uipment and au/iliary elements cleaned after their use$ is it documented" or fluid bed dryers: is there a set of sleeves for each product$ or is there a cleaning validation process that guarantees no cross*contamination" 14
1.?.3.. 1.?.3.<. 1.?.3.1=. 1.?.3.11. 1.4.3.
Are the integrity$ measurements$ and identity of the punches confirmed" Are records ept" Is the access to them restricted" Is the air inected in the coating e#uipment filtered" Is it included in the preventive maintenance plan" Are the filters used in filtration of li#uid disposable" Are the changes recorded" !peration
1.?.'.1. 1.?.'.3.
Is there a confirmation that only one product processed in each processing room" Do personnel in production carry out the verification of the )eight of the ra) materials used in the manufacturing of each lot" 1.?.'.'. Are the parameters of the drying operations measured and recorded" 1.?.'.(. Is there assurance that the drying ovens do not receive lots of different products or different lots from a single product at the same time" 1.?.'.8. Is the transfer of semi manufactured-buls products bet)een one step of the process and another carried out in a manner to prevent their contamination" 1.?.'.?. Is there confirmation that the suspensions and-or emulsions are maintained uniform throughout the bottling process" Do bottles receive some type of cleaning 0on line )ith before filling" 1.6.3.7. 1.?.'.. In the case of the automatic system$ are discarded units )hich are returned to the line$ previously inspected and approved by authori&ed personnel" 1.?.'.<. Are process controls performed at each production step" 1.4.+. Valiation 1.?.(.1. Is installation of e#uipment been #ualification ,IE" Is protocols 0report produced" 1.?.(.3. Is operation of e#uipment been #ualification ,>E" Is protocols 0report produced" 1.?.(.'. Is performance of e#uipment been #ualification ,PE" Is protocols 0report produced" 1.?.(.(. Is any deviation in the report of #ualification investigated 0action is taen" 1.8. %ERILE PR!D(#% 1.8.1. Premises9 Area Desi,n An Layout" 1.9.1.1. Does the design of the areas$ grade A and $ permit a visual vie) of all the operations from the outside" 1.9.1.3. Is the preparation environment )here a solution is subect to terminal sterili&ation a grade D at least" 1.9.1.'. Are sterile products that are to be terminally sterili&ed$ filled in a )orstation )ith 15
1.9.1.(. 1.9.1.8. 1.9.1.?.
1.9.1.9. 1.9.1.. 1.9.1.<. 1.9.1.1=. 1.9.1.11. 1.7.2.
1.9.3.1. 1.9.3.3. 1.9.3. '. 1.9.3.(. 1.9.3.8. 1.9.3.?. 1.9.3.9. 1.9.3.. 1.9.3.<. 1.8.3. 1.9.'. 1. 1.9.'.3. 1.9.'.'. 1.9.'.(.
laminar airflo) grade A surrounded by class C area" Are products that are sterili&ed by filtration$ is the preparation of the solution in closed tans carried out in a grade D environment at least" Are products that are sterili&ed by filtrationG is the preparation of the solution in opened tans carried out in a grade C environment" Are sterile filtered products$ after the sterili&ing filtration process is the product handled and filled under local grade A conditions )ithin a grade or C bacground environment" Is the )hole manufacturing process of products prepared )ith aseptic ra) materials$ carried out under local grade A )ithin a grade environment" Are the )all surfaces$ floors$ doors and ceilings smooth and impervious$ minimi&ing the shedding and the accumulation of particles and microorganisms" Are they easy to clean and maintain sanitary" Are the pipes$ lighting fi/tures$ points of ventilation and other services designed in such a )ay to permit their easy cleaning and sanitation" Are pipes of dangerous li#uids or gases identified and indicate the direction of flo)$ )henever necessary" #-an,in, Rooms" Are there ade#uate changing stages before entering the sterile areas" Is the entry of the personnel into the clean rooms )ith )atches$ e)elry$ or cosmetics prohibited" Is there )ritten instruction )ith that" Are there change rooms e/clusive for the controlled environment areas" Are changing rooms having the same class as the area they lead to" Are the change rooms designed )ith air locs0 interlocing" If no is there any type of alarm to prevent opening of more than one door in a time" Is a bench of sanitary conditions available" If no is there any alternative measure to separate the dirty &one from the clean one" %terile Go:nin," Is there an area for the conditio nin g o f t he clo thes fo r u se in the contro lled environments after its sterili&ation" Is there a validity period for the go)n after sterili&ation" Is the clothing used appropriate for the areas and tass that are carried out" Are the uniforms used for )or in aseptic areas$ clean$ in good condition and sterili&ed 16
1.9.'.8. 1.9.'.?. 1.9.'.9. 1.9.'.. 1.9.'.<. 1.8.+. 1.9.(.1. 1.9.(.3. 1.9.(.'. 1.7.5.
1.9.8.1. 1.9.8.3. 1.9.8.'. 1.9.8.(. 1.9.8.8. 1.9.8.?. 1.9.8. 9. 1.9.8. . 1.7.6.
1.9.?.1. 1.9.?.3. 1.9.?.'. 1.9.?.(. 1.9.?.8. 1.9.?.?. 1.9.?.9.
prior to their use" Is there validity time period established for the sterili&ation of the uniforms" Are protection elements utili&ed for the operations that re#uire them" If no does this compromise product #uality" Is there an e/clusive laundry for the sterile area separated from laundry of other department" Are the gloves free of lubricants" $as-in, Area Is there an area or sector for the )ashing of containers and-or tools" Is label attached to cleaned obects sho)ing its status" Is a validity period established for cleaned obects" Ampoules an Vial $as-in, Area: Is there a separate area for the )ashing and for the depyrogenation of empty bottles and ampoules" Is the operation of )ashing of empty bottles and ampoules done at the least in a grade D area" Do the cleaning machines of empty bottles and ampoules use )ater for inection$ for at least the last rinse" Do the compressed air used in these )ashing machines ade#uately filtered" Are depyrogenation ovens used are validated" Are depyrogenation tunnels used are validated" Are dep yrog enatio n cycles validated" Are dep yrog enatio n cycles recorded" #leanin,9 %aniti;ation an P for the cleaning and disinfection of every area" Is the area cleaned$ )ithin 3( hours after ending the process activities" Is a validity period established for area cleaning" Are records for cleaning ept" Is there 7>P of disinfection sho)ing sho) type$ conc0 contact time of disinfectants used" is there a record" Is there 7>P 0 record for disinfectant preparation and sterili&ation" 17
1.9.?.. 1.9.?.<. 1.9.?.1=. 1.8.8. 1.9.9.1.
1.9.9. 3. 1.9.9.'. 1.9.9.(. 1.9.9.8. 1.9.9.?. 1.9.9.9. 1.9.9.. 1.9.9.<. 1.9.9.1=. 1.9.9.11. 1.8.=. 1.9..1. 1.9..3. 1.9..'. 1.9..(. 1.9..8. 1.9..?. 1.9..9. 1.9... 1.9..<. 1.9..1=. 1.9..11.
Are disinfectant used in alternative basis to prevent resistant strains" Are containers for )aste collection identified as such" Are the materials used in containers construction compatible )ith the active ingredients handled" E7uipments" Does the location of the e#uipment facilitate their cleaning$ as )ell as$ the cleaning of the area in )hich are found" Do th e cleaning pro ced ure validated" Is there a log boo for every e#uipment usage" Are there calibration records of the e#uipment-instruments available" Is the unused e#uipment removed from the production areas" Is the e#uipment in repair identified as such" Are all e#uipment and au/iliary elements cleaned after their use" Is a validity period for the cleaning of the e#uipment established" Are all the hoses$ tubes and pipes used in the transfer of fluids identified" Fhen they are not dedicated$ is the cleaning validated" Are the connections and valves used of sanitary conditions" !perations Are there flo) charts sho)ing the production steps and identify critical points" Are process controls undertaen at the different steps of production" Are records ept" Is there ade#uate control on ma/imum number of personnel present in clean and aseptic area" If sterili&ing filtration systems utili&ed is the integrity of the filters confirmed before filtration" If the filters used are not disposable$ is their usage period established$are the sterili&ation number recorded" ,N>. of sterili&ation cycles" Are the changes recorded" Are the filters dedicated by active ra) material" Is the integrity of the filters confirmed after filtration" Are records ept" or each product$ is the ma/imum time bet)een the starting of the preparation of a solution and its sterili&ation or filtration through absolute filters established" 18
1.9..13. 1.9..1'. 1.9..1(. 1.9..18. 1.9..1?. 1.9..19. 1.9..1. 1.9..1<. 1.9..3=. 1.9..31. 1.9..33. 1.9..3'. 1.9..3(. 1 .8.>. 1.9.<.1. 1.9.<.3. 1.9.<.'. 1.9.<.(. 1.8.1?. 1.9.1=.1. 1.9.1=.3. 1.9.1=.'. 1.9.1= .(. 1.9.1=.8.
Are gases used to purge solutions ade#uately filtered" Is the batch sterili&ation in more than one cycle$ Is it divided to different identified lots for sterility testing" Are records of time$ temperature$ and-or pressure of the autoclave and depyrogenation oven maintained" Are records of sterili&ation and depyrogenation of the container for the filtrate product reception available" Is the transfer of intermediate-buls bet)een one step and another carried out in a manner )hich prevents their contamination" Is the ma/imum time elapsed bet)een the filtration and the product filling determined for products )ithout terminal sterili&ation" Are mi/*ups avoided bet)een the sterile and non*sterile material" Is clean steam used in the sterili&ation cycles monitored to assure suitable #uality" Is a validation program for moist heat sterili&ation cycles performed and recorded" Are indicators used at each cycle of sterili&ation" Are records ept" Is the product 1==J visually inspected" Incase inspected by operators do they a record for periodical medical e/amination " 'aterials an #omponents" Do they enter to the aseptic area by air loc" Is there a validity time period established for the sterili&ation of components$ containers of products in bul and other e#uipment" Do the sterili&ed material and components transferred in a manner to prevent its contamination or cross contamination" Do lea test is done for ampoules" Aseptic Process Valiation" Is media fill conducted )ith culture medium$ in the )oring conditions$ at least on a semiannual fre#uency" Are these tests carried out in such a)ay to most accurately reproduce the normal )oring conditions in the area" Are they carried out in a minimum of '?== units" Are there records of these tests" Are the causes of any detected contamination investigated" 19
1.9.1=.?. Are there records of this investigation" 1.9.1=.9. Are there records of the corrective actions taen in those cases" 1.=. Q(ALI& #!NR!L 1.=.1. La@oratory e7uipment 1..1.1. Does the Euality Control laboratory carry out its o)n Physicochemical$ 2icrobiological$ and iological controls" 1..1.3. Is a clearly defined flo) of samples and documentation established" 1..1.'. Are the physicochemical and microbiological controls sector physically separated" 1..1.(. Are the physicochemical and microbiological controls sector physically separated from the production" 1..1.8. Is the Euality Control Department responsible for approving or reecting the ra) materials$ pacaging materials$ intermediate products$ and finished products" 1..1.?. Are the installations and the e#uipment as appropriate )ith the type of manufacture 0 active ingredients handled" 1..1.9. Is there a defined area for the )ashing and conditioning of materials e/clusively destined for the physicochemical laboratory" 1..1.. Are there safety installations such as sho)er$ eye )asher$ fire e/tinguisher$ and protection elements" 1..1.<. Is there the necessary e#uipment for the analytical controls re#uired for the material 0 products" 1.=.2. %ta@ility 1..3.1. Does stability study program include a complete description of the product studied" 1..3.3. Does stability study program include the controlled parameters and validated analytical methods that demonstrate the stability of the product in concordance )ith the established specifications" Does stability study program include a sufficient number of lots ,no less than three" 1.8.2.3. 1..3.(. Does stability study program include timetable of the analytical tests to carry out for every product" 1..3.8. Does stability study program include the accelerated 0real time stability" 1..3.?. Does stability study program include sufficient #uantities of samples in order to fulfill )ith the program" 1..3.9. Is there a summary and obtained data including the evaluations and study conclusions" 1..3.. I7 there a record of monitoring of the mareted products that maes it possible to confirm that$ if the conditions of storage are met$ the product maintains its #uality 20
during its validity period" Valiation Does the Balidation 2aster Plan include the Euality Control laboratory" Does the laboratory have e#uipment #ualification protocol0report" If there is deviation in the #ualification is it investigated 0corrective action taen" is that recorded " 1..'. (. Is there a validatio n program for those analyt ical methods not published by internationally recogni&ed pharmacopoeias" 1..'.8. Are there documents supporting compliance )ith this procedure" 1..'.?. Are analytical methods verified )hen despite being coded by internationally recogni&ed pharmacopoeias$ these are performed differently to the coding" 1.=.+. %amplin, proceure 1..(.1. Are there 7>Ps )ith the detailed description for the sampling of !a) materials$ Pacaging materials$ intermediate$ finished product" 1..(.3. Are there sampling plan for ra)$pacging$intermediate 0finished product " 1..(.'. Are all incoming pacaging materials$ )ithout e/ception$ sampled by Euality Control in accordance )ith the established standard0 sampling plan" 1..(.(. Are the sampling elements duly stored and labeled" 1..(.8. Is there a )ritten procedure for the cleaning$ use$ and conservation of the sampling eleme 1.=.. Analytical met-o 1..8.1. Are the analytical methods utili&ed authori&ed by the one responsible of Euality Control" 1..8.3. Are there specifications for !a) materials$ Pacaging materials$ Intermediate$ finished$" 1..8.'. Are there records that Euality control checs if each manufactured lot meets the established specifications" 1..8.(. Is there 7>P for out of specification" 1..8.8. Are there records of this investigation 0action taen" 1..8.?. Do the records of the tests contain 7ample identification$ Date$ Name of the analyst$ Identification of the reference standard$ Parameters and conditions that correspond" 1..8.9. Do the analysts have a serial logboo in )hich are recorded the laboratory results" 1..8.. Are the calculations dated and signed by the analyst" 1..8.<. If there are observed modifications of data$ is the amendment carried out dated and 1.=.3. 1..'.1. 1..'.3. 1..'.'.
21
1..8.1=. 1..8.11.
1.=.4.
1..?.1. 1..?.3. 1..?.'. 1.=.8. 1..9.1. 1..9. 3. 1..9.'. 1..9.(. 1..9.8.
1..9.?. 1..9.9. 1..9.. 1..9.<. 1..9.1=. 1.=.=. 1... 1. 1...3. 1...'.
signed" Does the amendment mae possible to visuali&e the original datum" In the records of the analyses$ it is indicated: Name of the analy&ed material$ +ot number $ Analysis number $>btained results $ Date $ Ktili&ed methods and specifications $ 7igns- initials of the people )ho carried out the test $ 7ign-initials of the person that verified the tests and calculations " Retaine samples Are samples of retention of the active ra) materials and finished products$ in enough #uantity to carry out all the tests by duplicate$ ept in accordance to a 7>P" Are the retention samples of finished products ept until a year after the e/piry date of the product" Are the samples of retention of ra) materials ept until a year after the e/piry date of the last lot of product prepared )ith them" Reference stanar Are there standards and reference materials" Is a record of the primary stan dards ep t" Is a record of the secondary standards ept" Is a record of the reference materials ept" Does the company have primary standards$ coded by Pharmacopoeias or internationally recogni&ed agencies$ for each active ingredient" Do all the secondary standards and reference materials have current analytical certificate" Are there 7>Ps for the preparation$ use and conservation of standards and reference materials" Are those procedures fulfilled" Are the records sho)n" Does the company have impurities and related substances standards$ officials or non* officials$ especially for those considered to/ic" Rea,ents Are the reagents correctly labeled" Are volumetric solutions used" Is there a standard operating procedure for the preparation$ use$ and conservation of volumetric solutions" 22
1...(. 1...8.
1...?. 1 .=.>. 1..<.1. 1.8.9.2. 1.8.9.3. 1.8.9.4.
1..<.8. 1..<.?. 1.8.9.7.
1..<.. 1..<.<. 1..<.1=. 1..<.11. 1..<.13. 1..<.1'. 1..<.1(. 1..<.18. 1..<.1?. 1..<. 19. 1..<.1. 1..<.1<. 1..<.3=. 1..<.31. 1..<.33.
Is there log boo for the preparations of the reagent preparation include Name of the analyst$ Name of the reagent$ Calculations$ Date of the preparation 0 e/piration" Do every container of analytical solution have a label )here there is indicated: Name of the solution Concentration * standardi&ation factor Preparation date$ !esponsible$ !etest date$ e/pired date$ 7torage conditions$ 7afety category$ !eference to the 7>P" Are the unstable reagents labeled )ith reception date$ opening date and 6/piry date" 'icro@iolo, y la@ora tory Does the company have separated areas for sterility test and other microbiological controls " Is there any change room before entering the microbiology laboratory" Is there any change room before entering the areas for sterility test" Is there sop for the cleaning 0 disinfectant of the change room" Are there proper areas and laminar flo) for carry out the sterility tests" Are the filters of the laminar flo) periodically checed" Are the materials$ culture media and reagents )ithin the validity period" Are the dehydrated culture media stored in the conditions of humidity and temperature indicated by the manufacturer" Are the parameters of every sterili&ation cycle of culture Is there separated +A cabinet to perform gro)th promotion test" Is the gro)th promotion test carried out )henever ne) lots of culture media are utili&ed" Is negative control test done in accordance )ith every sterility test" Is a standard operating procedure for the preparation of culture media" Are there microbial reference strains" If there are reference strains$ are they certified by an internationally recogni&ed agency" Is there a record of identification and use of strains" Are sterilit y tests carried out" or sterility tests$ are coded methods utili&ed" If the lot fails the sterility test$ is it follo) >>7 " Are antibiotic potency assays carried out" Does the company have areas or sectors assigned for the sample Preparation" Does the company have areas or sectors assigned for the )ashing and Conditioning of 23
materials" Does the company have areas or sectors assigned for the preparation of culture media" Does microbiology sector have e#uipment for bacterial decontamination" Is there a procedure for the handling and disposal of chemical and microbial )aste" Does the procedure indicate that should not be permitted the accumulation of discarded materials" 1..<.39. Does Euality control carries out environmental microbiological controls" 1..<.3. Are there records" 1..<.3<. Are tests of bacterial endoto/ins carried out in ra) materials and goods declared as pyrogen*free by the supplier$ to be used in the inection manufacture" 1..<.'=. Are tests of pyrogens or bacterial endoto/ins carried out in the finished products for inection" 1..<.'1. Is an official method utili&ed for bacterial endoto/in control" 1..<.'3. Is the method validated" 1.=.1?. Animal -ouse 1..1=.1. Are pyrogen tests carried out in animals" 1..1=.3. If 45674 Does the company has its animal house or uses a contracted animal house" 1..1=.'. In any of both cases$ does animal house fulfills )ith the current regulations on animal operation and management" 1..1=.(. If the company have animal house$ is this separated from the other installations )ith separate AK" 1.>. Q(ALI& A%%(RAN#E 1.>.1. General 1.<.1.1. Is there in the company a #uality assurance system" 1.<.1.3. If the documentation is carried out through electronic data processing methods does the company ept a reserve copy of the documentation" 1.<.1.'. Is the admission of ne) data or modifying of the e/isting data in the computer system done only by the people authori&ed" 1.<.1.(. Is a record of the data modifications and-or elimination ept" 1.<.1.8. Are the records of lots electronically filed protected" 1.<.1. ?. Is there a program o f control of th e 7>Ps" 1.<.1.9. Does Euality assurance is responsible of release of every batch is that indicated in a 7>P " 1..<.3'. 1..<.3(. 1..<.38. 1..<.3?.
24
1.<.1..
If in the revie) of the production records are detected bypasses of the established procedures$ is #uality assurance responsible for ensuring a complete investigation of the bypasses and that the final conclusions are ustified" 1.<.1.<. If a lot does not meet specifications$ does the investigation is e/tended to other lots of the same product and of other products that could have had some relation )ith the defect or the discrepancy" 1.<.1.1=. Does the company ept originals of all procedures and records of distribution of the authori&ed copies" 1.<.1.11. If a procedure is modified$ is there a system by )hich the accidental use of a previous version is prevented" 1.<.1.13. I7 there a 7>P for change control" is it fullfield" 1.<.1.1'. Is there a 7>P for annual product revie)" Is that K+I+6D" Is there a 7>P for corrective 0preventive action" 1.9.1.14. 1.>.2. Preentatie maintenance/ cali@ration pro,ram 1.<.3.1. 1.<.3.3. 1.<.3.'. 1.<.3.(. 1.<.3.8. 1.<.3.?. 1.<.3.9. 1.<.3.. 1.<.3.<. 1.<.3.1=. 1.>.3. 1.<.'.1. 1.<.'.3. 1.<.'.'. 1.<.'.(. 1.<.'.8. 1.<.'.?.
Is there a program for preventive maintenance for all the e#uipment$ premises $utilities" Are there records that sho)n preventive maintenance program compliance" Is there a program of e#uipment calibration" In the e#uipment calibration program is indicated$ )hich operations are performed internally and )hich by contracted services" Is the fre#uency of calibration indicated in the e#uipment calibration program" Are records of calibration of each e#uipment that sho)n program Compliance" Are there )ritten procedures to perform the calibration of each e#uipment" Is the e#uipment correctly labeled indicating the calibration validity" In case of internal calibrations$ does the laboratory have certified standards" Are the corresponding certificates sho)n" Q(ALI& A(DI%0 %EL)5IN%PE#I!N% Are #uality self*inspections and-or audits carried out" Is Euality assurance responsible for the coordination of #uality self*inspections and-or audits" Are the self*inspections-audits carried out )ith a pre*established plan" Are the necessary corrective taen )ith in the time limit specified" Do the )ritten instructions of #uality self*inspection- audits include the entire factory" Are the !esults of previous self*inspections and adopted corrective measures 25
1.<.'.9. 1.<.'.. 1.<.'.<. 1.<.'.1=. 1 .>.+. 1.<.(.1. 1.<.(.3. 1.<.(.'. 1.>.. 1.<.8.1. 1.<.8.3.
1.<.8.'. 1.<.8.(. 1.<.8.8. 1.<.8.?. 1.<.8. 9. 1.<.8.. 1.>.4. 1.<.?.1. 1.<.?. 3. 1.<.?.'. 1.<.?.(. 1.<.?.8.
documented" Does the report issued once finished the self*inspection contain the !esults of the self* inspection" Does the report issued once finished the self*inspection contain evaluation and conclusions" Does the report issued once finished the self*inspection contain corrective measures recommended" Is the monitoring of the corrective measures carried out" %(PPLIER% Q(ALI )I#AI !N Is there a record of approved suppliers available for the areas that re#uire it" Is there a program for evaluation and audits to suppliers" Is it fulfilled" RE#ALL Is there A sop to recall products from the local and international maret$ if necessary" Is there a responsible person ,independent from the mareting department designated by or in accordance )ith the #ualified person responsible for the coordination and e/ecution of the recall procedure" Is Euality control-Euality assurance-!egulatory Affairs notified of undertaen recall operations" Does the procedure indicate the mandatory re#uirement of notifying the ealth Authority immediately in the event that the cause is for health reasons" In the case of having distributed products to other countries$ is the ealth Authority of the recipient country and the recipient of these products informed immediately" Are distribution records available for a prompt recall of products from the maret" Is there a clas sification of recall" Is there an updated list of contact persons of the distributors" #!'PLAIN Is Euality assurance responsible for coordinating the reception and the monitoring of the received complain" Is there a respo nsible perso n assigned" Are there )ritten procedures for the reception and investigation of the complain" Is record of the complain ept" If necessary$ is analytical control made" 26
1.<.?.?. 1.1?.
Do the decisions 0corrective action made concerning the complaints remain documented$ in the lot records" PA#BAGING"
1.1?.1. 1.1=.1.1.
1.1=.1.3. 1.1=.1.'. 1.1=.1.(. 1.1=.1.8. 1.1=.1.?. 1.1=.1.9. 1.10.1.8.
1.1=.1.<. 1.1=.1.1=.
>P6!ATI>N: Is the mi/*up of different products or different lots of same product avoided by having physical separation among the pacaging lines" Do all finished products have a printed batch number and an e/piry date on their primary container" Is the printed information resistant to fading or erasing" If automatic machines are used to control dimensions$ )eights$ labels$ prospects$ bar code$ etc.$ is their proper performance verified" If the revie)-verification of product done visually$ Is there a changeover of staff" If it is done automatically is it challenged for its performance " Are conditions of lighting and contrast for the revie)-verification controlled" Are the containers that contain the already inspected material labeled as such" Are the right batch number and e/piry date confirmed by authori&ed personnel" Are precautions taen on dispensing labels to prevent mi/*ups"
D>CK26NT7: Does the company have pacaging orders )ith A full list of all pacaging material re#uired for a normal si&e batch$ including #uantities$ si&es and types$ )ith the lot number$ code or reference number related to specifications for every pacaging material" 1.1=.3.3. Does the company have pacaging orders )ith Details concerning process control )ith instructions for the sampling and acceptable limits" 1.1=.3.'. Is there a 7>P available for the process of the return of unused non*coded printed material to the )arehouse"
1.11.
27
1.11.1.(. 1.11.1.8.
1.11.1.18.
Is the filters efficiency is ade#uate for such classes" In the areas of controlled environment ,grade $ C and D$ is the number of air Changes by hour is sufficient for such areas" Are the integrity and the sealing of the filters confirmed" Is there a 7>P for the revie) and changing of filters" Are there records" Do the areas have instruments )ith current calibration$ )hich mae it possible to confirm a cascade of pressure differential" Are there records" Do the air flo) patterns prevent contamination" Is there an alarm system that indicates a deviation in the air supply to the aseptic areas" Is there a 7>P for ho) to proceed in the event that this occurs" Is there a measure in place to avoid a conveyor belt going from a grade area to one of lo)er air #uality" Are the actual results complying )ith the designed criteria"
1.11.1.1?.
Are there air locs bet)een different classes"
1.11.1.19.
Is there a reasonable upgrading of area cleanliness from blac$ grey$ clean area"
1.11.1.1.
Are the toilets air not returned or mi/ed )ith production air"
1.11.1.1<.
Is there ventilation )ith ade#uate temperature$ humidity$ and air filtration$ if the ra) materials and-or handled products re#uire it" Are the temperature and relative humidity measured and recorded" Are pressure differential values in the different areas measured and recorded" Are records ept" Are particulate counts conducted in the controlled environments" Are records ept" Is the fre#uency for performing the test in different classes suitable" Are microbiological controls conducted in the controlled environments" Are records ept" Is the fre#uency for performing the test in different classes suitable" Are air conditioning and-or ventilation systems for each area in accordance )ith the operation to be carried out"
1.11.1.?. 1.11.1.9. 1.11.1.. 1.11.1.<. 1.11.1.1=. 1.11.1.11. 1.11.1.13. 1.11.1.1'. 1.11.1.1(.
1.11.1.3=. 1.11.1.31. 1.11.1.33. 1.11.1.3'. 1.11.1.3(. 1.11.1.38. 1.11.1.3?. 1.11.1.39. 1.11.1.3. 1.11.1.3<.
28
1.11.2.
1.12.
Valiation:
1.11.3.1.
Is the system installation has been #ualified 0 a protocol )ith a report has been produced"
1.11.3.3.
Is the system operation has been #ualified 0a protocol )ith a report has been produced"
1.11.3.'.
Is the system performance has been #ualified 0a protocol )ith a report has been produced"
1.11.3.(.
Does D>P test done in the performance #ualification"
1.11.3.8.
Is the air velocity in grade A has been measured"
1.11.3.?.
Is a preventive maintenance program has been produced from the #ualification"
1.11.3.9.
Is any deviation during #ualification investigated 0a corrective action taen to close the case"
PER%!NNEL 1.12.1. 1.13.1.1. 1.13.1.3.
1.13.1.'. 1.12.2.
1.13.3.1. 1.13.3.3. 1.13.3.'. 1.13.3.(.
General Is there an updated organi&ation chart of the company" Is there a description of the responsibilities and functions of production and #uality control personnel" Are the responsibilities of production and #uality control personnel independent of each other" rainin, Is there a program for on ob training 0 2P$ including specific training appropriate to the duties assigned to them" Is there a program for refreshment training on 2P$ including specific training appropriate to the duties assigned to them" Are the training records for the personnel in charge of cleaning$ if in*house personnel$ sho)n" Is the >perating Personnel trained by Euality Control on sampling methods ,s)abs$ 29
