21 CFR Parts 210 and 211 - Current Good Manufacturing Practice In Manufacturing, Processing, Packing or Holding of Drugs; General

and Current Good Manufacturing Practice For Finis ed P ar!aceuticals

Revisions as of 2 May 2006 Part 210 - C"RR#$% G&&D M'$"F'C%"RI$G PR'C%IC# I$ M'$"F'C%"RI$G, PR&C#((I$G, P'C)I$G, &R H&*DI$G &F DR"G(; G#$#R'*
Sec. 210.1 Status of current good manufacturing practice regulations. 210.2 Applicability of current good manufacturing practice regulations. 210.3 Definitions.

Part 211 - C"RR#$% G&&D M'$"F'C%"RI$G PR'C%IC# F&R FI$I(H#D PH'RM'C#"%IC'*( Subpart A !eneral "rovisions
Sec. 211.1 Scope. 211.3 Definitions.

Subpart # $rgani%ation and "ersonnel

211.22 Responsibilities of &uality control unit. 211.2' "ersonnel &ualifications. 211.2( "ersonnel responsibilities. 211.3) *onsultants.

Subpart * #uildings and +acilities

211.)2 Design and construction features. 211.)) ,ig-ting. 211.)6 .entilation/ air filtration/ air -eating and cooling. 211.)( "lumbing. 211.'0 Se0age and refuse. 211.'2 1as-ing and toilet facilities.

211.'6 Sanitation. 211.'( Maintenance.

Subpart D 2&uipment
211.63 2&uipment design/ si%e/ and location. 211.6' 2&uipment construction. 211.63 2&uipment cleaning and maintenance. 211.6( Automatic/ mec-anical/ and electronic e&uipment. 211.32 +ilters.

Subpart 2 *ontrol of *omponents and Drug "roduct *ontainers and *losures

211.(0 !eneral re&uirements. 211.(2 Receipt and storage of untested components/ drug product containers/ and closures. 211.() 4esting and approval or re5ection of components/ drug product containers/ and closures. 211.(6 6se of approved components/ drug product containers/ and closures. 211.(3 Retesting of approved components/ drug product containers and closures. 211.(7 Re5ected components/ drug product containers/ and closures. 211.7) Drug product containers and closures.

Subpart + "roduction and "rocess *ontrols

211.100 1ritten procedures8 deviations. 211.101 *-arge in of components. 211.103 *alculation of yield. 211.10' 2&uipment identification. 211.110 Sampling and testing of in process materials and drug products. 211.111 4ime limitations on production. 211.113 *ontrol of microbiological contamination. 211.11' Reprocessing.

Subpart ! "ac9aging and ,abeling *ontrol

211.122 Materials e:amination and usage criteria. 211.12' ,abeling issuance. 211.130 "ac9aging and labeling operations. 211.132 4amper evident pac9aging re&uirements for over t-e counter ;$4*< -uman drug products. 211.13) Drug product inspection. 211.133 2:piration dating.

Subpart = =olding and Distribution

211.1)2 1are-ousing procedures. 211.1'0 Distribution procedures.

Subpart > ,aboratory *ontrols

211.160 !eneral re&uirements. 211.16' 4esting and release for distribution. 211.166 Stability testing.

211.163 Special testing re&uirements. 211.130 Reserve samples. 211.133 ,aboratory animals. 211.136 "enicillin contamination.

Subpart ? Records and Reports

211.1(0 !eneral re&uirements. 211.1(2 2&uipment cleaning and use log. 211.1() *omponent/ drug product container/ closure/ and labeling records. 211.1(6 Master production and control records. 211.1(( #atc- production and control records. 211.172 "roduction record revie0. 211.17) ,aboratory records. 211.176 Distribution records. 211.17( *omplaint files.

Subpart @ Returned and Salvaged Drug "roducts

211.20) Returned drug products. 211.20( Drug product salvaging.

Part 210 - C"RR#$% G&&D M'$"F'C%"RI$G PR'C%IC# I$ M'$"F'C%"RI$G, PR&C#((I$G, P'C)I$G, &R H&*DI$G &F DR"G(; G#$#R'*
A64=$R>4AB 21 6.S.*. 321/ 3'1/ 3'2/ 3''/ 360b/ 331/ 33)8 )2 6.S.*. 216/ 262/ 263a/ 26). S$6R*2B )3 +R )'036/ Sept. 27/ 173(/ unless ot-er0ise noted.

+ 210,1 (tatus of current good !anufacturing -ractice regulations,

;a< 4-e regulations set fort- in t-is part and in parts 211 t-roug- 226 of t-is c-apter contain t-e minimum current good manufacturing practice for met-ods to be used in/ and t-e facilities or controls to be used for/ t-e manufacture/ processing/ pac9ing/ or -olding of a drug to assure t-at suc- drug meets t-e re&uirements of t-e act as to safety/ and -as t-e identity and strengt- and meets t-e &uality and purity c-aracteristics t-at it purports or is represented to possess. ;b< 4-e failure to comply 0it- any regulation set fort- in t-is part and in parts 211 t-roug- 226 of t-is c-apter in t-e manufacture/ processing/ pac9ing/ or -olding of a drug s-all render suc- drug to be adulterated under section '01;a<;2<;#< of t-e act and suc- drug/ as 0ell as t-e person 0-o is responsible for t-e failure to comply/ s-all be sub5ect to regulatory action. ;c< $0ners and operators of establis-ments engaged in t-e recovery/ donor screening/ testing ;including donor testing</ processing/ storage/ labeling/ pac9aging/ or distribution of -uman cells/ tissues/ and cellular and tissue based products ;=*4C"s</ as defined in D1231.3;d< of t-is c-apter/ t-at are drugs ;sub5ect to revie0 under an application submitted under section '0' of t-e act or under a biological product license application under section 3'1 of t-e "ublic =ealtService Act</ are sub5ect to t-e donor eligibility and applicable current good tissue practice procedures set fort- in part 1231 subparts * and D of t-is c-apter/ in addition to t-e regulations in

t-is part and in parts 211 t-roug- 226 of t-is c-apter. +ailure to comply 0it- any applicable regulation set fort- in t-is part/ in parts 211 t-roug- 226 of t-is c-apter/ in part 1231 subpart * of t-is c-apter/ or in part 1231 subpart D of t-is c-apter 0it- respect to t-e manufacture/ processing/ pac9ing or -olding of a drug/ renders an =*4C" adulterated under section '01;a<;2< ;#< of t-e act. Suc- =*4C"/ as 0ell as t-e person 0-o is responsible for t-e failure to comply/ is sub5ect to regulatory action. E)3 +R )'036/ Sept. 27/ 173(/ as amended at 67 +R 27(2(/ May 2'/ 200).F

+ 210,2 '--lica.ilit/ of current good !anufacturing -ractice regulations,

;a< 4-e regulations in t-is part and in parts 211 t-roug- 226 of t-is c-apter as t-ey may pertain to a drug8 in parts 600 t-roug- 6(0 of t-is c-apter as t-ey may pertain to a biological product for -uman use8 and in part 1231 of t-is c-apter as t-ey are applicable to a -uman cell/ tissue/ or cellular or tissue based product ;=*4C"< t-at is a drug ;sub5ect to revie0 under an application submitted under section '0' of t-e act or under a biological product license application under section 3'1 of t-e "ublic =ealt- Service Act<8 s-all be considered to supplement/ not supersede/ eac- ot-er/ unless t-e regulations e:plicitly provide ot-er0ise. >n t-e event of a conflict bet0een applicable regulations in t-is part and in ot-er parts of t-is c-apter/ t-e regulation specifically applicable to t-e drug product in &uestion s-all supersede t-e more general. ;b< >f a person engages in only some operations sub5ect to t-e regulations in t-is part/ in parts 211 t-roug- 226 of t-is c-apter/ in parts 600 t-roug- 6(0 of t-is c-apter/ and in part 1231 of t-is c-apter/ and not in ot-ers/ t-at person need only comply 0it- t-ose regulations applicable to t-e operations in 0-ic- -e or s-e is engaged. E)3 +R )'036/ Sept. 27/ 173(/ as amended at 67 +R 27(2(/ May 2'/ 200)/ 31 +R 2)'(/ ?anuary 13/ 2006.F

+ 210,0 Definitions,
;a< 4-e definitions and interpretations contained in section 201 of t-e act s-all be applicable to suc- terms 0-en used in t-is part and in parts 211 t-roug- 226 of t-is c-apter. ;b< 4-e follo0ing definitions of terms apply to t-is part and to parts 211 t-roug- 226 of t-is c-apter. ;1< Act means t-e +ederal +ood/ Drug/ and *osmetic Act/ as amended ;21 6.S.*. 301 et seq.<. ;2< Batch means a specific &uantity of a drug or ot-er material t-at is intended to -ave uniform c-aracter and &uality/ 0it-in specified limits/ and is produced according to a single manufacturing order during t-e same cycle of manufacture. ;3< Component means any ingredient intended for use in t-e manufacture of a drug product/ including t-ose t-at may not appear in suc- drug product. ;)< Drug product means a finis-ed dosage form/ for e:ample/ tablet/ capsule/ solution/ etc./ t-at contains an active drug ingredient generally/ but not necessarily/ in association 0it- inactive ingredients. 4-e term also includes a finis-ed dosage form t-at does not contain an active ingredient but is intended to be used as a placebo. ;'< Fiber means any particulate contaminant 0it- a lengt- at least t-ree times greater t-an its 0idt-.

;6< Non-fiber-releasing filter means any filter/ 0-ic- after any appropriate pretreatment suc- as 0as-ing or flus-ing/ 0ill not release fibers into t-e component or drug product t-at is being filtered. All filters composed of asbestos are deemed to be fiber releasing filters. ;3< Active ingredient means any component t-at is intended to furnis- p-armacological activity or ot-er direct effect in t-e diagnosis/ cure/ mitigation/ treatment/ or prevention of disease/ or to affect t-e structure or any function of t-e body of man or ot-er animals. 4-e term includes t-ose components t-at may undergo c-emical c-ange in t-e manufacture of t-e drug product and be present in t-e drug product in a modified form intended to furnis- t-e specified activity or effect. ;(< Inactive ingredient means any component ot-er t-an an active ingredient. ;7< In-process material means any material fabricated/ compounded/ blended/ or derived by c-emical reaction t-at is produced for/ and used in/ t-e preparation of t-e drug product. ;10< Lot means a batc-/ or a specific identified portion of a batc-/ -aving uniform c-aracter and &uality 0it-in specified limits8 or/ in t-e case of a drug product produced by continuous process/ it is a specific identified amount produced in a unit of time or &uantity in a manner t-at assures its -aving uniform c-aracter and &uality 0it-in specified limits. ;11< Lot number, control number, or batch number means any distinctive combination of letters/ numbers/ or symbols/ or any combination of t-em/ from 0-ic- t-e complete -istory of t-e manufacture/ processing/ pac9ing/ -olding/ and distribution of a batc- or lot of drug product or ot-er material can be determined. ;12< anufacture, processing, pac!ing, or holding of a drug product includes pac9aging and labeling operations/ testing/ and &uality control of drug products. ;13< 4-e term medicated feed means any 4ype # or 4ype * medicated feed as defined in D''(.3 of t-is c-apter. 4-e feed contains one or more drugs as defined in section 201;g< of t-e act. 4-e manufacture of medicated feeds is sub5ect to t-e re&uirements of part 22' of t-is c-apter. ;1)< 4-e term medicated premi" means a 4ype A medicated article as defined in D''(.3 of t-is c-apter. 4-e article contains one or more drugs as defined in section 201;g< of t-e act. 4-e manufacture of medicated premi:es is sub5ect to t-e re&uirements of part 226 of t-is c-apter. ;1'< #ualit$ control unit means any person or organi%ational element designated by t-e firm to be responsible for t-e duties relating to &uality control. ;16< %trength meansB ;i< 4-e concentration of t-e drug substance ;for e:ample/ 0eig-tC0eig-t/ 0eig-tCvolume/ or unit doseCvolume basis</ andCor ;ii< 4-e potency/ t-at is/ t-e t-erapeutic activity of t-e drug product as indicated by appropriate laboratory tests or by ade&uately developed and controlled clinical data ;e:pressed/ for e:ample/ in terms of units by reference to a standard<. ;13< &heoretical $ield means t-e &uantity t-at 0ould be produced at any appropriate p-ase of manufacture/ processing/ or pac9ing of a particular drug product/ based upon t-e &uantity of components to be used/ in t-e absence of any loss or error in actual production.

;1(< Actual $ield means t-e &uantity t-at is actually produced at any appropriate p-ase of manufacture/ processing/ or pac9ing of a particular drug product. ;17< 'ercentage of theoretical $ield means t-e ratio of t-e actual yield ;at any appropriate p-ase of manufacture/ processing/ or pac9ing of a particular drug product< to t-e t-eoretical yield ;at t-e same p-ase</ stated as a percentage. ;20< Acceptance criteria means t-e product specifications and acceptanceCre5ection criteria/ sucas acceptable &uality level and unacceptable &uality level/ 0it- an associated sampling plan/ t-at are necessary for ma9ing a decision to accept or re5ect a lot or batc- ;or any ot-er convenient subgroups of manufactured units<. ;21< (epresentative sample means a sample t-at consists of a number of units t-at are dra0n based on rational criteria suc- as random sampling and intended to assure t-at t-e sample accurately portrays t-e material being sampled. ;22< !ang printed labeling means labeling derived from a s-eet of material on 0-ic- more t-an one item of labeling is printed. E)3 +R )'036/ Sept. 27/ 173(/ as amended at '1 +R 33(7/ Mar. 3/ 17(68 '( +R )13'3/ Aug. 3/ 1773F

Part 211 - Current Good Manufacturing Practice For Finis ed P ar!aceuticals

Aut-orityB 21 6.S.*. 321/ 3'1/ 3'2/ 3''/ 360b/ 331/ 33)8 )2 6.S.*. 216/ 262/ 263a/ 26). SourceB )3 +R )'033/ Sept. 27/ 173(/ unless ot-er0ise noted.

(u.-art '-General Pro1isions

+ 211,1 (co-e
;a< 4-e regulations in t-is part contain t-e minimum current good manufacturing practice for preparation of drug products for administration to -umans or animals. ;b< 4-e current good manufacturing practice regulations in t-is c-apter as t-ey pertain to drug products8 in parts 600 t-roug- 6(0 of t-is c-apter/ as t-ey pertain to drugs t-at are also biological products for -uman use8 and in part 1231 of t-is c-apter/ as t-ey are applicable to drugs t-at are also -uman cells/ tissues/ and cellular and tissue based products ;=*4C"s< and t-at are drugs ;sub5ect to revie0 under an application submitted under section '0' of t-e act or under a biological product license application under section 3'1 of t-e "ublic =ealt- Service Act<8 supplement and do not supersede t-e regulations in t-is part unless t-e regulations e:plicitly provide ot-er0ise. >n t-e event of a conflict bet0een applicable regulations in t-is part and in ot-er parts of t-is c-apter/ or in parts 600 t-roug- 6(0 of t-is c-apter/ or in part 1231 of t-is c-apter/ t-e regulation specifically applicable to t-e drug product in &uestion s-all supersede t-e more general. ;c< "ending consideration of a proposed e:emption/ publis-ed in t-e +2D2RA, R2!>S42R of September 27/ 173(/ t-e re&uirements in t-is part s-all not be enforced for $4* drug products if t-e products and all t-eir ingredients are ordinarily mar9eted and consumed as -uman foods/ and

0-ic- products may also fall 0it-in t-e legal definition of drugs by virtue of t-eir intended use. 4-erefore/ until furt-er notice/ regulations under part 110 of t-is c-apter/ and 0-ere applicable/ parts 113 to 127 of t-is c-apter/ s-all be applied in determining 0-et-er t-ese $4* drug products t-at are also foods are manufactured/ processed/ pac9ed/ or -eld under current good manufacturing practice. E)3 +R )'033/ Sept. 27/ 173(/ as amended at 62 +R 66'22/ Dec. 17/ 17738 67 +R 27(2(/ May 2'/ 200).F

+ 211,0 Definitions,
4-e definitions set fort- in D210.3 of t-is c-apter apply in t-is part.

(u.-art 2-&rgani3ation and Personnel

+ 211,22 Res-onsi.ilities of 4ualit/ control unit,
;a< 4-ere s-all be a &uality control unit t-at s-all -ave t-e responsibility and aut-ority to approve or re5ect all components/ drug product containers/ closures/ in process materials/ pac9aging material/ labeling/ and drug products/ and t-e aut-ority to revie0 production records to assure t-at no errors -ave occurred or/ if errors -ave occurred/ t-at t-ey -ave been fully investigated. 4-e &uality control unit s-all be responsible for approving or re5ecting drug products manufactured/ processed/ pac9ed/ or -eld under contract by anot-er company. ;b< Ade&uate laboratory facilities for t-e testing and approval ;or re5ection< of components/ drug product containers/ closures/ pac9aging materials/ in process materials/ and drug products s-all be available to t-e &uality control unit. ;c< 4-e &uality control unit s-all -ave t-e responsibility for approving or re5ecting all procedures or specifications impacting on t-e identity/ strengt-/ &uality/ and purity of t-e drug product. ;d< 4-e responsibilities and procedures applicable to t-e &uality control unit s-all be in 0riting8 suc- 0ritten procedures s-all be follo0ed.

+ 211,25 Personnel 4ualifications,

;a< 2ac- person engaged in t-e manufacture/ processing/ pac9ing/ or -olding of a drug product s-all -ave education/ training/ and e:perience/ or any combination t-ereof/ to enable t-at person to perform t-e assigned functions. 4raining s-all be in t-e particular operations t-at t-e employee performs and in current good manufacturing practice ;including t-e current good manufacturing practice regulations in t-is c-apter and 0ritten procedures re&uired by t-ese regulations< as t-ey relate to t-e employeeGs functions. 4raining in current good manufacturing practice s-all be conducted by &ualified individuals on a continuing basis and 0it- sufficient fre&uency to assure t-at employees remain familiar 0it- *!M" re&uirements applicable to t-em. ;b< 2ac- person responsible for supervising t-e manufacture/ processing/ pac9ing/ or -olding of a drug product s-all -ave t-e education/ training/ and e:perience/ or any combination t-ereof/ to perform assigned functions in suc- a manner as to provide assurance t-at t-e drug product -as t-e safety/ identity/ strengt-/ &uality/ and purity t-at it purports or is represented to possess. ;c< 4-ere s-all be an ade&uate number of &ualified personnel to perform and supervise t-e manufacture/ processing/ pac9ing/ or -olding of eac- drug product.

+ 211,26 Personnel res-onsi.ilities,

;a< "ersonnel engaged in t-e manufacture/ processing/ pac9ing/ or -olding of a drug product s-all 0ear clean clot-ing appropriate for t-e duties t-ey perform. "rotective apparel/ suc- as -ead/ face/ -and/ and arm coverings/ s-all be 0orn as necessary to protect drug products from contamination. ;b< "ersonnel s-all practice good sanitation and -ealt- -abits. ;c< $nly personnel aut-ori%ed by supervisory personnel s-all enter t-ose areas of t-e buildings and facilities designated as limited access areas. ;d< Any person s-o0n at any time ;eit-er by medical e:amination or supervisory observation< to -ave an apparent illness or open lesions t-at may adversely affect t-e safety or &uality of drug products s-all be e:cluded from direct contact 0it- components/ drug product containers/ closures/ in process materials/ and drug products until t-e condition is corrected or determined by competent medical personnel not to 5eopardi%e t-e safety or &uality of drug products. All personnel s-all be instructed to report to supervisory personnel any -ealt- conditions t-at may -ave an adverse effect on drug products.

+ 211,07 Consultants,
*onsultants advising on t-e manufacture/ processing/ pac9ing/ or -olding of drug products s-all -ave sufficient education/ training/ and e:perience/ or any combination t-ereof/ to advise on t-e sub5ect for 0-ic- t-ey are retained. Records s-all be maintained stating t-e name/ address/ and &ualifications of any consultants and t-e type of service t-ey provide.

(u.-art C-2uildings and Facilities

+ 211,72 Design and construction features,
;a< Any building or buildings used in t-e manufacture/ processing/ pac9ing/ or -olding of a drug product s-all be of suitable si%e/ construction and location to facilitate cleaning/ maintenance/ and proper operations. ;b< Any suc- building s-all -ave ade&uate space for t-e orderly placement of e&uipment and materials to prevent mi:ups bet0een different components/ drug product containers/ closures/ labeling/ in process materials/ or drug products/ and to prevent contamination. 4-e flo0 of components/ drug product containers/ closures/ labeling/ in process materials/ and drug products t-roug- t-e building or buildings s-all be designed to prevent contamination. ;c< $perations s-all be performed 0it-in specifically defined areas of ade&uate si%e. 4-ere s-all be separate or defined areas or suc- ot-er control systems for t-e firmGs operations as are necessary to prevent contamination or mi:ups during t-e course of t-e follo0ing proceduresB ;1< Receipt/ identification/ storage/ and 0it--olding from use of components/ drug product containers/ closures/ and labeling/ pending t-e appropriate sampling/ testing/ or e:amination by t-e &uality control unit before release for manufacturing or pac9aging8 ;2< =olding re5ected components/ drug product containers/ closures/ and labeling before disposition8

;3< Storage of released components/ drug product containers/ closures/ and labeling8 ;)< Storage of in process materials8 ;'< Manufacturing and processing operations8 ;6< "ac9aging and labeling operations8 ;3< Huarantine storage before release of drug products8 ;(< Storage of drug products after release8 ;7< *ontrol and laboratory operations8 ;10< Aseptic processing/ 0-ic- includes as appropriateB ;i< +loors/ 0alls/ and ceilings of smoot-/ -ard surfaces t-at are easily cleanable8 ;ii< 4emperature and -umidity controls8 ;iii< An air supply filtered t-roug- -ig- efficiency particulate air filters under positive pressure/ regardless of 0-et-er flo0 is laminar or nonlaminar8 ;iv< A system for monitoring environmental conditions8 ;v< A system for cleaning and disinfecting t-e room and e&uipment to produce aseptic conditions8 ;vi< A system for maintaining any e&uipment used to control t-e aseptic conditions. ;d< $perations relating to t-e manufacture/ processing/ and pac9ing of penicillin s-all be performed in facilities separate from t-ose used for ot-er drug products for -uman use. E)3 +R )'033/ Sept. 27/ 173(/ as amended at 60 +R )071/ ?an. 20/ 177'F

+ 211,77 *ig ting,

Ade&uate lig-ting s-all be provided in all areas.

+ 211,78 9entilation, air filtration, air eating and cooling,

;a< Ade&uate ventilation s-all be provided. ;b< 2&uipment for ade&uate control over air pressure/ micro organisms/ dust/ -umidity/ and temperature s-all be provided 0-en appropriate for t-e manufacture/ processing/ pac9ing/ or -olding of a drug product. ;c< Air filtration systems/ including prefilters and particulate matter air filters/ s-all be used 0-en appropriate on air supplies to production areas. >f air is recirculated to production areas/ measures s-all be ta9en to control recirculation of dust from production. >n areas 0-ere air contamination occurs during production/ t-ere s-all be ade&uate e:-aust systems or ot-er systems ade&uate to control contaminants.

;d< Air -andling systems for t-e manufacture/ processing/ and pac9ing of penicillin s-all be completely separate from t-ose for ot-er drug products for -uman use.

+ 211,76 Plu!.ing,
;a< "otable 0ater s-all be supplied under continuous positive pressure in a plumbing system free of defects t-at could contribute contamination to any drug product. "otable 0ater s-all meet t-e standards prescribed in t-e 2nvironmental "rotection AgencyGs "rimary Drin9ing 1ater Regulations set fort- in )0 *+R part 1)1. 1ater not meeting suc- standards s-all not be permitted in t-e potable 0ater system. ;b< Drains s-all be of ade&uate si%e and/ 0-ere connected directly to a se0er/ s-all be provided 0it- an air brea9 or ot-er mec-anical device to prevent bac9 sip-onage. E)3 +R )'033/ Sept. 27/ 173(/ as amended at )( +R 11)26/ Mar. 1(/ 17(3F

+ 211,50 (e:age and refuse,

Se0age/ tras-/ and ot-er refuse in and from t-e building and immediate premises s-all be disposed of in a safe and sanitary manner.

+ 211,52 ;as ing and toilet facilities,

Ade&uate 0as-ing facilities s-all be provided/ including -ot and cold 0ater/ soap or detergent/ air driers or single service to0els/ and clean toilet facilities easily accessible to 0or9ing areas.

+ 211,58 (anitation,
;a< Any building used in t-e manufacture/ processing/ pac9ing/ or -olding of a drug product s-all be maintained in a clean and sanitary condition/ Any suc- building s-all be free of infestation by rodents/ birds/ insects/ and ot-er vermin ;ot-er t-an laboratory animals<. 4ras- and organic 0aste matter s-all be -eld and disposed of in a timely and sanitary manner. ;b< 4-ere s-all be 0ritten procedures assigning responsibility for sanitation and describing in sufficient detail t-e cleaning sc-edules/ met-ods/ e&uipment/ and materials to be used in cleaning t-e buildings and facilities8 suc- 0ritten procedures s-all be follo0ed. ;c< 4-ere s-all be 0ritten procedures for use of suitable rodenticides/ insecticides/ fungicides/ fumigating agents/ and cleaning and saniti%ing agents. Suc- 0ritten procedures s-all be designed to prevent t-e contamination of e&uipment/ components/ drug product containers/ closures/ pac9aging/ labeling materials/ or drug products and s-all be follo0ed. Rodenticides/ insecticides/ and fungicides s-all not be used unless registered and used in accordance 0it- t-e +ederal >nsecticide/ +ungicide/ and Rodenticide Act ;3 6.S.*. 13'<. ;d< Sanitation procedures s-all apply to 0or9 performed by contractors or temporary employees as 0ell as 0or9 performed by full time employees during t-e ordinary course of operations.

+ 211,56 Maintenance,
Any building used in t-e manufacture/ processing/ pac9ing/ or -olding of a drug product s-all be maintained in a good state of repair.

(u.-art D-#4ui-!ent
+ 211,80 #4ui-!ent design, si3e, and location,
2&uipment used in t-e manufacture/ processing/ pac9ing/ or -olding of a drug product s-all be of appropriate design/ ade&uate si%e/ and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.

+ 211,85 #4ui-!ent construction,

;a< 2&uipment s-all be constructed so t-at surfaces t-at contact components/ in process materials/ or drug products s-all not be reactive/ additive/ or absorptive so as to alter t-e safety/ identity/ strengt-/ &uality/ or purity of t-e drug product beyond t-e official or ot-er establis-ed re&uirements. ;b< Any substances re&uired for operation/ suc- as lubricants or coolants/ s-all not come into contact 0it- components/ drug product containers/ closures/ in process materials/ or drug products so as to alter t-e safety/ identity/ strengt-/ &uality/ or purity of t-e drug product beyond t-e official or ot-er establis-ed re&uirements.

+ 211,8< #4ui-!ent cleaning and !aintenance,

;a< 2&uipment and utensils s-all be cleaned/ maintained/ and saniti%ed at appropriate intervals to prevent malfunctions or contamination t-at 0ould alter t-e safety/ identity/ strengt-/ &uality/ or purity of t-e drug product beyond t-e official or ot-er establis-ed re&uirements. ;b< 1ritten procedures s-all be establis-ed and follo0ed for cleaning and maintenance of e&uipment/ including utensils/ used in t-e manufacture/ processing/ pac9ing/ or -olding of a drug product. 4-ese procedures s-all include/ but are not necessarily limited to/ t-e follo0ingB ;1< Assignment of responsibility for cleaning and maintaining e&uipment8 ;2< Maintenance and cleaning sc-edules/ including/ 0-ere appropriate/ saniti%ing sc-edules8 ;3< A description in sufficient detail of t-e met-ods/ e&uipment/ and materials used in cleaning and maintenance operations/ and t-e met-ods of disassembling and reassembling e&uipment as necessary to assure proper cleaning and maintenance8 ;)< Removal or obliteration of previous batc- identification8 ;'< "rotection of clean e&uipment from contamination prior to use8 ;6< >nspection of e&uipment for cleanliness immediately before use. ;c< Records s-all be 9ept of maintenance/ cleaning/ saniti%ing/ and inspection as specified in DD 211.1(0 and 211.1(2.

+ 211,86 'uto!atic, !ec anical, and electronic e4ui-!ent,

;a< Automatic/ mec-anical/ or electronic e&uipment or ot-er types of e&uipment/ including computers/ or related systems t-at 0ill perform a function satisfactorily/ may be used in t-e

manufacture/ processing/ pac9ing/ and -olding of a drug product. >f suc- e&uipment is so used/ it s-all be routinely calibrated/ inspected/ or c-ec9ed according to a 0ritten program designed to assure proper performance. 1ritten records of t-ose calibration c-ec9s and inspections s-all be maintained. ;b< Appropriate controls s-all be e:ercised over computer or related systems to assure t-at c-anges in master production and control records or ot-er records are instituted only by aut-ori%ed personnel. >nput to and output from t-e computer or related system of formulas or ot-er records or data s-all be c-ec9ed for accuracy. 4-e degree and fre&uency of inputCoutput verification s-all be based on t-e comple:ity and reliability of t-e computer or related system. A bac9up file of data entered into t-e computer or related system s-all be maintained e:cept 0-ere certain data/ suc- as calculations performed in connection 0it- laboratory analysis/ are eliminated by computeri%ation or ot-er automated processes. >n suc- instances a 0ritten record of t-e program s-all be maintained along 0it- appropriate validation data. =ard copy or alternative systems/ suc- as duplicates/ tapes/ or microfilm/ designed to assure t-at bac9up data are e:act and complete and t-at it is secure from alteration/ inadvertent erasures/ or loss s-all be maintained. E)3 +R )'033/ Sept. 27/ 173(/ as amended at 60 +R )071/ ?an. 20/ 177'F

+ 211,<2 Filters,
+ilters for li&uid filtration used in t-e manufacture/ processing/ or pac9ing of in5ectable drug products intended for -uman use s-all not release fibers into suc- products. +iber releasing filters may not be used in t-e manufacture/ processing/ or pac9ing of t-ese in5ectable drug products unless it is not possible to manufacture suc- drug products 0it-out t-e use of suc- filters. >f use of a fiber releasing filter is necessary/ an additional non fiber releasing filter of 0.22 micron ma:imum mean porosity ;0.)' micron if t-e manufacturing conditions so dictate< s-all subse&uently be used to reduce t-e content of particles in t-e in5ectable drug product. 6se of an asbestos containing filter/ 0it- or 0it-out subse&uent use of a specific non fiber releasing filter/ is permissible only upon submission of proof to t-e appropriate bureau of t-e +ood and Drug Administration t-at use of a non fiber releasing filter 0ill/ or is li9ely to/ compromise t-e safety or effectiveness of t-e in5ectable drug product.

(u.-art #-Control of Co!-onents and Drug Product Containers and Closures

+ 211,60 General re4uire!ents,
;a< 4-ere s-all be 0ritten procedures describing in sufficient detail t-e receipt/ identification/ storage/ -andling/ sampling/ testing/ and approval or re5ection of components and drug product containers and closures8 suc- 0ritten procedures s-all be follo0ed. ;b< *omponents and drug product containers and closures s-all at all times be -andled and stored in a manner to prevent contamination. ;c< #agged or bo:ed components of drug product containers/ or closures s-all be stored off t-e floor and suitably spaced to permit cleaning and inspection. ;d< 2ac- container or grouping of containers for components or drug product containers/ or closures s-all be identified 0it- a distinctive code for eac- lot in eac- s-ipment received. 4-is

code s-all be used in recording t-e disposition of eac- lot. 2ac- lot s-all be appropriately identified as to its status ;i.e./ &uarantined/ approved/ or re5ected<.

+ 211,62 Recei-t and storage of untested co!-onents, drug -roduct containers, and closures,
;a< 6pon receipt and before acceptance/ eac- container or grouping of containers of components/ drug product containers/ and closures s-all be e:amined visually for appropriate labeling as to contents/ container damage or bro9en seals/ and contamination. ;b< *omponents/ drug product containers/ and closures s-all be stored under &uarantine until t-ey -ave been tested or e:amined/ as appropriate/ and released. Storage 0it-in t-e area s-all conform to t-e re&uirements of D211.(0.

+ 211,67 %esting and a--ro1al or re=ection of co!-onents, drug -roduct containers, and closures,
;a< 2ac- lot of components/ drug product containers/ and closures s-all be 0it--eld from use until t-e lot -as been sampled/ tested/ or e:amined/ as appropriate/ and released for use by t-e &uality control unit. ;b< Representative samples of eac- s-ipment of eac- lot s-all be collected for testing or e:amination. 4-e number of containers to be sampled/ and t-e amount of material to be ta9en from eac- container/ s-all be based upon appropriate criteria suc- as statistical criteria for component variability/ confidence levels/ and degree of precision desired/ t-e past &uality -istory of t-e supplier/ and t-e &uantity needed for analysis and reserve 0-ere re&uired by D211.130. ;c< Samples s-all be collected in accordance 0it- t-e follo0ing proceduresB ;1< 4-e containers of components selected s-all be cleaned 0-ere necessary/ by appropriate means. ;2< 4-e containers s-all be opened/ sampled/ and resealed in a manner designed to prevent contamination of t-eir contents and contamination of ot-er components/ drug product containers/ or closures. ;3< Sterile e&uipment and aseptic sampling tec-ni&ues s-all be used 0-en necessary. ;)< >f it is necessary to sample a component from t-e top/ middle/ and bottom of its container/ suc- sample subdivisions s-all not be composited for testing. ;'< Sample containers s-all be identified so t-at t-e follo0ing information can be determinedB name of t-e material sampled/ t-e lot number/ t-e container from 0-ic- t-e sample 0as ta9en/ t-e date on 0-ic- t-e sample 0as ta9en/ and t-e name of t-e person 0-o collected t-e sample. ;6< *ontainers from 0-ic- samples -ave been ta9en s-all be mar9ed to s-o0 t-at samples -ave been removed from t-em. ;d< Samples s-all be e:amined and tested as follo0sB ;1< At least one test s-all be conducted to verify t-e identity of eac- component of a drug product. Specific identity tests/ if t-ey e:ist/ s-all be used.

;2< 2ac- component s-all be tested for conformity 0it- all appropriate 0ritten specifications for purity/ strengt-/ and &uality. >n lieu of suc- testing by t-e manufacturer/ a report of analysis may be accepted from t-e supplier of a component/ provided t-at at least one specific identity test is conducted on suc- component by t-e manufacturer/ and provided t-at t-e manufacturer establis-es t-e reliability of t-e supplierGs analyses t-roug- appropriate validation of t-e supplierGs test results at appropriate intervals. ;3< *ontainers and closures s-all be tested for conformance 0it- all appropriate 0ritten procedures. >n lieu of suc- testing by t-e manufacturer/ a certificate of testing may be accepted from t-e supplier/ provided t-at at least a visual identification is conducted on succontainersCclosures by t-e manufacturer and provided t-at t-e manufacturer establis-es t-e reliability of t-e supplierGs test results t-roug- appropriate validation of t-e supplierGs test results at appropriate intervals. ;)< 1-en appropriate/ components s-all be microscopically e:amined. ;'< 2ac- lot of a component/ drug product container/ or closure t-at is liable to contamination 0itfilt-/ insect infestation/ or ot-er e:traneous adulterant s-all be e:amined against establis-ed specifications for suc- contamination. ;6< 2ac- lot of a component/ drug product container/ or closure t-at is liable to microbiological contamination t-at is ob5ectionable in vie0 of its intended use s-all be sub5ected to microbiological tests before use. ;e< Any lot of components/ drug product containers/ or closures t-at meets t-e appropriate 0ritten specifications of identity/ strengt-/ &uality/ and purity and related tests under paragrap- ;d< of t-is section may be approved and released for use. Any lot of suc- material t-at does not meet sucspecifications s-all be re5ected. E)3 +R )'033/ Sept. 27/ 173(/ as amended at 63 +R 1)3'6/ Mar. 2'/ 177(F

+ 211,68 "se of a--ro1ed co!-onents, drug -roduct containers, and closures,

*omponents/ drug product containers/ and closures approved for use s-all be rotated so t-at t-e oldest approved stoc9 is used first. Deviation from t-is re&uirement is permitted if suc- deviation is temporary and appropriate.

+ 211,6< Retesting of a--ro1ed co!-onents, drug -roduct containers, and closures,

*omponents/ drug product containers/ and closures s-all be retested or ree:amined/ as appropriate/ for identity/ strengt-/ &uality/ and purity and approved or re5ected by t-e &uality control unit in accordance 0it- D211.() as necessary/ e.g./ after storage for long periods or after e:posure to air/ -eat or ot-er conditions t-at mig-t adversely affect t-e component/ drug product container/ or closure.

+ 211,6> Re=ected co!-onents, drug -roduct containers, and closures,

Re5ected components/ drug product containers/ and closures s-all be identified and controlled under a &uarantine system designed to prevent t-eir use in manufacturing or processing operations for 0-ic- t-ey are unsuitable.

+ 211,>7 Drug -roduct containers and closures,

;a< Drug product containers and closures s-all not be reactive/ additive/ or absorptive so as to alter t-e safety/ identity/ strengt-/ &uality/ or purity of t-e drug beyond t-e official or establis-ed re&uirements. ;b< *ontainer closure systems s-all provide ade&uate protection against foreseeable e:ternal factors in storage and use t-at can cause deterioration or contamination of t-e drug product. ;c< Drug product containers and closures s-all be clean and/ 0-ere indicated by t-e nature of t-e drug/ sterili%ed and processed to remove pyrogenic properties to assure t-at t-ey are suitable for t-eir intended use. ;d< Standards or specifications/ met-ods of testing/ and/ 0-ere indicated/ met-ods of cleaning/ sterili%ing/ and processing to remove pyrogenic properties s-all be 0ritten and follo0ed for drug product containers and closures.

(u.-art F-Production and Process Controls

+ 211,100 ;ritten -rocedures; de1iations,
;a< 4-ere s-all be 0ritten procedures for production and process control designed to assure t-at t-e drug products -ave t-e identity/ strengt-/ &uality/ and purity t-ey purport or are represented to possess. Suc- procedures s-all include all re&uirements in t-is subpart. 4-ese 0ritten procedures/ including any c-anges/ s-all be drafted/ revie0ed/ and approved by t-e appropriate organi%ational units and revie0ed and approved by t-e &uality control unit. ;b< 1ritten production and process control procedures s-all be follo0ed in t-e e:ecution of t-e various production and process control functions and s-all be documented at t-e time of performance. Any deviation from t-e 0ritten procedures s-all be recorded and 5ustified.

+ 211,101 C arge-in of co!-onents,

1ritten production and control procedures s-all include t-e follo0ing/ 0-ic- are designed to assure t-at t-e drug products produced -ave t-e identity/ strengt-/ &uality/ and purity t-ey purport or are represented to possessB ;a< 4-e batc- s-all be formulated 0it- t-e intent to provide not less t-an 100 percent of t-e labeled or establis-ed amount of active ingredient. ;b< *omponents for drug product manufacturing s-all be 0eig-ed/ measured/ or subdivided as appropriate. >f a component is removed from t-e original container to anot-er/ t-e ne0 container s-all be identified 0it- t-e follo0ing informationB ;1< *omponent name or item code8 ;2< Receiving or control number8 ;3< 1eig-t or measure in ne0 container8

;)< #atc- for 0-ic- component 0as dispensed/ including its product name/ strengt-/ and lot number. ;c< 1eig-ing/ measuring/ or subdividing operations for components s-all be ade&uately supervised. 2ac- container of component dispensed to manufacturing s-all be e:amined by a second person to assure t-atB ;1< 4-e component 0as released by t-e &uality control unit8 ;2< 4-e 0eig-t or measure is correct as stated in t-e batc- production records8 ;3< 4-e containers are properly identified. ;d< 2ac- component s-all be added to t-e batc- by one person and verified by a second person.

+ 211,100 Calculation of /ield,

Actual yields and percentages of t-eoretical yield s-all be determined at t-e conclusion of eacappropriate p-ase of manufacturing/ processing/ pac9aging/ or -olding of t-e drug product. Succalculations s-all be performed by one person and independently verified by a second person.

+ 211,105 #4ui-!ent identification,

;a< All compounding and storage containers/ processing lines/ and ma5or e&uipment used during t-e production of a batc- of a drug product s-all be properly identified at all times to indicate t-eir contents and/ 0-en necessary/ t-e p-ase of processing of t-e batc-. ;b< Ma5or e&uipment s-all be identified by a distinctive identification number or code t-at s-all be recorded in t-e batc- production record to s-o0 t-e specific e&uipment used in t-e manufacture of eac- batc- of a drug product. >n cases 0-ere only one of a particular type of e&uipment e:ists in a manufacturing facility/ t-e name of t-e e&uipment may be used in lieu of a distinctive identification number or code.

+ 211,110 (a!-ling and testing of in--rocess !aterials and drug -roducts,

;a< 4o assure batc- uniformity and integrity of drug products/ 0ritten procedures s-all be establis-ed and follo0ed t-at describe t-e in process controls/ and tests/ or e:aminations to be conducted on appropriate samples of in process materials of eac- batc-. Suc- control procedures s-all be establis-ed to monitor t-e output and to validate t-e performance of t-ose manufacturing processes t-at may be responsible for causing variability in t-e c-aracteristics of in process material and t-e drug product. Suc- control procedures s-all include/ but are not limited to/ t-e follo0ing/ 0-ere appropriateB ;1< 4ablet or capsule 0eig-t variation8 ;2< Disintegration time8 ;3< Ade&uacy of mi:ing to assure uniformity and -omogeneity8 ;)< Dissolution time and rate8 ;'< *larity/ completeness/ or p= of solutions.

;b< .alid in process specifications for suc- c-aracteristics s-all be consistent 0it- drug product final specifications and s-all be derived from previous acceptable process average and process variability estimates 0-ere possible and determined by t-e application of suitable statistical procedures 0-ere appropriate. 2:amination and testing of samples s-all assure t-at t-e drug product and in process material conform to specifications. ;c< >n process materials s-all be tested for identity/ strengt-/ &uality/ and purity as appropriate/ and approved or re5ected by t-e &uality control unit/ during t-e production process/ e.g./ at commencement or completion of significant p-ases or after storage for long periods. ;d< Re5ected in process materials s-all be identified and controlled under a &uarantine system designed to prevent t-eir use in manufacturing or processing operations for 0-ic- t-ey are unsuitable.

+ 211,111 %i!e li!itations on -roduction,

1-en appropriate/ time limits for t-e completion of eac- p-ase of production s-all be establis-ed to assure t-e &uality of t-e drug product. Deviation from establis-ed time limits may be acceptable if suc- deviation does not compromise t-e &uality of t-e drug product. Suc- deviation s-all be 5ustified and documented.

+ 211,110 Control of !icro.iological conta!ination,

;a< Appropriate 0ritten procedures/ designed to prevent ob5ectionable microorganisms in drug products not re&uired to be sterile/ s-all be establis-ed and follo0ed. ;b< Appropriate 0ritten procedures/ designed to prevent microbiological contamination of drug products purporting to be sterile/ s-all be establis-ed and follo0ed. Suc- procedures s-all include validation of any sterili%ation process.

+ 211,115 Re-rocessing,
;a< 1ritten procedures s-all be establis-ed and follo0ed prescribing a system for reprocessing batc-es t-at do not conform to standards or specifications and t-e steps to be ta9en to insure t-at t-e reprocessed batc-es 0ill conform 0it- all establis-ed standards/ specifications/ and c-aracteristics. ;b< Reprocessing s-all not be performed 0it-out t-e revie0 and approval of t-e &uality control unit.

(u.-art G-Packaging and *a.eling Control

+ 211,122 Materials e?a!ination and usage criteria,
;a< 4-ere s-all be 0ritten procedures describing in sufficient detail t-e receipt/ identification/ storage/ -andling/ sampling/ e:amination/ andCor testing of labeling and pac9aging materials8 suc- 0ritten procedures s-all be follo0ed. ,abeling and pac9aging materials s-all be representatively sampled/ and e:amined or tested upon receipt and before use in pac9aging or labeling of a drug product.

;b< Any labeling or pac9aging materials meeting appropriate 0ritten specifications may be approved and released for use. Any labeling or pac9aging materials t-at do not meet sucspecifications s-all be re5ected to prevent t-eir use in operations for 0-ic- t-ey are unsuitable. ;c< Records s-all be maintained for eac- s-ipment received of eac- different labeling and pac9aging material indicating receipt/ e:amination or testing/ and 0-et-er accepted or re5ected. ;d< ,abels and ot-er labeling materials for eac- different drug product/ strengt-/ dosage form/ or &uantity of contents s-all be stored separately 0it- suitable identification. Access to t-e storage area s-all be limited to aut-ori%ed personnel. ;e< $bsolete and outdated labels/ labeling/ and ot-er pac9aging materials s-all be destroyed. ;f< 6se of gang printed labeling for different drug products or different strengt-s or net contents of t-e same drug product/ is pro-ibited unless t-e labeling from gang printed s-eets is ade&uately differentiated by si%e/ s-ape/ or color. ;g< >f cut labeling is used/ pac9aging and labeling operations s-all include one of t-e follo0ing special control proceduresB ;1< Dedication of labeling and pac9aging lines to eac- different strengt- of eac- different drug product. ;2< 6se of appropriate electronic or electromec-anical e&uipment to conduct a 100 percent e:amination for correct labeling during or after completion of finis-ing operations8 or ;3< 6se of visual inspection to conduct a 100 percent e:amination for correct labeling during or after completion of finis-ing operations for -and applied labeling. Suc- e:amination s-all be performed by one person and independently verified by a second person. ;-< "rinting devices on/ or associated 0it-/ manufacturing lines used to imprint labeling upon t-e drug product unit label or case s-all be monitored to assure t-at all imprinting conforms to t-e print specified in t-e batc- production record. E)3 +R )'033/ Sept. 27/ 173(/ as amended at '( +R )13'3/ Aug. 3/ 1773F

+ 211,125 *a.eling issuance,

;a< Strict control s-all be e:ercised over labeling issued for use in drug product labeling operations. ;b< ,abeling materials issued for a batc- s-all be carefully e:amined for identity and conformity to t-e labeling specified in t-e master or batc- production records. ;c< "rocedures s-all be used to reconcile t-e &uantities of labeling issued/ used/ and returned/ and s-all re&uire evaluation of discrepancies found bet0een t-e &uantity of drug product finis-ed and t-e &uantity of labeling issued 0-en suc- discrepancies are outside narro0 preset limits based on -istorical operating data. Suc- discrepancies s-all be investigated in accordance 0itD 211.172. ,abeling reconciliation is 0aived for cut or roll labeling if a 100 percent e:amination for correct labeling is performed in accordance 0it- D 211.122;g<;2<. ;d< All e:cess labeling bearing lot or control numbers s-all be destroyed.

;e< Returned labeling s-all be maintained and stored in a manner to prevent mi:ups and provide proper identification. ;f< "rocedures s-all be 0ritten describing in sufficient detail t-e control procedures employed for t-e issuance of labeling8 suc- 0ritten procedures s-all be follo0ed. E)3 +R )'033/ Sept. 27/ 173(/ as amended at '( +R )13')/ Aug. 3/ 1773F

+ 211,100 Packaging and la.eling o-erations,

4-ere s-all be 0ritten procedures designed to assure t-at correct labels/ labeling/ and pac9aging materials are used for drug products8 suc- 0ritten procedures s-all be follo0ed. 4-ese procedures s-all incorporate t-e follo0ing featuresB ;a< "revention of mi:ups and cross contamination by p-ysical or spatial separation from operations on ot-er drug products. ;b< >dentification and -andling of filled drug product containers t-at are set aside and -eld in unlabeled condition for future labeling operations to preclude mislabeling of individual containers/ lots/ or portions of lots. >dentification need not be applied to eac- individual container but s-all be sufficient to determine name/ strengt-/ &uantity of contents/ and lot or control number of eaccontainer. ;c< >dentification of t-e drug product 0it- a lot or control number t-at permits determination of t-e -istory of t-e manufacture and control of t-e batc-. ;d< 2:amination of pac9aging and labeling materials for suitability and correctness before pac9aging operations/ and documentation of suc- e:amination in t-e batc- production record. ;e< >nspection of t-e pac9aging and labeling facilities immediately before use to assure t-at all drug products -ave been removed from previous operations. >nspection s-all also be made to assure t-at pac9aging and labeling materials not suitable for subse&uent operations -ave been removed. Results of inspection s-all be documented in t-e batc- production records. E)3 +R )'033/ Sept. 27/ 173(/ as amended at '( +R )13')/ Aug. 3/ 1773F

+ 211,102 %a!-er-e1ident -ackaging re4uire!ents for o1er-t e-counter @&%CA u!an drug -roducts,
;a< )eneral* 4-e +ood and Drug Administration -as t-e aut-ority under t-e +ederal +ood/ Drug/ and *osmetic Act ;t-e act< to establis- a uniform national re&uirement for tamper evident pac9aging of $4* drug products t-at 0ill improve t-e security of $4* drug pac9aging and -elp assure t-e safety and effectiveness of $4* drug products. An $4* drug product ;e:cept a dermatological/ dentifrice/ insulin/ or lo%enge product< for retail sale t-at is not pac9aged in a tamper resistant pac9age or t-at is not properly labeled under t-is section is adulterated under section '01 of t-e act or misbranded under section '02 of t-e act/ or bot-. ;b< (equirements for tamper-evident pac!age* ;1< 2ac- manufacturer and pac9er 0-o pac9ages an $4* drug product ;e:cept a dermatological/ dentifrice/ insulin/ or lo%enge product< for retail sale s-all pac9age t-e product in a tamper evident pac9age/ if t-is product is accessible to t-e public 0-ile -eld for sale. A tamper evident pac9age

is one -aving one or more indicators or barriers to entry 0-ic-/ if breac-ed or missing/ can reasonably be e:pected to provide visible evidence to consumers t-at tampering -as occurred. 4o reduce t-e li9eli-ood of successful tampering and to increase t-e li9eli-ood t-at consumers 0ill discover if a product -as been tampered 0it-/ t-e pac9age is re&uired to be distinctive by design or by t-e use of one or more indicators or barriers to entry t-at employ an identifying c-aracteristic ;e.g./ a pattern/ name/ registered trademar9/ logo/ or picture<. +or purposes of t-is section/ t-e term Idistinctive by designGG means t-e pac9aging cannot be duplicated 0itcommonly available materials or t-roug- commonly available processes. A tamper evident pac9age may involve an immediate container and closure system or secondary container or carton system or any combination of systems intended to provide a visual indication of pac9age integrity. 4-e tamper evident feature s-all be designed to and s-all remain intact 0-en -andled in a reasonable manner during manufacture/ distribution/ and retail display. ;2< >n addition to t-e tamper evident pac9aging feature described in paragrap- ;b<;1< of t-is section/ any t0o piece/ -ard gelatin capsule covered by t-is section must be sealed using an acceptable tamper evident tec-nology. ;c< Labeling* ;1< >n order to alert consumers to t-e specific tamper evident feature;s< used/ eac- retail pac9age of an $4* drug product covered by t-is section ;e:cept ammonia in-alant in crus-able glass ampules/ containers of compressed medical o:ygen/ or aerosol products t-at depend upon t-e po0er of a li&uefied or compressed gas to e:pel t-e contents from t-e container< is re&uired to bear a statement t-atB ;i< >dentifies all tamper evident feature;s< and any capsule sealing tec-nologies used to comply 0it- paragrap- ;b< of t-is section8 ;ii< >s prominently placed on t-e pac9age8 and ;iii< >s so placed t-at it 0ill be unaffected if t-e tamper evident feature of t-e pac9age is breac-ed or missing. ;2< >f t-e tamper evident feature c-osen to meet t-e re&uirements in paragrap- ;b< of t-is section uses an identifying c-aracteristic/ t-at c-aracteristic is re&uired to be referred to in t-e labeling statement. +or e:ample/ t-e labeling statement on a bottle 0it- a s-rin9 band could say I+or your protection/ t-is bottle -as an imprinted seal around t-e nec9.I ;d< (equest for e"emptions from pac!aging and labeling requirements* A manufacturer or pac9er may re&uest an e:emption from t-e pac9aging and labeling re&uirements of t-is section. A re&uest for an e:emption is re&uired to be submitted in t-e form of a citi%en petition under D 10.30 of t-is c-apter and s-ould be clearly identified on t-e envelope as a IRe&uest for 2:emption from t-e 4amper 2vident "ac9aging Rule.GG 4-e petition is re&uired to contain t-e follo0ingB ;1< 4-e name of t-e drug product or/ if t-e petition see9s an e:emption for a drug class/ t-e name of t-e drug class/ and a list of products 0it-in t-at class. ;2< 4-e reasons t-at t-e drug productGs compliance 0it- t-e tamper evident pac9aging or labeling re&uirements of t-is section is unnecessary or cannot be ac-ieved. ;3< A description of alternative steps t-at are available/ or t-at t-e petitioner -as already ta9en/ to reduce t-e li9eli-ood t-at t-e product or drug class 0ill be t-e sub5ect of malicious adulteration.

;)< $t-er information 5ustifying an e:emption. ;e< +&C drug products sub,ect to approved ne- drug applications* =olders of approved ne0 drug applications for $4* drug products are re&uired under D31).30 of t-is c-apter to provide t-e agency 0it- notification of c-anges in pac9aging and labeling to comply 0it- t-e re&uirements of t-is section. *-anges in pac9aging and labeling re&uired by t-is regulation may be made before +DA approval/ as provided under D 31).30;c< of t-is c-apter. Manufacturing c-anges by 0-iccapsules are to be sealed re&uire prior +DA approval under D 31).30;b< of t-is c-apter. ;f< 'oison 'revention 'ac!aging Act of ./01* 4-is section does not affect any re&uirements for Ispecial pac9agingGG as defined under D 310.3;l< of t-is c-apter and re&uired under t-e "oison "revention "ac9aging Act of 1730. ;Approved by t-e $ffice of Management and #udget under $M# control number 0710 01)7< E') +R '22(/ +eb. 2/ 17(7 as amended at 63 +R '7)30/ Jov. )/ 177(F

+ 211,107 Drug -roduct ins-ection,

;a< "ac9aged and labeled products s-all be e:amined during finis-ing operations to provide assurance t-at containers and pac9ages in t-e lot -ave t-e correct label. ;b< A representative sample of units s-all be collected at t-e completion of finis-ing operations and s-all be visually e:amined for correct labeling. ;c< Results of t-ese e:aminations s-all be recorded in t-e batc- production or control records.

+ 211,10< #?-iration dating,

;a< 4o assure t-at a drug product meets applicable standards of identity/ strengt-/ &uality/ and purity at t-e time of use/ it s-all bear an e:piration date determined by appropriate stability testing described in D211.166. ;b< 2:piration dates s-all be related to any storage conditions stated on t-e labeling/ as determined by stability studies described in D211.166. ;c< >f t-e drug product is to be reconstituted at t-e time of dispensing/ its labeling s-all bear e:piration information for bot- t-e reconstituted and unreconstituted drug products. ;d< 2:piration dates s-all appear on labeling in accordance 0it- t-e re&uirements of D 201.13 of t-is c-apter. ;e< =omeopat-ic drug products s-all be e:empt from t-e re&uirements of t-is section. ;f< Allergenic e:tracts t-at are labeled IJo 6.S. Standard of "otencyGG are e:empt from t-e re&uirements of t-is section. ;g< Je0 drug products for investigational use are e:empt from t-e re&uirements of t-is section/ provided t-at t-ey meet appropriate standards or specifications as demonstrated by stability studies during t-eir use in clinical investigations. 1-ere ne0 drug products for investigational use are to be reconstituted at t-e time of dispensing/ t-eir labeling s-all bear e:piration information for t-e reconstituted drug product.

;-< "ending consideration of a proposed e:emption/ publis-ed in t-e +2D2RA, R2!>S42R of September 27/ 173(/ t-e re&uirements in t-is section s-all not be enforced for -uman $4* drug products if t-eir labeling does not bear dosage limitations and t-ey are stable for at least 3 years as supported by appropriate stability data. E)3 +R )'033/ Sept. 27/ 173(/ as amended at )6 +R '6)12/ Jov. 13/ 17(18 60 +R )071/ ?an. 20/ 177'F

(u.-art H-Holding and Distri.ution

+ 211,172 ;are ousing -rocedures,
1ritten procedures describing t-e 0are-ousing of drug products s-all be establis-ed and follo0ed. 4-ey s-all includeB ;a< Huarantine of drug products before release by t-e &uality control unit. ;b< Storage of drug products under appropriate conditions of temperature/ -umidity/ and lig-t so t-at t-e identity/ strengt-/ &uality/ and purity of t-e drug products are not affected.

+ 211,150 Distri.ution -rocedures,

1ritten procedures s-all be establis-ed/ and follo0ed/ describing t-e distribution of drug products. 4-ey s-all includeB ;a< A procedure 0-ereby t-e oldest approved stoc9 of a drug product is distributed first. Deviation from t-is re&uirement is permitted if suc- deviation is temporary and appropriate. ;b< A system by 0-ic- t-e distribution of eac- lot of drug product can be readily determined to facilitate its recall if necessary.

(u.-art I-*a.orator/ Controls

+ 211,180 General re4uire!ents,
;a< 4-e establis-ment of any specifications/ standards/ sampling plans/ test procedures/ or ot-er laboratory control mec-anisms re&uired by t-is subpart/ including any c-ange in sucspecifications/ standards/ sampling plans/ test procedures/ or ot-er laboratory control mec-anisms/ s-all be drafted by t-e appropriate organi%ational unit and revie0ed and approved by t-e &uality control unit. 4-e re&uirements in t-is subpart s-all be follo0ed and s-all be documented at t-e time of performance. Any deviation from t-e 0ritten specifications/ standards/ sampling plans/ test procedures/ or ot-er laboratory control mec-anisms s-all be recorded and 5ustified. ;b< ,aboratory controls s-all include t-e establis-ment of scientifically sound and appropriate specifications/ standards/ sampling plans/ and test procedures designed to assure t-at components/ drug product containers/ closures/ in process materials/ labeling/ and drug products conform to appropriate standards of identity/ strengt-/ &uality/ and purity. ,aboratory controls s-all includeB

;1< Determination of conformance to appropriate 0ritten specifications for t-e acceptance of eaclot 0it-in eac- s-ipment of components/ drug product containers/ closures/ and labeling used in t-e manufacture/ processing/ pac9ing/ or -olding of drug products. 4-e specifications s-all include a description of t-e sampling and testing procedures used. Samples s-all be representative and ade&uately identified. Suc- procedures s-all also re&uire appropriate retesting of any component/ drug product container/ or closure t-at is sub5ect to deterioration. ;2< Determination of conformance to 0ritten specifications and a description of sampling and testing procedures for in process materials. Suc- samples s-all be representative and properly identified. ;3< Determination of conformance to 0ritten descriptions of sampling procedures and appropriate specifications for drug products. Suc- samples s-all be representative and properly identified. ;)< 4-e calibration of instruments/ apparatus/ gauges/ and recording devices at suitable intervals in accordance 0it- an establis-ed 0ritten program containing specific directions/ sc-edules/ limits for accuracy and precision/ and provisions for remedial action in t-e event accuracy andCor precision limits are not met. >nstruments/ apparatus/ gauges/ and recording devices not meeting establis-ed specifications s-all not be used.

+ 211,185 %esting and release for distri.ution,

;a< +or eac- batc- of drug product/ t-ere s-all be appropriate laboratory determination of satisfactory conformance to final specifications for t-e drug product/ including t-e identity and strengt- of eac- active ingredient/ prior to release. 1-ere sterility andCor pyrogen testing are conducted on specific batc-es of s-ort lived radiop-armaceuticals/ suc- batc-es may be released prior to completion of sterility andCor pyrogen testing/ provided suc- testing is completed as soon as possible. ;b< 4-ere s-all be appropriate laboratory testing/ as necessary/ of eac- batc- of drug product re&uired to be free of ob5ectionable microorganisms. ;c< Any sampling and testing plans s-all be described in 0ritten procedures t-at s-all include t-e met-od of sampling and t-e number of units per batc- to be tested8 suc- 0ritten procedure s-all be follo0ed. ;d< Acceptance criteria for t-e sampling and testing conducted by t-e &uality control unit s-all be ade&uate to assure t-at batc-es of drug products meet eac- appropriate specification and appropriate statistical &uality control criteria as a condition for t-eir approval and release. 4-e statistical &uality control criteria s-all include appropriate acceptance levels andCor appropriate re5ection levels. ;e< 4-e accuracy/ sensitivity/ specificity/ and reproducibility of test met-ods employed by t-e firm s-all be establis-ed and documented. Suc- validation and documentation may be accomplis-ed in accordance 0it- D211.17);a<;2<. ;f< Drug products failing to meet establis-ed standards or specifications and any ot-er relevant &uality control criteria s-all be re5ected. Reprocessing may be performed. "rior to acceptance and use/ reprocessed material must meet appropriate standards/ specifications/ and any ot-er relevant criteria.

+ 211,188 (ta.ilit/ testing,

;a< 4-ere s-all be a 0ritten testing program designed to assess t-e stability c-aracteristics of drug products. 4-e results of suc- stability testing s-all be used in determining appropriate storage conditions and e:piration dates. 4-e 0ritten program s-all be follo0ed and s-all includeB ;1< Sample si%e and test intervals based on statistical criteria for eac- attribute e:amined to assure valid estimates of stability8 ;2< Storage conditions for samples retained for testing8 ;3< Reliable/ meaningful/ and specific test met-ods8 ;)< 4esting of t-e drug product in t-e same container closure system as t-at in 0-ic- t-e drug product is mar9eted8 ;'< 4esting of drug products for reconstitution at t-e time of dispensing ;as directed in t-e labeling< as 0ell as after t-ey are reconstituted. ;b< An ade&uate number of batc-es of eac- drug product s-all be tested to determine an appropriate e:piration date and a record of suc- data s-all be maintained. Accelerated studies/ combined 0it- basic stability information on t-e components/ drug products/ and container closure system/ may be used to support tentative e:piration dates provided full s-elf life studies are not available and are being conducted. 1-ere data from accelerated studies are used to pro5ect a tentative e:piration date t-at is beyond a date supported by actual s-elf life studies/ t-ere must be stability studies conducted/ including drug product testing at appropriate intervals/ until t-e tentative e:piration date is verified or t-e appropriate e:piration date determined. ;c< +or -omeopat-ic drug products/ t-e re&uirements of t-is section are as follo0sB ;1< 4-ere s-all be a 0ritten assessment of stability based at least on testing or e:amination of t-e drug product for compatibility of t-e ingredients/ and based on mar9eting e:perience 0it- t-e drug product to indicate t-at t-ere is no degradation of t-e product for t-e normal or e:pected period of use. ;2< 2valuation of stability s-all be based on t-e same container closure system in 0-ic- t-e drug product is being mar9eted. ;d< Allergenic e:tracts t-at are labeled IJo 6.S. Standard of "otencyGG are e:empt from t-e re&uirements of t-is section. E)3 +R )'033/ Sept. 27/ 173(/ as amended at )6 +R '6)12/ Jov. 13/ 17(1F

+ 211,18< (-ecial testing re4uire!ents,

;a< +or eac- batc- of drug product purporting to be sterile andCor pyrogen free/ t-ere s-all be appropriate laboratory testing to determine conformance to suc- re&uirements. 4-e test procedures s-all be in 0riting and s-all be follo0ed. ;b< +or eac- batc- of op-t-almic ointment/ t-ere s-all be appropriate testing to determine conformance to specifications regarding t-e presence of foreign particles and -ars- or abrasive substances. 4-e test procedures s-all be in 0riting and s-all be follo0ed.

;c< +or eac- batc- of controlled release dosage form/ t-ere s-all be appropriate laboratory testing to determine conformance to t-e specifications for t-e rate of release of eac- active ingredient. 4-e test procedures s-all be in 0riting and s-all be follo0ed.

+ 211,1<0 Reser1e sa!-les,

;a< An appropriately identified reserve sample t-at is representative of eac- lot in eac- s-ipment of eac- active ingredient s-all be retained. 4-e reserve sample consists of at least t0ice t-e &uantity necessary for all tests re&uired to determine 0-et-er t-e active ingredient meets its establis-ed specifications/ e:cept for sterility and pyrogen testing. 4-e retention time is as follo0sB ;1< +or an active ingredient in a drug product ot-er t-an t-ose described in paragrap-s ;a< ;2< and ;3< of t-is section/ t-e reserve sample s-all be retained for 1 year after t-e e:piration date of t-e last lot of t-e drug product containing t-e active ingredient. ;2< +or an active ingredient in a radioactive drug product/ e:cept for nonradioactive reagent 9its/ t-e reserve sample s-all be retained forB ;i< 4-ree mont-s after t-e e:piration date of t-e last lot of t-e drug product containing t-e active ingredient if t-e e:piration dating period of t-e drug product is 30 days or less8 or ;ii< Si: mont-s after t-e e:piration date of t-e last lot of t-e drug product containing t-e active ingredient if t-e e:piration dating period of t-e drug product is more t-an 30 days. ;3< +or an active ingredient in an $4* drug product t-at is e:empt from bearing an e:piration date under D211.133/ t-e reserve sample s-all be retained for 3 years after distribution of t-e last lot of t-e drug product containing t-e active ingredient. ;b< An appropriately identified reserve sample t-at is representative of eac- lot or batc- of drug product s-all be retained and stored under conditions consistent 0it- product labeling. 4-e reserve sample s-all be stored in t-e same immediate container closure system in 0-ic- t-e drug product is mar9eted or in one t-at -as essentially t-e same c-aracteristics. 4-e reserve sample consists of at least t0ice t-e &uantity necessary to perform all t-e re&uired tests/ e:cept t-ose for sterility and pyrogens. 2:cept for t-ose drug products described in paragrap- ;b<;2< of t-is section/ reserve samples from representative sample lots or batc-es selected by acceptable statistical procedures s-all be e:amined visually at least once a year for evidence of deterioration unless visual e:amination 0ould affect t-e integrity of t-e reserve sample. Any evidence of reserve sample deterioration s-all be investigated in accordance 0it- D211.172. 4-e results of e:amination s-all be recorded and maintained 0it- ot-er stability data on t-e drug product. Reserve samples of compressed medical gases need not be retained. 4-e retention time is as follo0sB ;1< +or a drug product ot-er t-an t-ose described in paragrap-s ;b<;2< and ;3< of t-is section/ t-e reserve sample s-all be retained for 1 year after t-e e:piration date of t-e drug product. ;2< +or a radioactive drug product/ e:cept for nonradioactive reagent 9its/ t-e reserve sample s-all be retained forB ;i< 4-ree mont-s after t-e e:piration date of t-e drug product if t-e e:piration dating period of t-e drug product is 30 days or less8 or

;ii< Si: mont-s after t-e e:piration date of t-e drug product if t-e e:piration dating period of t-e drug product is more t-an 30 days. ;3< +or an $4* drug product t-at is e:empt for bearing an e:piration date under D211.133/ t-e reserve sample must be retained for 3 years after t-e lot or batc- of drug product is distributed. E)( +R 1302'/ Mar. 27/ 17(3/ as amended at 60 +R )071/ ?an. 20/ 177'F

+ 211,1<0 *a.orator/ ani!als,

Animals used in testing components/ in process materials/ or drug products for compliance 0itestablis-ed specifications s-all be maintained and controlled in a manner t-at assures t-eir suitability for t-eir intended use. 4-ey s-all be identified/ and ade&uate records s-all be maintained s-o0ing t-e -istory of t-eir use.

+ 211,1<8 Penicillin conta!ination,

>f a reasonable possibility e:ists t-at a non penicillin drug product -as been e:posed to cross contamination 0it- penicillin/ t-e non penicillin drug product s-all be tested for t-e presence of penicillin. Suc- drug product s-all not be mar9eted if detectable levels are found 0-en tested according to procedures specified in K"rocedures for Detecting and Measuring "enicillin *ontamination in Drugs/G 0-ic- is incorporated by reference. *opies are available from t-e Division of Researc- and 4esting ;=+D )30</ *enter for Drug 2valuation and Researc-/ +ood and Drug Administration/ '100 "aint #ranc- "90y./ *ollege "ar9/ MD 203)0/ or available for inspection at t-e Jational Arc-ives and Records Administration ;JARA<. +or information on t-e availability of t-is material at JARA/ call 202 3)1 6030/ or go to -ttpBCC000.arc-ives.govCfederalLregisterCcodeLofLfederalLregulationsCibrLlocations.-tml. E)3 +R )'033/ Sept. 27/ 173(/ as amended at )3 +R 7376/ Mar. '/ 17(28 '0 +R (776/ Mar. 6/ 17('8 '' +R 11'33/ Mar. 27/ 17708 66 +R '603'/ Jov. 6/ 20018 67 +R 1((03/ Apr.7/ 200)F

(u.-art B-Records and Re-orts

+ 211,160 General re4uire!ents,
;a< Any production/ control/ or distribution record t-at is re&uired to be maintained in compliance 0it- t-is part and is specifically associated 0it- a batc- of a drug product s-all be retained for at least 1 year after t-e e:piration date of t-e batc- or/ in t-e case of certain $4* drug products lac9ing e:piration dating because t-ey meet t-e criteria for e:emption under D 211.133/ 3 years after distribution of t-e batc-. ;b< Records s-all be maintained for all components/ drug product containers/ closures/ and labeling for at least 1 year after t-e e:piration date or/ in t-e case of certain $4* drug products lac9ing e:piration dating because t-ey meet t-e criteria for e:emption under D 211.133/ 3 years after distribution of t-e last lot of drug product incorporating t-e component or using t-e container/ closure/ or labeling. ;c< All records re&uired under t-is part/ or copies of suc- records/ s-all be readily available for aut-ori%ed inspection during t-e retention period at t-e establis-ment 0-ere t-e activities described in suc- records occurred. 4-ese records or copies t-ereof s-all be sub5ect to p-otocopying or ot-er means of reproduction as part of suc- inspection. Records t-at can be

immediately retrieved from anot-er location by computer or ot-er electronic means s-all be considered as meeting t-e re&uirements of t-is paragrap-. ;d< Records re&uired under t-is part may be retained eit-er as original records or as true copies suc- as p-otocopies/ microfilm/ microfic-e/ or ot-er accurate reproductions of t-e original records. 1-ere reduction tec-ni&ues/ suc- as microfilming/ are used/ suitable reader and p-otocopying e&uipment s-all be readily available. ;e< 1ritten records re&uired by t-is part s-all be maintained so t-at data t-erein can be used for evaluating/ at least annually/ t-e &uality standards of eac- drug product to determine t-e need for c-anges in drug product specifications or manufacturing or control procedures. 1ritten procedures s-all be establis-ed and follo0ed for suc- evaluations and s-all include provisions forB ;1< A revie0 of a representative number of batc-es/ 0-et-er approved or re5ected/ and/ 0-ere applicable/ records associated 0it- t-e batc-. ;2< A revie0 of complaints/ recalls/ returned or salvaged drug products/ and investigations conducted under D211.172 for eac- drug product. ;f< "rocedures s-all be establis-ed to assure t-at t-e responsible officials of t-e firm/ if t-ey are not personally involved in or immediately a0are of suc- actions/ are notified in 0riting of any investigations conducted under DD 211.17(/ 211.20)/ or 211.20( of t-ese regulations/ any recalls/ reports of inspectional observations issued by t-e +ood and Drug Administration/ or any regulatory actions relating to good manufacturing practices broug-t by t-e +ood and Drug Administration. E)3 +R )'033/ Sept. 27/ 173(/ as amended at 60 +R )701/ ?an. 20/ 177'F

+ 211,162 #4ui-!ent cleaning and use log,

A 0ritten record of ma5or e&uipment cleaning/ maintenance ;e:cept routine maintenance suc- as lubrication and ad5ustments</ and use s-all be included in individual e&uipment logs t-at s-o0 t-e date/ time/ product/ and lot number of eac- batc- processed. >f e&uipment is dedicated to manufacture of one product/ t-en individual e&uipment logs are not re&uired/ provided t-at lots or batc-es of suc- product follo0 in numerical order and are manufactured in numerical se&uence. >n cases 0-ere dedicated e&uipment is employed/ t-e records of cleaning/ maintenance/ and use s-all be part of t-e batc- record. 4-e persons performing and double c-ec9ing t-e cleaning and maintenance s-all date and sign or initial t-e log indicating t-at t-e 0or9 0as performed. 2ntries in t-e log s-all be in c-ronological order.

+ 211,167 Co!-onent, drug -roduct container, closure, and la.eling records,

4-ese records s-all include t-e follo0ingB ;a< 4-e identity and &uantity of eac- s-ipment of eac- lot of components/ drug product containers/ closures/ and labeling8 t-e name of t-e supplier8 t-e supplierGs lot number;s< if 9no0n8 t-e receiving code as specified in D211.(08 and t-e date of receipt. 4-e name and location of t-e prime manufacturer/ if different from t-e supplier/ s-all be listed if 9no0n. ;b< 4-e results of any test or e:amination performed ;including t-ose performed as re&uired by D211.(2;a</ D211.();d</ or D211.122;a<< and t-e conclusions derived t-erefrom.

;c< An individual inventory record of eac- component/ drug product container/ and closure and/ for eac- component/ a reconciliation of t-e use of eac- lot of suc- component. 4-e inventory record s-all contain sufficient information to allo0 determination of any batc- or lot of drug product associated 0it- t-e use of eac- component/ drug product container/ and closure. ;d< Documentation of t-e e:amination and revie0 of labels and labeling for conformity 0itestablis-ed specifications in accord 0it- DD 211.122;c< and 211.130;c<. ;e< 4-e disposition of re5ected components/ drug product containers/ closure/ and labeling.

+ 211,168 Master -roduction and control records,

;a< 4o assure uniformity from batc- to batc-/ master production and control records for eac- drug product/ including eac- batc- si%e t-ereof/ s-all be prepared/ dated/ and signed ;full signature/ -and0ritten< by one person and independently c-ec9ed/ dated/ and signed by a second person. 4-e preparation of master production and control records s-all be described in a 0ritten procedure and suc- 0ritten procedure s-all be follo0ed. ;b< Master production and control records s-all includeB ;1< 4-e name and strengt- of t-e product and a description of t-e dosage form8 ;2< 4-e name and 0eig-t or measure of eac- active ingredient per dosage unit or per unit of 0eig-t or measure of t-e drug product/ and a statement of t-e total 0eig-t or measure of any dosage unit8 ;3< A complete list of components designated by names or codes sufficiently specific to indicate any special &uality c-aracteristic8 ;)< An accurate statement of t-e 0eig-t or measure of eac- component/ using t-e same 0eig-t system ;metric/ avoirdupois/ or apot-ecary< for eac- component. Reasonable variations may be permitted/ -o0ever/ in t-e amount of components necessary for t-e preparation in t-e dosage form/ provided t-ey are 5ustified in t-e master production and control records8 ;'< A statement concerning any calculated e:cess of component8 ;6< A statement of t-eoretical 0eig-t or measure at appropriate p-ases of processing8 ;3< A statement of t-eoretical yield/ including t-e ma:imum and minimum percentages of t-eoretical yield beyond 0-ic- investigation according to D211.172 is re&uired8 ;(< A description of t-e drug product containers/ closures/ and pac9aging materials/ including a specimen or copy of eac- label and all ot-er labeling signed and dated by t-e person or persons responsible for approval of suc- labeling8 ;7< *omplete manufacturing and control instructions/ sampling and testing procedures/ specifications/ special notations/ and precautions to be follo0ed.

+ 211,166 2atc -roduction and control records,

#atc- production and control records s-all be prepared for eac- batc- of drug product produced and s-all include complete information relating to t-e production and control of eac- batc-. 4-ese records s-all includeB ;a< An accurate reproduction of t-e appropriate master production or control record/ c-ec9ed for accuracy/ dated/ and signed8 ;b< Documentation t-at eac- significant step in t-e manufacture/ processing/ pac9ing/ or -olding of t-e batc- 0as accomplis-ed/ includingB ;1< Dates8 ;2< >dentity of individual ma5or e&uipment and lines used8 ;3< Specific identification of eac- batc- of component or in process material used8 ;)< 1eig-ts and measures of components used in t-e course of processing8 ;'< >n process and laboratory control results8 ;6< >nspection of t-e pac9aging and labeling area before and after use8 ;3< A statement of t-e actual yield and a statement of t-e percentage of t-eoretical yield at appropriate p-ases of processing8 ;(< *omplete labeling control records/ including specimens or copies of all labeling used8 ;7< Description of drug product containers and closures8 ;10< Any sampling performed8 ;11< >dentification of t-e persons performing and directly supervising or c-ec9ing eac- significant step in t-e operation8 ;12< Any investigation made according to D211.172. ;13< Results of e:aminations made in accordance 0it- D211.13).

+ 211,1>2 Production record re1ie:,

All drug product production and control records/ including t-ose for pac9aging and labeling/ s-all be revie0ed and approved by t-e &uality control unit to determine compliance 0it- all establis-ed/ approved 0ritten procedures before a batc- is released or distributed. Any une:plained discrepancy ;including a percentage of t-eoretical yield e:ceeding t-e ma:imum or minimum percentages establis-ed in master production and control records< or t-e failure of a batc- or any of its components to meet any of its specifications s-all be t-oroug-ly investigated/ 0-et-er or not t-e batc- -as already been distributed. 4-e investigation s-all e:tend to ot-er batc-es of t-e same drug product and ot-er drug products t-at may -ave been associated 0itt-e specific failure or discrepancy. A 0ritten record of t-e investigation s-all be made and s-all include t-e conclusions and follo0up.

+ 211,1>7 *a.orator/ records,

;a< ,aboratory records s-all include complete data derived from all tests necessary to assure compliance 0it- establis-ed specifications and standards/ including e:aminations and assays/ as follo0sB ;1< A description of t-e sample received for testing 0it- identification of source ;t-at is/ location from 0-ere sample 0as obtained</ &uantity/ lot number or ot-er distinctive code/ date sample 0as ta9en/ and date sample 0as received for testing. ;2< A statement of eac- met-od used in t-e testing of t-e sample. 4-e statement s-all indicate t-e location of data t-at establis- t-at t-e met-ods used in t-e testing of t-e sample meet proper standards of accuracy and reliability as applied to t-e product tested. ;>f t-e met-od employed is in t-e current revision of t-e 6nited States "-armacopeia/ Jational +ormulary/ A$A* >J42RJA4>$JA,/ #oo9 of Met-ods/M1N or in ot-er recogni%ed standard references/ or is detailed in an approved ne0 drug application and t-e referenced met-od is not modified/ a statement indicating t-e met-od and reference 0ill suffice<. 4-e suitability of all testing met-ods used s-all be verified under actual conditions of use.
2.3 Copies ma$ be obtained from4 Association of +fficial Anal$tical Chemists, 5511 6ilson Blvd*, %uite 711, Arlington, 8A 5551.991.*

;3< A statement of t-e 0eig-t or measure of sample used for eac- test/ 0-ere appropriate. ;)< A complete record of all data secured in t-e course of eac- test/ including all grap-s/ c-arts/ and spectra from laboratory instrumentation/ properly identified to s-o0 t-e specific component/ drug product container/ closure/ in process material/ or drug product/ and lot tested. ;'< A record of all calculations performed in connection 0it- t-e test/ including units of measure/ conversion factors/ and e&uivalency factors. ;6< A statement of t-e results of tests and -o0 t-e results compare 0it- establis-ed standards of identity/ strengt-/ &uality/ and purity for t-e component/ drug product container/ closure/ in process material/ or drug product tested. ;3< 4-e initials or signature of t-e person 0-o performs eac- test and t-e date;s< t-e tests 0ere performed. ;(< 4-e initials or signature of a second person s-o0ing t-at t-e original records -ave been revie0ed for accuracy/ completeness/ and compliance 0it- establis-ed standards. ;b< *omplete records s-all be maintained of any modification of an establis-ed met-od employed in testing. Suc- records s-all include t-e reason for t-e modification and data to verify t-at t-e modification produced results t-at are at least as accurate and reliable for t-e material being tested as t-e establis-ed met-od. ;c< *omplete records s-all be maintained of any testing and standardi%ation of laboratory reference standards/ reagents/ and standard solutions. ;d< *omplete records s-all be maintained of t-e periodic calibration of laboratory instruments/ apparatus/ gauges/ and recording devices re&uired by D211.160;b<;)<. ;e< *omplete records s-all be maintained of all stability testing performed in accordance 0itD211.166.

E)3 +R )'033/ Sept. 27/ 173(/ as amended at '' +R 11'33/ Mar. 27/ 17708 6' +R 1(((7/ Apr. 10/ 20008 30 +R 636'0/ Jov. (/ 200'F

+ 211,1>8 Distri.ution records,

Distribution records s-all contain t-e name and strengt- of t-e product and description of t-e dosage form/ name and address of t-e consignee/ date and &uantity s-ipped/ and lot or control number of t-e drug product. +or compressed medical gas products/ distribution records are not re&uired to contain lot or control numbers. ;Approved by t-e $ffice of Management and #udget under control number 0710 0137< E)7 +R 7(6'/ Mar. 16/ 17()F

+ 211,1>6 Co!-laint files,

;a< 1ritten procedures describing t-e -andling of all 0ritten and oral complaints regarding a drug product s-all be establis-ed and follo0ed. Suc- procedures s-all include provisions for revie0 by t-e &uality control unit/ of any complaint involving t-e possible failure of a drug product to meet any of its specifications and/ for suc- drug products/ a determination as to t-e need for an investigation in accordance 0it- D211.172. Suc- procedures s-all include provisions for revie0 to determine 0-et-er t-e complaint represents a serious and une:pected adverse drug e:perience 0-ic- is re&uired to be reported to t-e +ood and Drug Administration in accordance 0itDD310.30' and '1).(0 of t-is c-apter. ;b< A 0ritten record of eac- complaint s-all be maintained in a file designated for drug product complaints. 4-e file regarding suc- drug product complaints s-all be maintained at t-e establis-ment 0-ere t-e drug product involved 0as manufactured/ processed/ or pac9ed/ or sucfile may be maintained at anot-er facility if t-e 0ritten records in suc- files are readily available for inspection at t-at ot-er facility. 1ritten records involving a drug product s-all be maintained until at least 1 year after t-e e:piration date of t-e drug product/ or 1 year after t-e date t-at t-e complaint 0as received/ 0-ic-ever is longer. >n t-e case of certain $4* drug products lac9ing e:piration dating because t-ey meet t-e criteria for e:emption under D211.133/ suc- 0ritten records s-all be maintained for 3 years after distribution of t-e drug product. ;1< 4-e 0ritten record s-all include t-e follo0ing information/ 0-ere 9no0nB t-e name and strengt- of t-e drug product/ lot number/ name of complainant/ nature of complaint/ and reply to complainant. ;2< 1-ere an investigation under D211.172 is conducted/ t-e 0ritten record s-all include t-e findings of t-e investigation and follo0up. 4-e record or copy of t-e record of t-e investigation s-all be maintained at t-e establis-ment 0-ere t-e investigation occurred in accordance 0itD211.1(0;c<. ;3< 1-ere an investigation under D211.172 is not conducted/ t-e 0ritten record s-all include t-e reason t-at an investigation 0as found not to be necessary and t-e name of t-e responsible person ma9ing suc- a determination. E)3 +R )'033/ Sept. 27/ 173(/ as amended at '1 +R 2))37/ ?uly 3/ 17(68 6( +R 1'36)/ Marc31/ 2003.F

(u.-art )-Returned and (al1aged Drug Products

+ 211,207 Returned drug -roducts,

Returned drug products s-all be identified as suc- and -eld. >f t-e conditions under 0-icreturned drug products -ave been -eld/ stored/ or s-ipped before or during t-eir return/ or if t-e condition of t-e drug product/ its container/ carton/ or labeling/ as a result of storage or s-ipping/ casts doubt on t-e safety/ identity/ strengt-/ &uality or purity of t-e drug product/ t-e returned drug product s-all be destroyed unless e:amination/ testing/ or ot-er investigations prove t-e drug product meets appropriate standards of safety/ identity/ strengt-/ &uality/ or purity. A drug product may be reprocessed provided t-e subse&uent drug product meets appropriate standards/ specifications/ and c-aracteristics. Records of returned drug products s-all be maintained and s-all include t-e name and label potency of t-e drug product dosage form/ lot number ;or control number or batc- number</ reason for t-e return/ &uantity returned/ date of disposition/ and ultimate disposition of t-e returned drug product. >f t-e reason for a drug product being returned implicates associated batc-es/ an appropriate investigation s-all be conducted in accordance 0it- t-e re&uirements of D211.172. "rocedures for t-e -olding/ testing/ and reprocessing of returned drug products s-all be in 0riting and s-all be follo0ed.

+ 211,206 Drug -roduct sal1aging,

Drug products t-at -ave been sub5ected to improper storage conditions including e:tremes in temperature/ -umidity/ smo9e/ fumes/ pressure/ age/ or radiation due to natural disasters/ fires/ accidents/ or e&uipment failures s-all not be salvaged and returned to t-e mar9etplace. 1-enever t-ere is a &uestion 0-et-er drug products -ave been sub5ected to suc- conditions/ salvaging operations may be conducted only if t-ere is ;a< evidence from laboratory tests and assays ;including animal feeding studies 0-ere applicable< t-at t-e drug products meet all applicable standards of identity/ strengt-/ &uality/ and purity and ;b< evidence from inspection of t-e premises t-at t-e drug products and t-eir associated pac9aging 0ere not sub5ected to improper storage conditions as a result of t-e disaster or accident. $rganoleptic e:aminations s-all be acceptable only as supplemental evidence t-at t-e drug products meet appropriate standards of identity/ strengt-/ &uality/ and purity. Records including name/ lot number/ and disposition s-all be maintained for drug products sub5ect to t-is section.