Document 6w4MjpaXLK4gQ9JLe8BL3oEm4

1 5 2 4 CHA?T ti tV -* * . /? ? * > lubty c h a ract-eriu k s as determ m id by th e chem ical occur if th e p H changed ay^preciahly. B uffer system s o r p h y sic a l form o f th e co m p o u n d , arid free d o m from em p lo y ed scv>uid r.o rm a 2 y r a v e a s low a b u ffer c a p a c ity gross dirt. A d d e d S u b s ta n c e s --T he U S P includes in this category ah substance.; added to a preparation to im a s f*-aribie in o rd e r n o t to d ^ -tu rb sig n ifican tly th e is A y buffer system s v.nen injected. In a d c . t:on, th e b jff-r ra r.r e a n d tzir e-fff-ci oi t h e r/uffer o n m e a c tiv ity o f th e p ro v e o r safeg u ard t t e q u a lity of th e p ro d u ct. An p roduct m u st be ev alu ated carefully.*'' T h e acid salts added suhstar.ee m ay effect solubility, as does sodium m ost frequently em ruoyed as buffers a re citrates, ace b e n z o a te i t C affeine an d S odium rh-ri7/>ate Injectio n , ta te s , an d n.nospr.ates. o r provide pac.ent com fort. as do s - tn a n c e s added to A n tio x id a n ts --A r.tioxidantsare frequently required m ake a solution isotonic. T hey m ay enfram e th e chem to preserve pro d u cts because of th e ease w ith wnich ical stab ility of a solution, as co antioxidants, inert m any drugs are oxidized. Sodium bisulfite 0.1'', gases, chelating a genu, and buffers, or they m ay pre U m ost frequently used. T h e use of sulfites as an ti se rv e a p re p a ra tio n a r a m s t th e g ro w m o f m icro o rg an o x id an ts r_as been rev iew ed b y S c b ro e te r." A cetone ism s. T h e t e r m `'p r e s e r v a tiv e " is s o m e tim e s a p p lie d s o d iu m b isu lfite , so d iu m fo rm a ld e h y d e su lfo x y la te , only to those substance? which prevent th e grow th of and thiourea are also som etim es used. T h e sodium m icroorgarT sm s ir. a'.r* -p arai .cn. T n .c term should n o t , salt of ethy len cdiam inetem aacetic acid has been found be so lim ited o u t shoulo include all substances triat act to enhance th e activ ity of antioxidants in som e cases, to re ta rd o r p rev en t th e chem ical, pn> sicai, or biological ap p aren tly by chelating m etallic ions th a t w ould o th er degradation of a preparation. wise cataly ze th e o x idation reaction. W hile added substances m ay prevent a certain reac tio n from taking place, t noy m ay induce others. N ot only m ay vislole incom patibilities occur, b u t hydrolysis, Pyrogens c o m p u ta tio n , oxidation, and other invisible reactions m ay decom pose or otherw ise inactivate the therapeutic agent. T herefore, added substances m ust oe selected Pyrogens are not predeterm ined com ponents of parenteral preparations, b u t they m ay be present as unw anted contam inants. If they are present, the w ith d u e c o n s id e ra tio n a n d in v e s tig a tio n o f th e e tie c t p ro d u c t rrt3' h a v e to be d isc a rd e d sin c e it is v e ry diffi o f th e substance on th e to tal form ulation. cult to rem ove th em w ithout adversely affecting the A n tim ic ro b ia l A g e n ts--T he U SP states th a t anti- product. T h e only safe and proper w ay to m anage m icrobial ag en ts in b acteriostatic or fungistatic con pvrogen con tam in atio n is to keep it o u t of th e prod c e n tra tio n s m u st be aa dec to p rep aratio n s contained in u ct. P resence o f pyrogens, therefore, is indicative m ultiple-dose containers. T hey m u st be present in of an im properly prep ared product. ad eq u ate concentration a t the tim e of use*1 to prevent P yrogens cause a febrde reactio n in hu m an beings. th e m u ltip lic a tio n of m icro o rg an ism s in a d v e rte n tly O xher sy m p to m s in clu d e chills, p a in s in b ack a n d legs, introduced in to th e preparation while w ithdraw ing a and m alaise. W hile pyrogens are rarely fatal, they p o rtio n o f th e co n ten ts w ith a hypoderm ic needle and produce significant discom fort for th e p atien t. O n the syringe. A m ong the com pounds m ost frequently other hand, pyrogens have been show n to induce a gen C. .ll.Jpi1O.N. .C. JU, -O--!l.li1.l LLilC. ^ 1. .1. . . '*- (J .4.X ..UVV U eral iiuib,eoific isitance to m icroorganism s*' and, th e U S P , a re : phenyl m ercuric n itra te a n d thim erosal on th is bosds, h a v e been used th erap eu tically . 0.015c b e n z e th o n iu m c h lo rid e a n d b e n z a lk o n iu m ch lo P yrogens are products of th e grow th of m icroorgan r id e 0.0 1 p h e n o l o r cresol 0.5'- '_. a n d c n lo r o b u ta n o l ism s. T h e m o s t p o te n t p y ro g e n ic s u b s ta n c e s are 0.55c- T h e ab o v e lim it is rareiv used for phenyl- produced by G ram -n eg ativ e b acteria, b u t G ram -posi ` m ercuric n itra te , bein-: m ost frequently em ployed in a tiv e b acteria and fungi also produce pyrogenic su b co n c e n tra tio n of 0.002 M ethyl p -hydrory benzoate stances. T h e potency varies w ith th e species produc 0.185c a n d pro p y l p-h.ydroxybenzoate 0.02 in com ing it. C hem ically, pyrogenic m aterial h as been shown b in a tio n , a n d b e n z y l a lc o h o l 2 LT 2re frequently to be lipid in n atu re, som etim es containing phosphorus, used. In oleaginous preparations, no an tib acterial and is a ttach ed to a polysaccharide or a protein or both. a g e n t com m only em ployed a p p ears to be effective. W hen so c o m p leted , it is a w eak antigen.-- A tolerance H ow ever, it h as been reported th a t hexyiresorcinol to pyrogens will develop in m an an d susceptible 0.5 5V S p h e n y lm e r c u ric b e n z o a te 0 .1 5 c 1* a r e m o d a n im a ls. e ra te ly bacrexicidaU Pyrogens can be destroyed by heating a t high tem A ntim icrobial agents m ust be studied w ith respect to peratures. T he recom m ended procedure for depyro- com p atib ility w ith all other com ponents of th e form ula. zenation o f glassw are and equipm ent is heating at a I n addition, their activity m ust be evaluated in the tem perature of 250- C for 45 m in. It has been reported to ta l fo rm u la. I t is n o t unco m m o n to find th a t a th a t 6 5 0 *C for I m in o r 1 5 0 "C for 4 h r w ill likewise p articu lar ag en t w ill be effective in one form ulation destroy pyrogens. T h e usual autoclaving cycle wuj b u t ineffective in another. T h is m ay be due to the n o t do so. A lthough h eatin g w ith strong alkaii effect o f v ario u s com ponents o f th e form ula on th e solutions will d estro y pyrogens, th e usual washing biological activ ity o r availability o f th e com pound; cycles, including d eterg en t tre a tm e n t, can n o t be relied for exam ple, th e binding and inactivation of esters of on to com pletely elim inate pyrogens from glassw are. p - h y d ro x v b e n z o ic a c id b y m a c ro m o le c u le s su c h a s H e a tin g -"ith o x id iz in g a g e n ts , su c h a s h y d ro g e n ;>'** P o ly s o r b a te 8 0 * o r t h e re d u c tio n o f p h e n y lm e rc u ric o x id e, w il d e s tro y p y ro g e n s . I t h a s b e e n r e p o rte d t*-*l n itra te b y sulfide residues in ru b b er closures. A anion exchange rosm s will ad so rb pyrogens irora w ater. p hysical reactio n encountered is th a t b acterio static H ow ever, d ie m ost reliable m ethod for th e eliniinat.on a g e n ts a r e s o m e tim e s re m o v e d fro m s o lu tio n b y r u b b e r o f th e s e s u b s t a r .-vs fro m w a te r is d is tilla tio n . closures.'* T hose facts estab lish th e p rinciple th a t genic su b sta n c e s re n o t v o latile a n d th u s will renvua an tim icro b ial agents m u st be evaluated lor their ac in th e distilland. T h e only m ethod available lor tiv ity in th e to tal form ula to assure their activity when sideratson for th e rem oval of pyrogenic su h s ta -'^ ' Deeded, n o r m a lly a t th e time* o f u se. from solutions is n itratio n through asbestos B u ffe rs-- B uffers a re used prim arily to stabilize a T h is m eth o d is q u ite lim ited, how ever, since so lu tio n a g ain st th e chem ical d eg rad atio n th a t w ould fibers rem ove th e pyrogen by ad so rp tio n an d th e >nna p h y s ic a l p h e n o m e r o - ?~s t i t u e n t i as well. jr. r actio n ri ad-orj/tio-- - s a tu ra te d , th e r^rr.i - * th ro u g h tno i.rs.r. j-_ 1 in p lia r m s c e j t i c a i *r< Bom etirr.es by c .r - f * i d ilu te a d d , or :r,, : S ources o f Pyrogen > ' r a t i o n b y a n y m e a - - . - ' m icroorganism s cr ! P e r h a p s th e g r e a te s t j*_: | n a tio n is th e w ater : | d istillatio n will rrovio-^ ; potential source of ) genic m aterials a -- -re p a rtic u la r, b u t a^-o to t r ' R eusing container^ e ; is a d a n g e r o u s a n d a s,;-*; I* ta m in a tio n . R e s. d_ e s c : becom e bacterial cu.tures f vironm eni. Such ee:;..-- j ^ t h p y ro g en s. E-. en posed to the atm osphere n for m icroorganism s to c d e s t r o y p y ro g e n s, tr.-r . ; long periods of tim e. Ac by dry heat depyrogem : eq u ip m e n t su itab le for ui. T h e solute also m av be . m ay be crystali^-i-d or liquids containing pvrog p ro c e ss p;.TOgens rr.sv he layers. In such cases tn recrystallization, creed:.:, to elim in ate th e pyrotrer.s. T h e m an u factu rin g pro. w ith great care and ,, t , th e risk of microb_aJ cor m o r e p r o d u c t s h o u ld he nr* processed w ithin one c r tio n . B y far th e best pn.v d u ctio n of pyrogens rathe: th e m , a task w hich weii m Containers C ontainers are an integr a n injection an d m ay be ` th ere is no container th at t in s o m e w a y a ffe c t t h e 1: if th e liquid is aqueous, container for a oarticuiar : consideration of th e com r w ell as o f th e solution, ar.d be subjected. PL T herm oplastic polym er a few are being used as selected sterile products solutions. H ow ever, it : therm oplastic com pounds r ctently to prove then- non: dennite reactivity p attern : packaging o f injections. A u tia n has thoroagh.K m a te r i a l s in p h a r m a e c u : :ce. bave show n th a t extractive: tA M JiTEfcM. K fA K A T)OmS 1 5 2 5 1p h y sic a l p h e n o m e n o n m a y a c t to re m o v e ch em ical c o n an s stitu e n ts as well. In ad d itio n , since th e m echanism o f a ty action is adsorption, once tn e fibers of asbestos are >dy sa tu ra te d , th e rem ain in g pyrogenic m aterial will pass iier ir.ro Jgh th e niter. In-process d estru ctio n of pyrocens th e in p n arm aceu ticai p rep aratio n s m ay be accom p:Isr.ed a lts som etim es by careful heating w ith dilute alsaii, ace- d ilu te a cid , o r rr.iJd o x idizing ag en ts. ired hich S o u rc e s o f P y ro g en s--Pyrogens m ay enter a prepa ratio n b y a n y m eans th a t will in tro d u ce U sing or dead m icroorganism s or th e products of their growth- -1Tt intito n e Perhaps the greatest yotential source of such contam icatfo n is th e w a te r used in p ro d u cts. H ow ever, pror>er d istillatio n will p rovide pyrogen-free w ater. A nother late, lium >und l potential source o f co n tam ination is eq u ip m en t. P y ro genic m aterials adhere strongly to glass surfaces in particular, b u t also to th e surface o f other equipm ent. ases, ther- R eusing containers, as is often practiced in Hospitals, is a d a n g e ro u s a n d a sig n ifican t source o f p y ro ren ic c o n tam in atio n . R esidues of solutions in used bo ttles often become bacterial cultures from septic patients or the en v iro n m en t. Such b o ttles will be heavily co n tam in ated w ith pyrogens. E ven w ashed bottles left wet and ex ts of n t as . the diffiig the anage prodcative j j j j j posed to th e atm osphere m ay contain sufficient n u trie n ts for m icroorganism s to grow. Since drying does n o t destroy pyrogens, th e y m ay rem ain in eq u ip m en t for long p erio d s o f tim e. A d eq u ate w ashing accom panied by d ry h e a t depyrogenation will render co n tam in ated equipm ent suitable for use. T he solute also m ay be a source of pyrogens. S olutes may be crystallized or precipitated from aqueous liquids containing pyrogenic contam ination. In th e jeings. | process pyrogens m ay be trap p ed w ithin th e particle d legs, , they Dn the a gen* and, t i j i j layers. In su ch cases th e so lu te m u st be purified by recrystallization, precipitate w ashing, or o th er m eans to elim inate th e pyrogens. T he m anufacturing process also m u st be carried o u t with great care an d as rapidly as possible to m inim ize the risk of m icrobial contam ination. P referably, no organ- 1 m ore p ro d u c t sh o u ld be p rep ared th a n c a n be co m p letely e s are | m-posi- processed w ithin one w orking day. including steriliza tion. B y far th e best procedure is to prev en t th e in tro ic sub- j produc- . duction o f pyrogens ra th e r th a n to a tte m p t to rem ove them, a ta s k w hich well m ay be v irtu a lly im possible. ishow n ; pborus. ! ar both- ! . Containers deranoe | ceptible j Containers a re an in te g ra l p a r t o f th e fo rm u la tio n o f Bn in je c tio n a n d m a y b e c o n sid e re d a c o m p o n e n t, fo r g h tern- i depvro- 1 mg at * ' neportet i likewise; ; fd e ` g alki" - there is no c o n ta in e r th a t is to ta lly insoluble o r does n o t Y} som e w ay a ffe c t t h e liq u id it c o n ta in s , p a r tic u la r ly liquid is aqueous. T herefore, the selection of a container for a p articu lar injection m u st be based on a consideration o f th e com position of th e container, as well as o f t h e solution, a n d th e tr e a tm e n t to w h ic h it will subjected. -shir- i b e relief \ P la stic lassvrJTt ' >gen ! rted th : i water- xninatv- * X- I V ' a rein ' ' ; for <V ubst-i^' as fih<~ asJV ~ . the i i "Therm oplastic polym ers are being considered an d * few- a r e b e in g u s e d a s t h e c o n ta in e r m a te r ia l fo r "" ^cted s te r i l e p r o d u c ts , p a r tic u la r ly o p h th a lm ic ^uXJons. H ow ever, it is generally conceded th a t %* n ao p lastic c o m p o u n d s h a v e n o t b e e n s tu d ie d sufffi>'n tly t o p r o v e t h e ir n o n r e a c tiv ity , o r to e s ta b lis h a ""nue re a c tiv ity p a tte rn to define th eir sa fety for th e *' **ging o f injections. Auttan h as tlioroughiv review ed th e use o f plastic '"e ria ls in p h arm acv u ticsU p r a c tic e .3* H e a n d o th e r s uv* show n th a t ex tractiv es a re o b tain ed from th erm o plastic m aterials and, w ith certain polym ers, sorp tio n 'ab so rp tio n an d or adsorption* o f d ru g m olecules or ions m ay occur.-- T h e la tte r is observed in p articu lar w ith polyam ides such as nylon. T h e lack o f sufficiently hig.n s ta n d a rd s in th e m a n u factu re of plastics and th e fact th a t th e low er-cost polym ers can n o t be sterilized by th erm al m ethods are also d eterren ts to th eir use. T hese and o th er prob lem s are receiving concentrated a tten tio n . I t seem s reasonable to expect th a t eventually therm oplastic m aterials will be used for co n tain ers o f selected in ject able preparations. A t present, how ever, th e use of these m aterials is lim ited largely to com ponents of dis posable injection u nits w here contact w ith th e solution is brief. F or ophthalm ic preparations th e flexibility of th e low -density polyetnylene polym er provides a signifi can t use cr.aracteristic, m aking it possible to squeeze o u t and ad m in ister one o r m ore drot/s o f th e p rep ara tion. T herefore, several ophthalm ic form ulations h a v e b e e n a d a p t e d to p la s tic c o n t a i n e r s .55 W hen therm oplastic containers are used for sterile solutions, th e em pty container m ust be sterilized by m eans of ethylene oxide or ionized rad iatio n s an d fiiled asep ticaiiy w ith a ste rile so lu tio n . C onsiderable a tte n tio n is being given to th e sm all a m o u n t o f ethylene oxide residue in plastics afte r sterilization a n d i t s p o t e n t i a l to x ic e f fe c ts .5* S e e C h a p t e r 91 o n P lastics. Glass G lass is em ployed as th e co n tain er m aterial o f choice for m o st in jectio n s. I t is com posed p rin cip ally of silicon dioxide w ith vary in g am o u n ts o f o th e r oxides such as those of sodium , potassium , calcium , m ag nesium . alum inum , boron, and iron. T h e basic stru c tu ra l n etw o rk o f glass is form ed b y th e silicon oxide t e t r a h e d r o n .54 B o ric o x id e w ill e n t e r in to t h i s s tr u c ture. b u t m ost of th e other oxides do n o t. T h e latter are only loosely bound, are p resent in tn e n etw o rk in ter stices, an d are relatively free to m igrate. T hese m igratory oxides m ay be leached into a solution in co n tact w ith th e glass, particu larly during th e increased reactiv ity of therm al sterilization. T h e oxides th u s dissolved m ay hydrolyze to raise th e pH of th e solution, catalyze reactions, or enter into reactions. In a m an ner as y et u n certain, som e glass com pounds will be attack ed by solutions and. in tim e, dislodge giass flakes into th e olution. D isturbing reactions suen as these can. how ever, be m inim ized by th e proper selection o f th e glass com position. T y p e s -- T h e IfiSP h as aid ed in th is selection by p ro v id in g a classificatio n o f glass; n a m e ly . T y p e I, a borosiiicate glass: T y p e II. a soda-lim e tre a te d glass: T y p e I I I , a soda-lim e glass; an d N P . a soda-lim e glass n o t suitable for containers for parent erals. T ype I glass is com posed principally o f silicon dioxide a n d boric oxide, w ith iow levels of th e norm etwotk-forrm r.g oxides. I t is a chem ically resistan t glass low leaeh ab iiity >ais> having a low th erm al coefficient o f expansion. T y p e I I and T y p e I II glass com pounds are com posed o f rela tively high proportions of sodium oxide an d calcium oxide. T h is m akes th e glass chem ically less resistan t. B o th o f these types m elt a t a low er tem p eratu re, are easier to m old into various shapes, and have a higher th erm al coefficient o f expansion th a n T y p e I. W hile th e re is no one sta n d ard form ulation for glass am ong m a n u fa c tu re rs o f th e se L*SP ty p e categ o ries. T y p e II glass usually h as a lower co ncentration o f th e m igratory