J Oncol Pharm Practice (2006) 12: 211 222
`
`Physical and chemical stability of paclitaxel infusions in
`different container types
`
`Parastou Donyai, PhD MRPharmS1
`Graham J Sewell, PhD MRPharmS1,2
`
`Objectives. To determine the physicochemical
`stability of generic (Teva Pharmaceuticals) pacli-
`taxel
`infusions (0.3 and 1.2 mg/mL) in 0.9%
`sodium chloride or 5% glucose in polyolefin
`(Viaflo†),
`low-density polyethylene (Ecoflac†),
`and glass containers at 2 8 and 258C.
`Methods. Paclitaxel
`infusions of various con-
`centration/diluent/container combinations were
`prepared. Containers were light-protected and
`incubated at
`test
`temperatures with further
`analysis at predetermined intervals of 1 3 days
`for up to 30 days. Infusions were monitored for
`pH, weight loss, precipitation, colour change, and
`subvisual particulates as indicators of physical
`stability, and assayed for drug concentration to
`determine chemical stability.
`Results. Precipitation was the limiting factor.
`Infusions of paclitaxel (0.3 mg/mL) in 0.9% sodium
`chloride remained stable for 13, 16 and 13 days at
`2 88C in polyolefin, low-density polyethylene and
`glass containers, respectively; in 5% glucose for 13,
`18, and 20 days, respectively. At 258C, paclitaxel
`infusions (0.3 mg/mL) remained stable for 3 days
`
`in all diluent/container combinations with the
`exception of 5% glucose in glass, where stability
`reached 7 days. Paclitaxel infusions (1.2 mg/mL) in
`0.9% sodium chloride remained stable for 9, 12,
`and 8 days at 2 88C in polyolefin,
`low-density
`polyethylene and glass containers, respectively; in
`5% glucose for 10, 12, and 10 days, respectively. At
`258C, paclitaxel 1.2 mg/mL remained stable for 3
`days in all diluent/container combinations with the
`exception of glass, where stability reached 5 days
`in 0.9% sodium chloride diluent, and 7 days in 5%
`glucose.
`Conclusion. Paclitaxel stability was influenced
`by storage temperature, with longer shelf-life at
`2 88C, and also by drug concentration, where
`0.3 mg/mL infusions were more stable than
`1.2 mg/mL for all diluent/container combinations.
`Physical stability (precipitation) was the limiting
`parameter in each case. J Oncol Pharm Practice
`
`(2006) 12: 211 222.
`
`Key words: compatibility; generic; infusion; pacli-
`taxel; stability
`
`Introduction
`
`Paclitaxel, a potent chemotherapeutic agent, was
`discovered during a large-scale screening programme
`conducted by the National Cancer Institute in the
`
`1School of Pharmacy and Chemistry, Kingston University, Kingston
`upon Thames, Surrey, UK; 2Plymouth Hospitals NHS Trust,
`Plymouth, UK
`
`Address correspondence and reprint requests to Professor
`Graham Sewell, School of Pharmacy and Chemistry, Kingston
`University, Penrhyn Road, Kingston upon Thames, Surrey
`KT1 2EE, UK
`E-mail: g.j.sewell@kingston.ac.uk
`
`1960s, and was initially extracted and isolated from
`the bark of Western Yew (Taxus brevifolia ).1 Since
`its discovery, paclitaxel has been indicated in the
`treatment of a variety of cancers, such as advanced
`ovarian and breast cancer, non-small cell lung cancer
`and AIDS-related Kaposi’s sarcoma.2 4
`The extreme lipophilicity of paclitaxel,5 7 pre-
`sented difficulties in developing stable parenteral
`formulations for iv infusion. To circumvent
`this
`problem, commercially available paclitaxel injection
`is formulated in a 50:50 solvent mixture of cremo-
`phor EL and dehydrated ethanol.8 However, cremo-
`phor EL causes severe hypersensitivity reactions in
`
`– 2006 SAGE Publications
`
`10.1177/1078155206073589
`
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`

`
`212 Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`patients and pre-medication with corticosteroids,
`antihistamines and H2-antagonists is required.9,10
`Furthermore, cremophor EL is incompatible with
`some plastics and is known to leach diethylhex-
`ylphthalate (DEHP) plasticisers from polyvinyl chlo-
`ride (PVC) infusion bags and administration sets.11,12
`It is, therefore, recommended that paclitaxel infusion
`is prepared and administered in non-PVC containers.
`For administration, paclitaxel concentrate is di-
`luted in infusions of 0.9% sodium chloride or 5%
`dextrose to achieve a final concentration of 0.3 1.2
`mg/mL.13 15 Adequate physical and chemical stabi-
`lity of infusions under clinically relevant conditions is
`essential
`to ensure safety and efficacy. Physical
`stability of paclitaxel infusions is the limiting factor,
`resulting in precipitate formation on storage,16 parti-
`cularly where the paclitaxel concentration exceeds
`0.6 mg/mL.17 However, long-term infusion stability is
`required for the development of dose-banding strate-
`gies,18 and to avoid wastage on occasions when
`treatment is delayed after the infusion has been
`prepared.
`In this study, the stability of infusions prepared
`from a generic paclitaxel presentation (Teva Pharma-
`ceuticals) was investigated. Low-density polyethylene
`containers were included as a non-PVC alternative to
`polyolefin, but with a lower environmental impact.
`Glass containers were included because of continued
`use in some European countries. The objective of this
`work was to determine the physical and chemical
`stability of paclitaxel infusion at concentrations of
`0.3 and 1.2 mg/mL in 0.9% sodium chloride or 5%
`glucose under storage at 5 and 258C in polyolefin
`low-density polyethylene Ecoflac†
`infusion bags,
`containers, and glass bottles.
`
`Materials and methods
`
`Materials
`Vials containing paclitaxel 6 mg/mL (batch No.
`A417745, expiry 3/2007) were supplied by Teva
`Pharmaceuticals
`(Leeds, UK).
`The
`polyolefin
`(Viaflo†)
`infusion bags, containing 0.9% sodium
`chloride 250 mL (batch No. 03F10E1D, expiry 05/
`2006) and 5% glucose 250 mL (batch No. 03E24E1E,
`expiry 04/2006), were supplied by Baxter Healthcare
`(Berkshire, UK). Glass containers of 0.9% sodium
`chloride 250 mL (batch No. 04F0262, expiry 05/07)
`and 5% glucose 250 mL (batch No. 02L2171, expiry
`10/05) were supplied by B Braun (Sheffield, UK).
`Low-density polyethylene (Ecoflac†) containers of
`0.9% sodium chloride 500 mL (batch No. 4124A141,
`
`expiry 02/2007) and 5% glucose 500 mL (batch No.
`4185A142, expiry 03/2009) were supplied by B
`Braun Melsungen AG (Melsungen, Germany). All
`pharmaceuticals were used within their expiry date.
`All other chemicals and reagents were of analytical
`grade or high-performance liquid chromatography
`(HPLC) grade.
`
`Preparation of paclitaxel infusions
`All paclitaxel
`infusions were prepared under
`European Grade A aseptic conditions in a Class II
`safety cabinet by trained and validated personnel, in
`accordance with the principles of Good Manufactur-
`ing Practice. Paclitaxel infusions, at concentrations of
`0.3 and 1.2 mg/mL, were prepared in 0.9% sodium
`chloride or 5% glucose in polyolefin,
`low-density
`polyethylene and glass containers. In each instance, a
`volume of
`the diluent equal
`to the volume of
`paclitaxel solution added was first withdrawn. After
`adding the drug concentrate, the containers were
`gently inverted to promote adequate mixing. Parti-
`cular care was taken to avoid excessive agitation of
`test infusions.
`
`Methods
`Incubation of test infusions
`Triplicate infusions of each concentration/diluent/
`container-type combination were placed in blue
`polythene over-wraps to protect
`from light and
`stored at the desired study temperatures using a
`LEC pharmacy refrigerator (58C) or a laboratory
`incubator (259/0.58C). The infusions were removed
`at selected time intervals (see below), and equili-
`brated to room temperature prior to analysis (in
`triplicate). Samples were analysed for physical stabi-
`lity (pH, and weight
`loss, visible and subvisual
`particulates) and chemical stability (HPLC assay)
`immediately after preparation (t/0), and subse-
`quently at the following scheduled time intervals:
`
`. Paclitaxel (0.3 mg/mL) in polyolefin and glass
`containers: t/0, 3, 7, 10, 13, 15, 20 and 30 days
`at 2 8 and 258C.
`. Paclitaxel (1.2 mg/mL) in polyolefin and glass
`containers: t/0, 3, 5, 7, 8, 9, 10, 12 and 14 days
`at 2 8 and 258C.
`. Paclitaxel (0.3 and 1.2 mg/mL) in low-density
`polyethylene containers: t/0, 3, 7, 10, 12, 14,
`16, 18, and 20 days at 58C and: t/0, 1, 3, 5, 7, 9
`and 11 days at 258C.
`
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`

`
`Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`213
`
`Physical stability of infusions
`The physical stability of paclitaxel was assessed using
`the following methods.
`
`pH measurement. A combinational glass elec-
`trode and a Good-Laboratory-Practice pH meter
`(Hanna pH 302 series) were first calibrated using
`standard reference solutions of pH 4.0 and 7.0, and
`then used to measure the pH of infusions. Each pH
`was recorded as mean value of three infusions.
`
`loss. The infusion bags were weighed
`Weight
`before and after sampling on a calibrated six-figure
`analytical balance (A&D Ltd, model AD-1131) and the
`percent weight
`increase or decrease on incu-
`bation calculated. Change in weight was recorded
`and expressed as mean moisture loss of
`three
`infusions.
`
`Visual inspection. This was assessed under stan-
`dard laboratory lighting. Each infusion was examined
`for any change in colour, clarity or for the presence of
`particulate matter.
`
`Subvisual particle counts
`Subvisual particulates.
`of infusion at 10 and 25 mm were conducted at
`predetermined time intervals in accordance with the
`method described in the British Pharmacopoeia
`(2000) using a Pacific Scientific light-scatter instru-
`ment. This was calibrated using certificated diameter
`latex spheres supplied by Pacific Scientific Ltd.
`
`Acceptance criteria: physical stability. The
`physical stability of all paclitaxel
`infusions was
`assessed according to the following acceptance
`criteria. Samples passed pH testing if
`the value
`obtained was within /0.5 pH unit of the initial pH
`t/0. Weight
`value at
`loss can indicate loss of
`moisture from the container, which can potentially
`mask a low assay result. The acceptance limit for
`weight variation was set at 9/3% w/w of the initial
`infusion weight.
`
`Chemical stability of infusions using HPLC
`Paclitaxel concentrations were analysed using a
`validated stability-indicating reverse-phase HPLC
`method. The HPLC system consisted of a quaternary
`gradient pump (Jasco PU-2089 plus), an in-line
`degasser, autosampler
`(Jasco AS-2057 plus), and
`photodiode array detector (Jasco MD-2010 plus).
`Separation and quantitative analysis of paclitaxel
`was achieved on a 5-mm Phenomenex C8 column
`(250/4.6 mm) with the mobile phase flowing at a
`
`rate of 1.5 mL/min and a detection wavelength of 227
`nm. The acquisition run-time for each analysis was 15
`minutes. Mobile phase composition for analysis
`contained 50% 20 mM ammonium acetate, pH
`5.0:40% acetonitrile:10% methanol. Samples were
`diluted with water and injected in duplicate, followed
`by an injection of
`the freshly-prepared external
`standard using the ‘bracketing’ technique.
`The assay was fully validated for linearity of
`analytical response, precision of system, precision
`of method, and stability-indication.
`A typical chromatogram obtained by injecting
`a solution of paclitaxel (60 mg/mL) is shown in
`Figure 1.
`
`Validation of LC assay
`Calibration curve
`(linearity of analytical
`response). A six-point calibration curve of pacli-
`taxel, over the range 15 90 mg/mL, was constructed
`with triplicate injections at each concentration. A
`plot of the mean peak height obtained for each
`concentration against the respective paclitaxel con-
`centration was subjected to linear least-square regres-
`sion analysis and was found to be linear over
`the range tested with a regression coefficient of
`0.9997.
`
`Precision of the method.
`Intra-day precision:
`Eight paclitaxel standard solutions (60 mg/mL) were
`prepared and each injected onto the LC system in
`duplicate. From the mean of each duplicate, the CV
`was calculated (n/8) as 1.9%.
`Inter-day precision: Paclitaxel solution (60 mg/mL)
`was prepared on each successive day for 7 days, and
`injected onto the LC system in duplicate. From the
`mean of each duplicate, the CV was calculated (n/
`7) as 1.6%.
`
`Stability indicating study. A stability indicating
`study was performed using forced degradation,
`in
`order to determine whether paclitaxel could be
`distinguished in terms of retention time from any
`degradation products. Table 1 reveals the effect of
`forcibly degrading paclitaxel by alkaline, acidic and
`oxidative conditions and by heating at 558C. Pacli-
`taxel (60 mg/mL) stored in the refrigerator was used
`as a control sample for comparison purposes. The
`assay of paclitaxel in the control sample was 61.65
`mg/mL. On exposure to each of
`the following
`treatments oxidative degradation, elevated tem-
`perature of 558C and acid hydrolysis paclitaxel
`assay was 57.89, 61.09 and 30.53 mg/mL, respectively.
`In all cases, there was a distinct separation between
`
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`

`
`214 Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`Paclitaxol standard 1476.DATA
`[227.00 nm]
`
`RT [min]
`
`mAU
`
`STH 10.00
`
`SPW 0.20
`
`0.085
`0.08
`0.075
`0.07
`0.065
`0.06
`0.055
`0.05
`0.045
`0.04
`0.035
`0.03
`0.025
`0.02
`0.015
`0.01
`0.005
`0
`−0.005
`−0.01
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`Figure 1. Typical LC chromatogram of paclitaxel (60 mg/mL) solution.
`
`the drug and degradation product peak. Peak purity
`of the paclitaxel analyte peak was confirmed (/
`0.97) by diode-array spectroscopy. A cloudy gel was
`observed in paclitaxel solution subjected to alkaline
`hydrolysis. The dispersion was filtered using a 0.2-mm
`filter, and the filtrate analysed for paclitaxel by LC.
`Results indicated absence of drug peak implying
`complete loss of the drug.
`
`Assay validation: summary
`The LC assay developed for paclitaxel was stability
`indicating for non-specific degradation of the parent
`drug, gave a linear analytical response and acceptable
`precision.
`Accuracy of the method was determined ‘in-use’ by
`routine QC samples (blinded to operator) and was
`within the range 98.6 101.2% (n/27).
`The assay was accepted as fit for purpose.
`
`Table 1. Effect of oxidative degradation, alkaline hydrolysis,
`acid hydrolysis and elevated temperature (558C) on paclitaxel
`stability
`
`Treatment
`
`Retention time (min)
`
`Quantity (mg/mL)
`
`Control
`Oxidative degrada-
`tion
`Alkaline hydrolysis
`Heat (558C)
`Acid hydrolysis
`
`11.37
`11.36
`
`
`11.35
`11.36
`
`61.65
`57.89
`
`
`61.09
`30.53
`
`Acceptance criteria: chemical stability
`The assay of drug concentration was accepted where
`the concentration of paclitaxel remaining at each
`time point was ]/95.0% of the initial concentration
`measured by HPLC.
`
`Results
`
`The physical and chemical stability of paclitaxel was
`determined at intervals over a period of up to 30
`days. The stability data for paclitaxel 0.3 mg/mL
`infusions at 2 8 and 258C are presented in Tables 2
`and 3, respectively, and for the 1.2 mg/mL infusions
`at 2 8 and 258C in Tables 4 and 5, respectively.
`Paclitaxel 0.3 mg/mL in 0.9% sodium chloride
`remained stable for 13, 16 and 13 days at 2 88C
`in polyolefin,
`low-density polyethylene and glass
`containers, respectively; in 5% glucose for 13, 18,
`and 20 days, respectively. At 258C, paclitaxel 0.3 mg/
`mL remained stable for 3 days in all diluent/container
`combinations with the exception of 5% glucose in
`glass, where stability lasted 7 days. Paclitaxel 1.2 mg/
`mL in 0.9% sodium chloride remained stable for
`9, 12, and 8 days at 2 88C in polyolefin, low-density
`polyethylene and glass containers, respectively; in 5%
`glucose for 10, 12, and 10 days, respectively. At 258C,
`paclitaxel 1.2 mg/mL remained stable for 3 days in all
`diluent/container combinations with the exception
`of glass, where stability of 5 days was obtained in
`
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`

`
`Table 2. Physical and chemical stability of paclitaxel 0.3 mg/mL in 0.9% sodium chloride or 5% glucose in polyolefin, low-density polyethylene and glass containers at 2
`
`88C
`
`Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`215
`
`% Concentration9/SD
`paclitaxel remaining
`
`0.296 mg/mL/100%
`99.549/1.7
`98.099/1.0
`98.099/0.9
`97.649/0.3
`
`
`0.292 mg/mL/100%
`97.329/0.2
`98.539/1.2
`98.449/1.4
`97.999/1.8
`
`
`0.292 mg/mL/100%
`100.669/0.97
`99.749/1.25
`99.279/0.91
`97.229/0.42
`99.299/0.84
`100.699/1.35
`101.159/0.12
`
`0.310 mg/mL/100%
`100.369/0.97
`99.759/0.51
`99.709/1.84
`98.199/0.44
`100.439/0.88
`100.419/0.98
`10.319/0.35
`
`
`0.289 mg/mL/100%
`98.099/0.4
`
`Time (days)
`
`pH
`
`Moisture loss (%)
`
`Subvisual particles/mL
`
`Visual appearance
`
`10 mM
`
`25 mM
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`
`
`0
`0
`0.14
`0.29
`0
`
`
`0.12
`0
`0
`0
`0
`
`
`0.06
`0.06
`0.13
`0.06
`0
`0
`0
`
`
`0
`0
`0.13
`0
`0
`0
`0
`0
`
`
`0
`
`25
`57
`80
`148
`628
`3417
`
`18
`68
`106
`121
`181
`367
`
`44.22
`73.33
`33.33
`25.22
`31.66
`26.66
`24.77
`51.44
`
`43.11
`55.89
`24.66
`47.88
`27.77
`24.66
`42.88
`40.88
`
`
`90
`97
`
`0
`0.22
`0.17
`0.77
`11.11
`94.3
`
`0.33
`0.61
`0.66
`0
`1.33
`5
`
`0
`0.33
`0.22
`0.22
`0.33
`0.11
`0.11
`0.11
`
`0.22
`0
`0
`0.33
`0.33
`0.33
`0.22
`0
`
`
`0.33
`0.5
`
`0.3 mg/mL Paclitaxel in 0.9% sodium
`chloride in polyolefin bags
`0
`3
`7
`10
`13
`15
`
`0.3 mg/mL Paclitaxel in 5% glucose in
`polyolefin bags
`0
`3
`7
`10
`13
`15
`
`0.3 mg/mL Paclitaxel in 0.9% sodium chloride
`in low-density polyethylene containers
`0
`3
`7
`10
`12
`14
`16
`18
`
`0.3 mg/mL Paclitaxel in 5% glucose in
`low-density polyethylene containers
`0
`3
`7
`10
`12
`14
`16
`18
`20
`
`0.3 mg/mL Paclitaxel in 0.9% sodium chloride
`in glass containers
`0
`3
`
`3.77
`3.95
`3.75
`3.75
`3.66
`3.97
`
`3.94
`4.09
`3.86
`3.92
`3.69
`4.06
`
`3.66
`3.56
`3.56
`3.69
`3.58
`3.55
`3.59
`3.56
`
`3.89
`3.58
`3.69
`3.78
`3.87
`3.81
`3.84
`3.81
`3.80
`
`3.71
`3.95
`
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`

`
`216 Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`0.9% sodium chloride, and 7 days in 5% glucose.
`These timescales are presented in Figure 2.
`
`Discussion
`
`infusion with a nominal
`Solutions for parenteral
`content of /100 mL comply with the British
`Pharmacopoeia (2000) requirements for sub-visual
`particulates,
`if
`the average number of particles
`present in the units tested does not exceed 25/mL
`]/10 mm, and does not exceed 3/mL ]/25 mm
`diameter. The particulate count data presented in
`Tables 2 5, show that the infusions would exceed
`the pharmacopoeial limits for particles of ]/10 mm
`diameter, but most would pass at the ]/25 mm level.
`However, in accordance with the marketing author-
`isation, paclitaxel
`infusion is administered to the
`patient via a 0.22 micron in-line filter and, therefore,
`it may not be realistic to apply pharmacopoeial limits
`for sub-visual particulate counts of
`this product.
`Nonetheless, sub-visual particle counts were moni-
`tored in order to predict possible product precipita-
`tion under visual observation, and in this role, the
`technique did exhibit some predictive capability.
`Products were considered to pass visual observation
`only on presentation of a clear, colourless solution
`with no visible precipitate. There was an exception
`to this criteria on day 9, where the assay result for
`paclitaxel 1.2 mg/mL in 5% glucose (glass container)
`at 2 88C gave a value of 94.62% of initial concentra-
`tion. This was rounded up to 95% on the basis that re-
`assay on the subsequent day (day 10) gave a result
`96.92% of initial concentration.
`In each instance, precipitation was the limiting
`factor for infusion stability, as reported in previous
`studies.19,20 Precipitation was at all times accompa-
`nied by a sharp reduction in the paclitaxel assay
`result. Storage temperature was a key factor affecting
`stability. Infusions stored under refrigeration (2 88C)
`(Tables 2 and 4) were stable for a longer period
`compared to the corresponding infusions stored at
`room temperature (258C)
`(Tables 3 and 5).
`In
`addition, under refrigerated storage, the 0.3 mg/mL
`infusions were more stable than the 1.2 mg/mL for all
`diluent/container combinations. Changes in infusion
`pH or significant weight loss were not observed in
`this study (Tables 2 5).
`In view of
`the subtle
`differences in the cremophor EL quality and the
`methods used to manufacture paclitaxel, the data
`presented in this study should be considered specific
`to paclitaxel (Teva Pharmaceuticals).
`
`84.089/1.1
`96.189/1.4
`98.259/0.6
`96.989/1.1
`95.879/0.4
`98.309/0.6
`96.039/1.5
`
`0.286mg/mL/100%
`
`96.669/0.2
`95.869/0.4
`98.089/0.9
`96.349/0.2
`
`paclitaxelremaining
`%Concentration9/SD
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`
`Pass
`Pass
`Pass
`
`Pass
`
`Fail
`
`0.33
`
`0
`
`0.33
`0.17
`0.33
`
`0
`
`0
`
`0
`
`0.7
`0.67
`0.17
`
`1
`
`35
`41
`46
`16
`25
`24
`16
`33
`
`215
`140
`107
`153
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0.13
`0.13
`
`0
`
`0
`
`
`
`0.14
`
`0
`
`4.03
`4.17
`4.28
`3.69
`3.95
`3.78
`4.16
`3.83
`
`4.03
`3.59
`3.72
`3.68
`
`25mM
`
`10mM
`
`30
`20
`15
`13
`10
`
`0
`
`3
`
`7
`
`0.3mg/mLPaclitaxelin5%glucoseinglass
`
`containers
`
`15
`13
`10
`
`7
`
`Visualappearance
`
`Subvisualparticles/mL
`
`Moistureloss(%)
`
`pH
`
`Time(days)
`
`Table2(Continued)
`
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`Hospira, Exh. 2014, p. 6
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`

`
`Table 3. Physical and chemical stability of paclitaxel 0.3 mg/mL in 0.9% sodium chloride or 5% glucose in polyolefin, low-density polyethylene and glass containers at
`258C
`
`Time (days)
`
`pH
`
`Moisture loss (%)
`
`Subvisual particles/mL
`
`10 mM
`
`25 mM
`
`Visual appearance % Concentration paclitaxel
`remaining
`
`Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`217
`
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Fail
`
`0.298 mg/mL/100%
`95.799/1.1
`
`
`0.305 mg/mL/100%
`98.659/0.3
`
`
`0.296 mg/mL/100%
`99.159/0.76
`100.849/0.5
`
`
`0.293 mg/mL/100%
`99.339/0.53
`100.689/1.24
`
`
`0.307 mg/mL/100%
`95.669/1.2
`
`
`0.302 mg/mL/100%
`96.609/0.7
`96.939/0.2
`
`
`0.3 mg/mL Paclitaxel in 0.9% sodium chloride
`in polyolefin bags
`0
`3
`7
`
`0.3 mg/mL Paclitaxel in 5% glucose in
`polyolefin bags
`0
`3
`7
`
`0.3 mg/mL Paclitaxel in 0.9% sodium chloride
`in low-density polyethylene containers
`0
`1
`3
`5
`
`0.3 mg/mL Paclitaxel in 5% glucose in low-
`density
`polyethylene containers
`0
`1
`3
`5
`
`0.3 mg/mL Paclitaxel in 0.9% sodium chloride
`in glass containers
`0
`3
`7
`
`0.3 mg/mL Paclitaxel in 5% glucose in
`glass containers
`0
`3
`7
`10
`
`3.76
`3.99
`
`3.94
`4.10
`
`3.65
`3.58
`3.52
`3.62
`
`3.85
`3.80
`3.58
`3.74
`
`3.75
`3.90
`
`3.84
`4.16
`3.80
`
`
`0
`
`
`0.12
`
`
`0
`0
`0
`
`
`0
`0.06
`0
`
`
`0
`
`
`0.13
`0.26
`
`27
`168
`
`
`27
`130
`
`
`53.88
`33.77
`43.55
`24.22
`
`32.66
`8
`36.66
`11.11
`
`62
`88
`
`
`56
`11
`10
`
`
`0.11
`0.22
`
`
`0.11
`0.44
`
`
`0.33
`0.22
`0.11
`0
`
`0
`0.11
`0.55
`0
`
`0.33
`0.7
`
`
`0.5
`0
`0
`
`
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`

`
`218 Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`Table 4. Physical and chemical stability of paclitaxel 1.2 mg/mL in 0.9% sodium chloride or 5% glucose in polyolefin, low-density polyethylene and glass containers at 2
`
`88C
`
`Time (days)
`
`pH
`
`Moisture loss (%)
`
`Subvisual particles/mL
`
`10 mM
`
`25 mM
`
`Visual appearance % Concentration paclitaxel
`remaining
`
`1.2 mg/mL Paclitaxel in 0.9% sodium chloride in
`polyolefin bags
`0
`3
`5
`7
`8
`9
`10
`
`1.2 mg/mL Paclitaxel in 5% glucose in
`polyolefin bags
`0
`3
`5
`7
`8
`9
`10
`12
`
`1.2 mg/mL Paclitaxel in 0.9% sodium chloride in
`low-density polyethylene containers
`0
`3
`7
`10
`12
`14
`
`1.2 mg/mL Paclitaxel in 5% glucose in low-density
`polyethylene containers
`0
`3
`7
`10
`12
`14
`
`1.2 mg/mL Paclitaxel in 0.9% sodium chloride in glass
`containers
`0
`3
`5
`7
`
`3.49
`3.56
`3.56
`3.61
`3.51
`3.55
`
`3.74
`3.74
`3.78
`3.75
`3.83
`3.83
`3.72
`
`3.52
`3.49
`3.40
`3.50
`3.53
`3.54
`
`3.67
`3.77
`3.72
`3.83
`3.76
`3.71
`
`3.59
`3.55
`3.57
`3.63
`
`0
`0
`0
`0
`0.15
`
`0
`0
`0
`0
`0
`0
`
`
`0
`0.06
`0.06
`0.13
`0.06
`
`
`0
`0.06
`0.064
`0
`0
`
`0.13
`0
`0
`
`68
`81
`113
`150
`182
`183
`
`
`67
`72
`86
`130
`88
`106
`111
`
`
`38.44
`52
`32.88
`31
`23.22
`36.44
`
`49.88
`31.66
`24.88
`30.66
`25.33
`34
`
`77
`99
`115
`175
`
`0.22
`0.66
`0.88
`0.88
`2
`1.44
`
`
`0.38
`0.11
`0.33
`0.22
`0.55
`1.44
`1.17
`
`
`0.11
`0.33
`0.11
`0
`0
`0.33
`
`0.22
`0.11
`0.11
`0.33
`0
`0
`
`0
`0.5
`0.66
`0.67
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Pass
`
`1.24 mg/mL/100%
`99.739/0.4
`96.219/0.9
`98.649/0.4
`97.019/1.2
`96.759/0.2
`
`
`1.20 mg/mL/100%
`97.319/1.1
`98.119/0.4
`99.739/1.7
`98.129/1.2
`97.579/0.8
`98.659/1.7
`
`
`1.17 mg/mL/100%
`100.629/1.22
`98.749/0.3
`97.979/0.61
`97.049/0.36
`
`
`1.17 mg/mL/100%
`98.999/2.5
`99.259/1.33
`98.699/0.96
`97.829/0.98
`
`
`1.22 mg/mL/100%
`95.789/0.5
`96.179/1.1
`96.179/1.1
`
`J Oncol Pharm Practice, Vol 12: No 4, 2006
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`Hospira, Exh. 2014, p. 8
`
`

`
`Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`219
`
`The use of glucose 5% w/v diluent, as opposed to
`sodium chloride 0.9% w/v, afforded a marginal
`increase
`in physical
`stability
`in some
`cases
`(Tables 2 5). A tentative explanation for this may
`relate to the higher ionic strength in the saline
`infusions causing more rapid degradation of
`the
`cremophor/ethanol miscelles formed with paclitaxel,
`and a concomitant reduction in drug solubility.
`The apparent increase in physical stability afforded
`by the low-density polyethylene and glass containers
`may be attributed to the lower sub-visual particulate
`counts of infusions stored in these containers com-
`pared to polyolefin bags (Tables 2 5). This could
`reduce the ‘seeding’ effect on unstable solutions of
`paclitaxel
`following dilution of
`the formulation
`vehicle.
`The stability profiles under refrigerated conditions
`obtained in this study were sufficient to develop
`dose-banding schemes, where extended stability of
`standard infusions is essential,18 and would also be
`adequate to avoid wastage in cases where treatment
`is deferred after infusion preparation. In the UK,
`there is a growing tendency to use 90 mg/m2
`/
`weekly schedules,13 for which the more stable,
`lower concentration infusions
`(0.3 mg/mL) are
`well suited.
`Absence of microbiological contamination is cru-
`cial with all aseptically prepared infusions.
`It
`is
`essential,
`therefore,
`that extended shelf-lives are
`only applied to infusions prepared under controlled
`conditions, which have been microbiologically vali-
`dated. Refrigerated storage conditions are also re-
`commended, not only for improved physico-chemical
`stability, but also for the inhibition of microbial
`growth should ingress inadvertently occur.
`
`Conclusion
`
`Paclitaxel at 0.3 and 1.2 mg/mL in 0.9% sodium
`chloride or 5% glucose is physically and chemically
`stable (as defined by the acceptance criteria in the
`Methods section) in polyolefin, low-density polyethy-
`lene and glass containers at 2 8 and 258C. Stability
`ranged from 3 to 20 days. Infusions were more stable
`when stored at 2 88C, where the lower concentra-
`tion of paclitaxel (0.3 mg/mL) was also more stable
`than the higher concentration (1.2 mg/mL) for all
`diluent/container combinations. Stability data for
`each concentration/diluent and temperature combi-
`nation are summarised in Figure 2. This study has
`demonstrated sufficient stability of
`infusions pre-
`pared from a generic paclitaxel (Teva) to support
`
`95.399/2.2
`96.929/1.1
`94.629/1.1
`95.009/1.7
`96.929/1.1
`95.769/0.5
`95.779/0.5
`
`1.25mg/mL/100%
`
`95.029/1.5
`95.029/1.6
`
`remaining
`
`Fail
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`Pass
`
`Fail
`Pass
`
`1
`
`0.83
`
`0
`
`2
`
`0
`
`1
`
`0.33
`0.17
`
`2.7
`0.17
`
`114
`89
`113
`67
`112
`73
`68
`45
`
`244
`155
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0.13
`
`0
`
`0
`
`3.82
`3.73
`3.82
`3.72
`3.83
`3.80
`3.74
`3.7
`
`3.55
`3.52
`
`25mM
`
`10mM
`
`12
`10
`
`0
`
`3
`
`5
`
`7
`
`8
`
`9
`
`1.2mg/mLPaclitaxelin5%glucoseinglasscontainers
`
`8
`
`9
`
`Visualappearance%Concentrationpaclitaxel
`
`Subvisualparticles/mL
`
`Moistureloss(%)
`
`pH
`
`Time(days)
`
`Table4(Continued)
`
`J Oncol Pharm Practice, Vol 12: No 4, 2006
`
`
`
`opp.sagepub.comDownloaded from
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`Hospira, Exh. 2014, p. 9
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`

`
`220 Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`Table 5. Physical and chemical stability of paclitaxel 1.2 mg/mL in 0.9% sodium chloride or 5% glucose in polyolefin, low-density polyethylene and glass containers
`at 258C
`
`Time (days)
`
`pH
`
`Moisture loss (%)
`
`Subvisual particles/mL
`
`10 mM
`
`25 mM
`
`Visual appearance % Concentration paclitaxel
`remaining
`
`1.2 mg/mL Paclitaxel in 0.9% sodium chloride in
`polyolefin bags
`0
`3
`5
`
`1.2 mg/mL Paclitaxel in 5% glucose in polyolefin bags
`0
`3
`5
`
`1.2 mg/mL Paclitaxel in 0.9% sodium chloride in
`low-density polyethylene containers
`0
`1
`3
`5
`
`1.2 mg/mL Paclitaxel in 5% glucose in low-density
`polyethylene containers
`0
`1
`3
`5
`
`1.2 mg/mL Paclitaxel in 0.9% sodium chloride in
`glass containers
`0
`3
`5
`7
`
`1.2 mg/mL Paclitaxel in 5% glucose in glass containers
`0
`3
`5
`7
`8
`
`3.48
`3.57
`3.58
`
`3.71
`3.74
`3.80
`
`3.49
`3.44
`3.48
`3.53
`
`3.69
`3.61
`3.75
`3.82
`
`3.46
`3.54
`3.58
`
`3.73
`3.76
`3.80
`3.76
`3.71
`
`0
`0
`
`0
`0.13
`
`
`0.12
`0.06
`0.06
`
`
`0.06
`0
`0.13
`
`0
`0
`
`0
`0.14
`0
`0
`
`101
`46
`60
`
`66
`27
`
`
`44.88
`64.11
`77.22
`32.11
`
`26.77
`59.77
`41
`16.44
`
`178
`126
`134
`
`
`40
`30
`24
`78
`63
`
`0.67
`0.77
`0.89
`
`0.22
`0.22
`
`
`0.33
`0.22
`0.22
`0
`
`0.11
`0.22
`0
`0.22
`
`1.17
`1.83
`1.33
`
`
`0
`0
`0
`0.5
`0
`
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Fail
`
`Pass
`Pass
`Pass
`Pass
`Fail
`
`1.21 mg/mL/100%
`99.209/1.3
`96.539/1.7
`
`1.24 mg/mL/100%
`98.939/1.7
`98.119/0.9
`
`1.20 mg/mL/100%
`99.049/0.11
`99.549/1.11
`
`
`1.24 mg/mL/100%
`100.919/0.93
`101.509/1.37
`
`
`1.18 mg/mL/100%
`98.819/0.5
`97.649/1.1
`
`
`1.17 mg/mL/100%
`95.549/1.3
`97.599/2.1
`94.069/1.4
`
`
`J Oncol Pharm Practice, Vol 12: No 4, 2006
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`
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`Hospira, Exh. 2014, p. 10
`
`

`
`Donyai and Sewell: Physical and chemical stability of paclitaxel infusions
`
`221
`
`Figure 2. Stability timescales for paclitaxel in fusions showing all concentration/diluent/container-type/storage-temperature combinations.
`
`efficient dose-banding schemes and to reduce infu-
`sion wastage in cases of deferred treatment.
`
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