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Case 1:04-cv—00833-KAJ Document 257-8 Filed 06/27/2006 Page1 0f4

’ . Case 1 :04-cv-00833-KAJ Document 257-8 Filed 06/27/2006 Page 2 of 4 f ~ y 7 Y
` _ Ph.;-{sari technician epcciaiist/nororoeicin rlycicciiiarim A . -' Y _ I _ g
U ` lil. Coordinates the orientation of trainees and new employees to the · Distribution services ` l$?
L technical functions cl` the assigned area. . Sgerile gud mmsgeyile prpduct [um-miagiom _ -
_ ` 14. Keeps all records and lu: sheets used in assigned area accurate and - • Packaging, printing and labeling , ` ,_ -
N ii`` \ _ ¤P‘i-°•d¤L¤- ` - Pharmacy service unit - .
li _ I *re¤ of Assignment: _ _ . I- Purchasing and inventory control = ·- _
· - · . Pharrriacy technician specialist: may be assigned to the following divisions - • Q¤¤ll*Y €¤¤¤’¤l _ ‘ n .- ----
H l ,.· areas of the Department of Pharmacy. · Systems - E' _
I Am J Boop Rlunrm J6:l53Ll53B (Nov) 1.979 l i . i
V _ . . . Because it is effective in a wide ran¤·e of mali an 'es,_ i __¤ K _
Stability of Refrigerated and Frozen . . ° sn cl .
, _ _ _ _ doxorubicin has become one of the most extensively used _ ,__
n Solullons Ol Dcxomblcm Hydrochlcrlde antineoplastic agents atour institution, anational oneologic _i` _ _
1 _ · Y ` referralcenter with treatment, teachinv and research ro- `
. ·= P -
Dennis M. Hollman, Dennis D. Grossano, LeeAnne Damin` grams .
. . _ and Tlwmas M' W°°dC°°k Last year, in addition to the many inpatients receiving · `
_ ‘ n Y chemotherapy at Memorial Sloan—Kettering Cancer Center, .
- n The stability of refrigerated and,frozen solutions uf demi-obi- , _ amor? than l··4DO patients were ligated inadult Chemotherapy ’ _ ‘ g
- ¤i¤ hydr¤¤hl¤rid= wv =¢¤di=d- i clinics and more than 1,150 children were treated in its Pe· » ·· · Y
· - "‘“" °‘ "°¥°'“"‘“‘T *""'°°¥*‘°"“° "‘“‘ ***9** ‘_*·*·*·¤·¥¤l¤> iiiaiiic Day Hospital. Tiieciiiiicai iceitiiricss Ortimitiiiiciii, Y · Y
were reconstituted w1th_Stenlc Water for Injection; USP, ta _ _ _ . , , , ·
I · provide a drug concentration ol`2 mg/mL`Samplc;-were ref;-iger. _`€¤mbln€d wlth ths large ¤¤mb¤r Oipauenu recewmg Ch'} · M _
, ated (4 C) for up to one year and frozen (·20 C) for 30 days chen ` mqtherapy, resulted in an expenditure of almost $290,000 _ 7* _
` ‘ assayed by high—perf¤rm:ujnce liquid chromatography, Gngrgam- for this drug last yean _ .· I ·` ·
. ple was assayed then refrozen each test period. _ Y _ _, - -- _ _ - _
’ . Refrigerated and frozen samplu showed no substantial lose Since the Pharmacist plays a key role ln preparing antl‘ · I
_ of potency after six months and one month of storage, rcspcc- ‘ negplgstidagerxts and in m0nll.0l’ll’lg patients who receive -_ ' . . A
» Y ”""l".m'“??°" °"°‘T‘l‘ ' °%2‘“.“‘ En'? M "F" ““°°‘ °°‘°"‘ · them we thought we could maximize use of the pharmacist'; Q
_ cy. Degradation products were not detected, except for gn uri. _ . _ ° _ _ _ ,- _ _ _ . i `
. _ , . gdemmed man ,,,3;, deemed in ih, mmpi, remgenwd fm, - Urge byrncluding doxorubicin in our rec0nst1tution_program _ . U.-
¤¤¤ ycar- . and et-ha s freezin the drug-. We have successfully done - #
. _ _ _ _ _ _ P P E
1 D°°`°mi' `FI " .hydr°°hl°r`d°'1wh°" '°°°"i'°`"°d ""Lh "°"l' this with other drugs."Such an undertaking would not be · -· '
· water [nr Il'I]QClJUl’\. may be ftllllgcfgtbd [Of SIX months ur frozen - _ _ I _ _ _ ‘ ·
I for une month without luas of putency. . , f8BSllZ7l€, hOWEVEl', ll, tl’1€ H13l'\Uf3CtU.\‘BI' 5 &Ipll'BlLl0l'l UITN} of · " -
- . - - ` 48 hours after reconstitution when stored in a refrigerator V
Y hiy `l'°rds° A°lJl`°°pl°su° agmlsl D°x°mb'°m h’d'°°hl°"d°° were accepted.7 Therefore, we decided to study doxorubicin _ e
-.\ Y _ . Injections; Stability: Temperature _ _ _ _ _ _ _· · _ _
` · stability after being refrigerated or frozen. lf stability could . _f ‘
` i _ _ be demonstrated, not only would there be operational ben- V Y -
~ ‘ - ems but waste could be reduced, resulting in cost savings. - _ - _-
U · _ _ . _ — Methods _ Y ` Y? _
Doxorubicm hydrochloride, an anthracycline antibiotic Y - ·
i i_ obtained from Streptorrtyces eucetius, ossesses marked V. Vials containirw I0 mg of lyophilized doxorubicin hy- i " Y
‘_ antitumor activity. lt thought to act by intergalation be, dinehlqride with 50 mg of lactose (Adriamycin, Adria Lab- · . _ . .. .
. h tweenbase pai_rs of the DNA double helix and by inhibition oratories, lot 402) were reconstituted with Sterile Water for _
, I of DNA and RNA $Y`¤th€$l$·1’2 _ Injection, USP, to yield a solution concentration of about 2 ` _ ·_
` Doxorubicin, alone or in combination with other anti-, _ mg/ml ofdcrtorublcln`l1yCll‘OCl'llOI'lCl€. The reconstituted drug ` -_ i ·` ' .. _
_ Y · l neoplastic agents, has been shown effective for the treatment was stored under refrigeration (4 C) for up to one year and . `°
_. ·ol` a wide range of tumors-including adenocarcinoma ofthe frozen (_-20 C) for as long as one month. Water for injection, i _ L ` ` V
_ _ breast, malignant sarcomas, urinary bladder carcinoma, a diluent commonly used for this drug in Europe, permits _ _ i . .
_ , gynecologicalitumors, Wilm's tumor and neuroblastuma as freezing of the solution, which is precluded with sodium i - _`
, . well as lymphomas and leukemias.“‘5 ` chloride injection. The manufacturer of Adriamyciu is cur- ` . _
- ` ` · _' rently amending its official package insert to include Sterile .
. _ Dennis M. Hulman. Pnarncb, is Director grpiwmacy S,,.,,im_ Mgmugd Water for Lnjection; USP, as an acceptable diIueriL“ " - . .,
Sloan-Kettering Cancer Center, 1275 York Avenue. New York, NY 10021. · Solutions were removed from refrigeration or thawed and . -, ` Y
'Dennis D. Gr-ossauo is Clinical Oncology Phat-mncisz; Leepmue Du-rin 5, - · _ f i· ·d h t h 5 . ;
i _ Research Technician; and_Tlwmas M. Woodcock, M,D_' is Assisgang A;- analyzed by high pg!. Orman? _lqul -c mma Dgrap y` _ ` ·.
_ ,tending Physician, Development;} Ch,,¤,,,u,c,.apy Sm,ic,_ Memorial Each sample was analyzed twice. once at 0.10 AUFS (ab~ U . · _
.. .. __ $l¤¤¤·}€¤¤·=fi¤¤ C¤¤¢¤rC=¤¢¢r- _ _ ~ _ __ ._ _ sorbance unig full scale) to ascertain peakheight and once __
U _ td';;ie assistance uf Dr. .·\i:r¤munc and Dr. Charles W.'Young is at:k.nuwl· ‘ at 0.02 ·AUFS to detect any trace of degradation pl.0duct£_ ‘
nitttidy at ttpptmti ii nit by pttiit time Sm. _.,,,,c ciiiiiii Because mw ¤¤ti¤¤*s r¤¤·=ivi¤= d<¤¤r¤*¤i¤i¤ as im- ` _Q_; __<; Y
. icnosazc imiii the Nati¤nalCancerlnstituLe, N11·1,¤i~ii:w. - mono-suppressed. we were ¢¤¤¢¤f¤¤d ¤b°¤*,¤$l¤€ ¤ ¤<>¤· »
Y ' ‘ i -· - YZ is
Y ctipyiigiit © me, .iiiiericiii stieiety or Hospital Piiiimncisir, ine Au iigiie Pmewed d’l“°“l l°' ·‘°‘d?"*“‘Y°‘“· We d““·l°d that mim“°“ Y jg ·
Y 3 I _ ` reserved. ‘ . through a sterile 0.22-pm filter (Millex filter unit, Millipore » · ··_ ‘‘‘‘ .
· `T" ‘ ° Y ‘ _ ‘ i ., YY Y Y v · ii ··»_· ·
. 1536 American Journal ol Hospital Pharmacy Vol 36 Nov 1579 _ 0002·92B9/79/110‘l·1535$01.¤G _______ .`·‘ iT" __ _
_ > _. __». wily, C:
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._ ~_s _Case 1 :04-cv—00833-KAJ Document 257-8 ; Filed 06/27/2006 Page 3 of 4 · {
I - I _ l s i i - Dcxnnrbidln hydrochloride `
A . Cor-p_) prior to dispensing would arford adequate assurance Frozen $8mPl€$ WEYB thawed and analyzedffhe results
` _ _ gflstgrility. To ascertain whether such Filtration would result are shown in Table 2- C0mparison of the concentrations - `
. _ in lass or drug, samples of diluted Adi-iamycin were assayed measured aff-er up in 30 days of freezing with those obtained or
_ = and filtered. The filtrate then was assayed. before f1'eeZ1¤§ shcwed D0 substantial loss gf pqtgncy F
i ’ . - The chromatograph (model 7000, Micrometrics, Norcross, Sample A, which was refrozen, thawed and assayed at each .
.- -. GA) used a 30-cm X 4-mm reverse-phase column (Micro time interval, showed no loss of potency. In comparin-¤
- D
, ` `» _ Eondapak C·18, Waters Associates, Milford, MA) eluted i concentrations measured on day 17 with those measured on ‘
. . ’ _ , with a solvent of l.:1 methanolzwater. One vial of proprietary days 4, 7, 10, 24- and 30, it is clear that some error occurred
"V · I ion reagent (PIC-B7, Water Associates) was added to each in the analytical procedure. The source of this error was . A
l ` liter of solvent. Aliquots of 10 ul were injected directly into impossible to determine but, in view of all other results, it
the chromatographic 5y5tgm_ Flgw rate was 3-ml/min with · ,Bpp€Hl'$ that Adl'i3¤\_YCi¤ is Stflblli l-OT at least 30 days when
.. __ , a corresponding pressure of 4,000 pounds per sq in. Chart f1'¤Z€¤- i · _
Speed was 4 mm/mi¤_ Absgrbance was measured at 254 The filtered sam-ples showed no loss dfpotency from the
` ir · nm _ . filtration process. " ·
- _ _ The degradation products of doxorubicin hydrochloride, » _ -
-. s ` if any, have not been identified. Talcanashi and Bachurw ` Conclusions _ ‘ ` _ .
_ . identified adriamycinol (13-dihydroadriamycin) and adri· _ ·
l ‘- amygingng (the aglycgng) as ·{#\et_abOlites_ A solution Qf ad, l R.€COI'1StltUt·€d 50l·UtiOHS of AdIl8H1yCiH W€!'E stable for up i
` _ ‘ ,.iamycinO{_(Fatmita1;a_ S_P_A_'- Ital},. lot pl592/5·y)_ adn, to six months when refrigerated and for up to 30.days when `
_ _ . - '_ ‘ amycinone (Farmitalia, lot- CC/187-91) and doxorubicin _ ` i _ _
l hydrochloride (Aldrich Chemical Co., Milwaukee, lot E399) T bl 1 Sl HH l _ _ I ‘ ;
_ ` was analyzed to verify that the methodology was capable of a Q ` 3 I I Y of Reggxxsd 2`mg/ml Adnamlcm ji
" I _ _ _ - - separating the active drug from known related substances.
· The separation is shown in Figure 1. _ l · .- $=r¤P'i¤9 ` _ _
- . ` » - Time ·Pe=k Height (cm) Com:. (mg/nin)- eeieney 4% )·
. n.: I ‘ _ . l · ° _ l 2** 2.13 _106.s _
_ - Resu l·$ I 1dgy .24.0 2.09 104.5 i- '
—-- —— . . . · . . . 24- . f
. -` The stability of refrigerated samples of Adnamycm is __ -22; - 13:18 -
` _ shown in Table 1. A typical curve obtained for a refrigerated 1 yr 14.7 1_24 5.i_2‘ . -
“ l r2.mg/ml Adriamycinsample at 0.02 A depicted in Figure - {Basu on peak height; . _ · _, _;
s 2- W€ d€i·€€l$€d UO 9Vldf!Nf€ ofdegradatrcn Pl'0dUCt$ except ° Expressed as percerit Of estimated doxorubicin hydrodnioridé soluiipn-2
`*~’i" ,. for an unidentified small peak detected in the sample stored mglml- - ` ~
. s' . i e for one year. . - _ -
I V _ l l Figure 2. Absurbunre rprclmm 1J/ 2-mg/ml solution u/;Adriizmyi.—[n a/ber
` - . · ` si; months o/refrigeration: meosurcd or 254 nm oirh 0.02 AUFS (absorbance ·
· - · - ` . , . units full scale) `
` . Figure I; Absorbunce spectrum ofaisoluiion containing approximately 2.5 . .
- · _ . pg of odriomycirmne (o), 6 pg of odriamycinol (b), and 10 ing of doxorubicin ·
_ hydrochloride (c); measured at 254 nm with 0.1 AUFS (obsorbonccunizs l V ’
_ _ _ I . j' _ fullseule) ` _ _ _
. _ = Q B . .
‘ 7 - y -5 ° _ . a s · r ‘ 1 .
.· _ "‘ - 7 . ,_
i · ..... ( , . . r
f __ _ _ V _ _' O 5 IO I5 ' ` O 5 _ IO l5 _ _ ls-- ·
‘ i ffjs- _ · `)’]mg(ri1in_) ` Time (min.) ` " "" "'T"
spi ·- .
5;- §.'§€1__v s . _
__: eg : . _ ‘ . . je. ·
I *33- · ' - —- - - — - - -_ . . - --·V¤| 36 Nov 1979 American Journal ol Hospital Pharmacy
.,-·.·,. . · - , ( - . - - i

’ V Case 1 :04-cv—OO833-KAJ Document 257-8 Fi led 06/27/2006 Page 4 of 4 ,
Lanfnshicln hydrochlorldn _ V I
- Table 2. Stability ol Frozen 2-mg/ml Adriamycin Solulion ‘ _
` \_ l _ Adrlamycin Samples , Y -
l A a c 0 - a Q · ea.
` sampllng ’ Peak, Peak Peak Peak, Peak °
_ A ¤ yi ` 11me Height Conc. Height Conc. Height Ccnc. Height ` Crm:. Height - Cong; · -
` P _ (day;) - (em) (mg/m|)· (em) (mg/ml) (cm) (mg/ml) (cn:) (mg/ml) (em) (mg/mi)
0 24.1 2.710 25.5 2.22 24.9 2.l7 23.3 2.03 21f‘| ]_35 I __ `
` . 4 24.a 2.15 · gt
7 22.2 1.94 22.3 2.03 W" g' . _
10 24.5 2.14 24.8 2.16 ‘ 1;
` . 17 20.8 1.82 T9.5 1.70 ,
2i 23.9 2.09 23.8 2.08 V
_ . r - 30 23.7 ` 2.09 g .

_ ‘· Gonoenvations based on peak heights. ` , . · _ _ i i _
, _ ` ` . .,.. _ _- ` E-
I · frozen, showing no substantial loss of potency. Although not metabolism by daunorubicin and ad riamycin in L-121.0 mouse ·
` · y leukemia. Cancer Res 32:1I37·-1142 (Jun) 1972. . ·
- ’°°°”‘“?°’Yd°d· f’°‘°“ “°l“°'°“S p’°bably °°“1d be “f'°“°" :4, owaryan nm. Luce J1<,mieyRw et ai;1>i.mn mienim. of — _- .
g ‘ I and Yemam stable- _ _» _ ‘ adriamycin in human neoplasia. Cancer 32:1-S (Jul) 1973, . zj
_ ` Based on the data p1'&S&¤l’.ed,\We believe that the stability 4. Tan C, EtCubam1s E, Wollner N et al; Adriamycin—an anti- _ i _ ·
l . U of Aériamycin Qlutiq? isjsugh Wat adwinég Pmpargtiottrand- · l an treatment of neoplastic diseases,_Cnm.-er 1 "
__ . refrlgmiatlon Or freezing ls feaslbllb an Important °°ns‘d€l" 5. Bonadcnna G. Mcnfardini S. DeLena M et al; Clinical trials wiph it _·
` ` ation when an-tineoplastic agents are a sizable portioniof the adriamycin. results of three year's study, In Carter SK, DiMm-GD \ _
· admixture prog1·am's vlorkloacl. Cost savings can berealizecl A- C'll'°"'i °t al ledsli l"***¤¤*i¤¤¤’ $Y""F’°$l““‘ °“ “d'l· - A
- _ . _ . _ _ amycm,Sprmger·Verlag. New York, 1972, p 139. ‘ A
. ’ by usmg the larger package SIZE (ol-named at a lower umt 6, Hofl`man'DlVl and Tczzl WZ Automated reconstitution proce- ‘
. price) as a mullildose vial and Storing the remaining drug {Or dure to support a high volume decentralized i.v. admixture n
_ ` later use. Filtration of stored solutions with a sterile 0.22-pm p'°g"""* em J ].V Ther 5:2%% (May) 1978- · Q `
.. . . . _ ‘ 7, ·-Anon: Adriamycm (package insert), Adria Laboratories, Inc., ·
- _ ~ ` - filter Just before use will assure sterility without loss of Columbug OH (Oct) 1971 . U . _ _
U - drug. . 8. ‘Mancini F (Mount Edison USA, Inc., New York)i Personal
_ · . _ communication (Jul ll) l979. , . . _ "" T"
V __ , ‘ y R.€l€l’€¤C@$ - 9_ Hahn P (PharmaceuticalApplications Laboratories, Waters ' `
\ _ ` ` Associates, Milford. MA): Personal communication (Feb 2) -
i _ i ` 1. Zuninu F; Garnbett:1 R, DiMarco A et al: Interaction of dau- - 1979. A _ _
Ti nomycin and its derivatives with DNA, Biochim Biophys Acta 10. Takahashi S arid B3Cl1ut NR New adriamycin (a) and daung- i _
V - 277:489498 [Sep) 1972. rubicin (d) metabolites in human urine, Proc Am Assoc Cancer ‘ V ‘ [
_ _ 2. Meriwether WD.and Bachur NR; Inhibition of DNA and RNA Res 15:76, l9'74. _ - . · ` ._ -
. i - . .
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Q gggisfant, American Journal of Hospital-Phzunacy, 4630 Montgomery Avenue. Washington, DC _ _:; _
-g';f_ _—__ Q-- I - . _ I I
. 1538 American Journal ol Hospital Pharmacy Vol 35 Nov 1979 . `
· . __ . __ LE >··‘¤"-=i._
. ·· i ° . -_ · _ _ __ T _ ____ _ 4;; _ `;. °