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Quality evaluation of radiographic contrast media in large-volume prefilled syringes and vials
Quality Evaluation of Radiographic Contrast Media in Large-Volume Prefilled Syringes and Vials Toshiaki Sendo, Phb, Masaaki Hirakawa, BS, Mizue Yaginuma, BS Toshinobu Aoyama, PhD2, Ryozo Oishi, PhD
: ~ationale a n d O b j ~ v e ~ ' V l a e authors::~Omp~ed the::: : Contrast:media :: 'paekagedin !al,ge-votume prefilled:Syringes:and vials. : : :Materials:and::Method~:Partidle ¢oun~ing::wasper-:i : ::formed:for four: ¢ontras~ media packaged in iarge-Volmnae
:::pr in
Oohe o ; iovor ol, iov=sor
g og-
::; raoh~!:: and: :ioxaglate~ and three :COntrasf media oackaeed : :
tefial:re!eaSedl from therubber stopper ok:inner Surface, i :i T heparticM :Counts for cOntra~t media pack- i ,ges and: vials:?caried:coasiderab!y among :the : ;:different Contrast media:mad :were:related to:the amount: ;silicone oil ::on: the inner:surface :and:rubber piston: of ~ ~ e Syrin:ge.:i: ::::i: i : :::i ;:Key: Wortts; C~ntrast ~edA~::iohe~a: :ik>v~l~::i6x:a] ::: : :: :~late~!:quaiityassurance.: : ::::: ::::::: :::::: ::: :: :
Sterile single-use glass syringes have been used as medical devices intended for the immediate administration of vaccine, hormones, local anesthetics, and narcotics (1). Recently, large-volume syringes prefilled with radiographic contrast media were developed, and their use is increasing. The large-volume prefilled syringe has the advantage of being immediately applicable to all automatic injector system and of remaining free from bacteria or pyrogen contamination (2). In a previous article (3), we reported that a dramatic increase in the particle contamination of contrast media occurred as a result of the possible interaction with silicone and sulfur on the surfaces of the disposable syringe components. Particles in the large-volume prefilled syringe might arise in the same manner from the inner surface of the packaging system of the syringe, because silicone oil is applied to the inner surface and the rubber stopper for smooth operation of the rubber piston. To our knowledge, however, there have been no reports about particle contamination of radiographic contrast media packaged in large-volume prefilled syringes. Therefore, we performed this study to compare particle contamination in radiographic contrast media packaged in largevolume prefilled syringes and vials and assessed the contribution of silicone to the overall particle load.
Radiographic Contrast Media Acad Radio11998; 5:444-447 From the Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Received February 12, 1997; revision requested April 28; revision received November 14; a c c e p t e d January 9, 1998. Address reprint requests to R,O. 2Current address: Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan. ©AUR, 1998
444
We evaluated contrast media packaged in large-volume prefilled syringes and vials. The following contrast media were packaged in large-volume prefilled syringes: iohexol (Omnipaque 300, 100 mL, lot FQ41; Daiichi Pharmaceutical, Tokyo, Japan), ioversol (Optiray 320 Uject, 50 mL, lot L082A; Mallinckrodt Medical, St Louis, Mo), ioversol for angiography (Optiray 320 U-ject for an-
Vol 5, No 6,June 1998 giography, lot L078A; Mallinckrodt Medical), and ioxaglate (Hexabrix 320 U-ject for angiography, 125 mL, lot L054A; Mallinckrodt Medical). The following contrast media were stored in vials: iohexol (Omnipaque 300, 100 mL, lot FQ41; Daiichi Pharmaceutical), ioversol (Optiray 320, 100 mL, lot 305465J; Mallinckrodt Medical), and ioxaglate (Hexabrix 320, 100 mL, lot 3100; Mallinckrodt Medical).
Sample Preparations and Particle Counting Particle counting was performed with an automated light extinction method by using an automatic parenteral sampling system (Particle Measuring Systems, Boulder, Colo) according to a previous study (3). The analyses were performed at the following particle size levels: >2 gm, _>5 gm, >10 gm, and _>25 gm in diameter. The counter system calculates the mean level of triplicate determinations after discounting the first. To count the particles in contrast media packaged in large-volume prefilled syringes, all contents were discharged directly into a particle-free glass bottle and then were left to stand at room temperature for 10 minutes; they were then assayed after direct introduction into the instrument. For the vial preparations, the sample tube was directly inserted into the vial after the rubber stopper was removed. Sample preparation was carried out in a laminar flow hood equipped with HEPA (high-efficiency particulate air) filters. The results were obtained by using five different samples for each of four and three contrast media in the syringes and vials, respectively.
Scanning Electron Microscopy and X-ray Emission Spectrometry Five milliliters of the sample used for particle counting was filtered through a 0.45-gm membrane (HA type; Nihon Millipore, Tokyo, Japan), and distilled water was run through to rinse out soluble materials. The filters were fixed on an aluminum stub (1 x 1 cm) with doubleside adhesive tape and carbon-coated in a high-vacuum evaporator (model 5GB; Hitachi, Tokyo, Japan). X-ray emission spectrometry of the individual particles was performed with an x-ray energy dispersive microanalyzer (EMAX-1770; Horiba, Kyoto, Japan) attached to a scanning electron microscope (model S-510; Hitachi).
Determination of Silicone Oil with Infrared Spectrophotometry The amount of silicone oil extracted from the syringe was quantified with infrared spectrophotometry at 1,260-
QUALITY EVALUATION OF CONTRAST MEDIA 1,270 cm -~ (polysiloxanes absorption wavelength). Silicone oil was extracted from the syringe as follows. The portion of the syringe filled with contrast medium was cut off. The contrast medium was removed, and the samples were washed and dried. Thereafter, a volume of 1,1,2-trichloro-l,2,2-trifluoroethane (Freon TF; Mitsui Fluorochemical, Tokyo, Japan) equal to half the nominal volume (about 50 mL) was put into the syringe, and silicone oil on the inner surface was washed out. The rubber piston was placed in a beaker, and 50 mL of 1,1,2-trichloro-l,2,2-trifluoroethane was added. The solution was stirred for 2 minutes. After the solvent was completely evaporated, the residue was reconstituted in 1 mL of carbon tetrachloride and analyzed at room temperature with an infrared spectrophotometer (model 270-30; Hitachi).
The average particle counts per milliliter for the four contrast media in syringes and the three contrast media in vials are presented in Table 1. In the syringe preparation, 123 particles per milliliter measuring 2 ~tm or greater were found in ioversol, which was much greater than the count of 11 particles per milliliter in iohexol and nine particles per milliliter in ioxaglate. The vial preparations had low levels of particle contamination, although the values were higher for ioxaglate than for the other two contrast media. In all samples, the mean particle counts for particles measuring 25 gm or greater were less than two per milliliter. In our study, the particle contamination in the syringes containing ioversol was greater than that in vials. Two types of particle sources for the syringes containing ioversol were observed with scanning electron micrography and EMAX spectrography. Results of EMAX analysis revealed elements of sulfur and silicone in most particles. For some particles, the element could not be determined because the particles were presumably organic material. To elucidate how the particles were generated, the amount of silicone oil on the inner surfaces and rubber pistons of the syringes was determined (Table 2). The amount of silicone oil on the rubber piston was the lowest for ioxaglate, and the amount of silicone oil on the inner surface was undetectable for iohexol. The injection may be controlled smoothly with silicone on the rubber piston in the syringe containing iohexol. In contrast, comparatively large amounts of silicone oil were shown on the inner surface of the syNlge containing ioversol, which contained more particles than did the syringes for the other contrast media.
445
Table 1 Comparison of the Particle Counts in the Large-Volume Prefilled Syringes and Vials Particle Count (pieces per milliliter) Contrast Medium
Type of Package
Iohexol
Syringe Vial
Ioversol
Syringe Syringe (angiography) Vial
Ioxaglate
Syringe Vial
British P h a r m a c o p o e i a * U.S. P h a r m a c o p o e i a *
>2 gm
>5 gm
>10 gm
11 + 2 6_+ 1
4+ 1 4+1
1+ 1 3+0
0 2+0
123 + 20 116 + 42 7+ 1
41 + 11 43 + 19 5+ 1
16 + 9 17 + 9 5+ 1
0 0 2+ 1
9+5 78+ 11
3 +_2 15+ 1
1+ 0 3+ 1
0 0
500
80
•.
.
.
.
>25 gm
. . . . . .
.
60
6
N o t e . - - D a t a are means + standard deviation of five samples. *Values represent the maximum number of particles a l l o w e d (4,5).
Table 2 Amount of Silicone Oil in the Large-Volume Prefilled Syringes as Determined with Infrared Spectrophotometry Area (cm 2)
A m o u n t of Silicone Oil t
Contrast Material
Inner Surface of Syringe*
Contact Portion~
Rubber Piston (mg)
Inner Surface of Syringe ( m g / c m 2, x 10-3)
Ioxaglate Ioversol (angiography) Ioversol Iohexol
135.6
14,3
2.12
23,2
53.2 78.5 122.8
14.3 10.6 13.5
6.82 5.28 10.79
64.8 68.8 ND
*The inner surface area of syringe was c a l c u l a t e d by using the following formula (12): 2~l(Vrch), w h e r e Vis the nominal volume corresponding to the volume filled with the radiographic contrast m e d i u m a n d h is the height of the portion in the syringe filled with the radiographic contrast medium. tThis area represents the c o n t a c t b e t w e e n the inner surface of the syringe and the rubber piston. tEa.ch value represents the m e a n of three different syringes. ND = not d e t e c t a b l e .
From the comparative evaluation of syringes and vials, the particle contamination in the ioxaglate vials was greater than that in the syringes containing ioxaglate. Elemental analysis of most particles in the vial of ioxaglate revealed some elements (eg, aluminum, silicone, calcium, sulfur, and titanium) that originated from the rubber stopper. The rubber stoppers of all vials examined in this study were made of butyrate rubber, which is essentially the same material except for possible variations in the same polymer, and scanning electron micrographs revealed no difference in the surface roughness of the stoppers in the vials.
446
All preparations could be examined satisfactorily by using the counter system and light extinction technique. The maximal allowable numbers of particles in parenteral preparations are described in the various pharmacopoeias. Contrast media should pass the minimum requirements of both small- and large-volume parenteral preparations. The U.S. Pharmacopoeia shows only the limits determined with the light extinction method for small-volume parenteral preparations (<100 mL) (4). The limits allowed by the U.S. Pharmacopoeia for particles with diameters
of _>10 gm and >25 gm are 6,000 and 600 per container, respectively. For all preparations examined in this study, the number of particles was below these limits. Furthermore, all preparations also passed the regulation of particle limits of the British Pharmacopoeia (>2 gm, 500 per milliliter; >_5 gm, 80 per milliliter) determined with the light extinction method for large-volume parenteral preparations (>_100 mL) (5). The literature contains a number of case reports about possible medical hazards of cerebral angiography owing to intraarterial injection of contrast material contaminated with particles (6-8). In a few animal experiments, attempts have been made to demonstrate the harmful effect of particles during angiography of the kidneys or brain (8,9), but the causal relationship between the harmful effect and number of particles in the contrast medium is practically unknown. Until the clinical importance of particle contamination in contrast medium is resolved, an inline final filter may be of value to patients. In clinical settings, however, an in-line final filter cannot be used for rapid infusion of highly viscous contrast media. Therefore, the contrast medium must be devoid of particles as completely as possible. At present, the practical method for reducing the number of particles seems to be improvement of the manufacturing processes (10). Thus, it is important to clarify the sources of particulate contaminants. The elements of the particulate contaminants from ioversol, which contained more particles than did the other contrast media in the syringes, were considered compositions released from the rubber piston and silicone oil coating on the inner surface of the syringe rather than utldissolved contrast media. From the qualitative study of silicone in various large-volume prefilled syringe preparations, it was suggested that silicone represented a substantial contribution to the particle contamination and that silicone shed from the syringe during loading or storage induced the particle contamination. Use of silicone, however, is absolutely necessary for smooth handling during the manufacturing process and for rapid injection during diagnostic radiology. Results of this study indicate that the amount of silicone used should be as small as possible and that is should be applied only to the appropriate portion in the syringe. In general, rubber stoppers in vials are considered prominent contamination sources in parenteral prepara-
tions because they contain leaching ingredients (11). In our study, we found that the sources of particle contaminants in the vial were rubber constituents. Although the reason is obscure, differences in the manufacturing process might be involved in the differences of the amount of silicone on the inner surface among the syringes and the quality of the rubber after cleaning and sterilization among the vial preparations. Finally, a large-volume syringe prefilled with contrast medium might be recommended compared with a vial preparation because of the dramatic particle contamination induced by transferring contrast medium from the vial to a disposable syringe (3). ~CKNOWLEDGMENT,c
The authors thank Masahiko Kikuchi, PhD, for suggestions and help with the determination of silicone oil. In addition, we thank Osamu Fujishita, PhD, and Ayako Hisazumi, MS, for helpful discussions during this study. !EFERENCE.(
1. Anand RD. Injection vials: a comparison with regard to composition, manufacturer and use of prefilled syringe, Pharm Ind 1992; 54:69-73. 2. Yashiro N, Kawahara K, Taniguchi T. Clinical trials of iohexol syringe. Jpn Pharmacol Ther 1992; 20:4769-4773. 3. Sendo T, Otsubo K, Hisazumi A, Aoyama T, Oishi R, Particle contamination in contrast media induced by disposable syringe, J Pharm Sci 1995; 84:1490-1491. 4. United States Pharmacopeial Convention. Particulate matter in injections: physical test 788, In: United States pharmacopoeia. Vo123. Rockville, Md: United States Pharmacopeial Convention, 1994; 1813-1819, 5. British Pharmacopeia Commission. Limit test for particulate matter. In: British pharmacopoeia. London, England: HMSO, 1993; 746-748. 6. Zatz LM, Lanone AM. Cerebral emboli complicating cerebral angiography. Acta Radiol Diagn 1966; 5:621-630. 7. Bates BF, Brochstein JJ. Intercurrent embolization during cerebral angiography: clinical and experimental observations. Invest Radio11966; 1:107-112. 8. Markus H, Loh A, Israel D, Buckenham T, Clifton A, Brown MM. Microscopic air embolism during cerebral angiography and strategies for its avoidance. Lancet 1993; 341;784-787. 9. Brekkgn A, Lexow PE, Woxholt G. Grass fragments and other particlescontaminating contrast media. Acta Radiol Diagn 1975; 16:600-608, 10. Borchert SJ, Abe A, Aldrich DS, Fox LE, Freeman JE, White RD. Particulate matter in parenteral products: a review, J Parenter Sci Tect~ 1986; 40:212-241. 11, Mannermaa JP, Raisanen J, Hyvonen-Dabek M, Spring E, Yliruusi J. Use of proton-induced x-ray emission (PIXE) analysis in the evaluation of large volume parenteral rubber stoppers. Int J Pharm 1994; 103:125-129. 12, Convention on the elaboration of European pharmacopeia, VI. 2.2.4: sterile single-use plastic syringes. In: European pharmacopoeia. Sainte-Ruffine-France: Maisonneuve, 1991; 1-5.
447
: ~ationale a n d O b j ~ v e ~ ' V l a e authors::~Omp~ed the::: : Contrast:media :: 'paekagedin !al,ge-votume prefilled:Syringes:and vials. : : :Materials:and::Method~:Partidle ¢oun~ing::wasper-:i : ::formed:for four: ¢ontras~ media packaged in iarge-Volmnae
:::pr in
Oohe o ; iovor ol, iov=sor
g og-
::; raoh~!:: and: :ioxaglate~ and three :COntrasf media oackaeed : :
tefial:re!eaSedl from therubber stopper ok:inner Surface, i :i T heparticM :Counts for cOntra~t media pack- i ,ges and: vials:?caried:coasiderab!y among :the : ;:different Contrast media:mad :were:related to:the amount: ;silicone oil ::on: the inner:surface :and:rubber piston: of ~ ~ e Syrin:ge.:i: ::::i: i : :::i ;:Key: Wortts; C~ntrast ~edA~::iohe~a: :ik>v~l~::i6x:a] ::: : :: :~late~!:quaiityassurance.: : ::::: ::::::: :::::: ::: :: :
Sterile single-use glass syringes have been used as medical devices intended for the immediate administration of vaccine, hormones, local anesthetics, and narcotics (1). Recently, large-volume syringes prefilled with radiographic contrast media were developed, and their use is increasing. The large-volume prefilled syringe has the advantage of being immediately applicable to all automatic injector system and of remaining free from bacteria or pyrogen contamination (2). In a previous article (3), we reported that a dramatic increase in the particle contamination of contrast media occurred as a result of the possible interaction with silicone and sulfur on the surfaces of the disposable syringe components. Particles in the large-volume prefilled syringe might arise in the same manner from the inner surface of the packaging system of the syringe, because silicone oil is applied to the inner surface and the rubber stopper for smooth operation of the rubber piston. To our knowledge, however, there have been no reports about particle contamination of radiographic contrast media packaged in large-volume prefilled syringes. Therefore, we performed this study to compare particle contamination in radiographic contrast media packaged in largevolume prefilled syringes and vials and assessed the contribution of silicone to the overall particle load.
Radiographic Contrast Media Acad Radio11998; 5:444-447 From the Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Received February 12, 1997; revision requested April 28; revision received November 14; a c c e p t e d January 9, 1998. Address reprint requests to R,O. 2Current address: Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan. ©AUR, 1998
444
We evaluated contrast media packaged in large-volume prefilled syringes and vials. The following contrast media were packaged in large-volume prefilled syringes: iohexol (Omnipaque 300, 100 mL, lot FQ41; Daiichi Pharmaceutical, Tokyo, Japan), ioversol (Optiray 320 Uject, 50 mL, lot L082A; Mallinckrodt Medical, St Louis, Mo), ioversol for angiography (Optiray 320 U-ject for an-
Vol 5, No 6,June 1998 giography, lot L078A; Mallinckrodt Medical), and ioxaglate (Hexabrix 320 U-ject for angiography, 125 mL, lot L054A; Mallinckrodt Medical). The following contrast media were stored in vials: iohexol (Omnipaque 300, 100 mL, lot FQ41; Daiichi Pharmaceutical), ioversol (Optiray 320, 100 mL, lot 305465J; Mallinckrodt Medical), and ioxaglate (Hexabrix 320, 100 mL, lot 3100; Mallinckrodt Medical).
Sample Preparations and Particle Counting Particle counting was performed with an automated light extinction method by using an automatic parenteral sampling system (Particle Measuring Systems, Boulder, Colo) according to a previous study (3). The analyses were performed at the following particle size levels: >2 gm, _>5 gm, >10 gm, and _>25 gm in diameter. The counter system calculates the mean level of triplicate determinations after discounting the first. To count the particles in contrast media packaged in large-volume prefilled syringes, all contents were discharged directly into a particle-free glass bottle and then were left to stand at room temperature for 10 minutes; they were then assayed after direct introduction into the instrument. For the vial preparations, the sample tube was directly inserted into the vial after the rubber stopper was removed. Sample preparation was carried out in a laminar flow hood equipped with HEPA (high-efficiency particulate air) filters. The results were obtained by using five different samples for each of four and three contrast media in the syringes and vials, respectively.
Scanning Electron Microscopy and X-ray Emission Spectrometry Five milliliters of the sample used for particle counting was filtered through a 0.45-gm membrane (HA type; Nihon Millipore, Tokyo, Japan), and distilled water was run through to rinse out soluble materials. The filters were fixed on an aluminum stub (1 x 1 cm) with doubleside adhesive tape and carbon-coated in a high-vacuum evaporator (model 5GB; Hitachi, Tokyo, Japan). X-ray emission spectrometry of the individual particles was performed with an x-ray energy dispersive microanalyzer (EMAX-1770; Horiba, Kyoto, Japan) attached to a scanning electron microscope (model S-510; Hitachi).
Determination of Silicone Oil with Infrared Spectrophotometry The amount of silicone oil extracted from the syringe was quantified with infrared spectrophotometry at 1,260-
QUALITY EVALUATION OF CONTRAST MEDIA 1,270 cm -~ (polysiloxanes absorption wavelength). Silicone oil was extracted from the syringe as follows. The portion of the syringe filled with contrast medium was cut off. The contrast medium was removed, and the samples were washed and dried. Thereafter, a volume of 1,1,2-trichloro-l,2,2-trifluoroethane (Freon TF; Mitsui Fluorochemical, Tokyo, Japan) equal to half the nominal volume (about 50 mL) was put into the syringe, and silicone oil on the inner surface was washed out. The rubber piston was placed in a beaker, and 50 mL of 1,1,2-trichloro-l,2,2-trifluoroethane was added. The solution was stirred for 2 minutes. After the solvent was completely evaporated, the residue was reconstituted in 1 mL of carbon tetrachloride and analyzed at room temperature with an infrared spectrophotometer (model 270-30; Hitachi).
The average particle counts per milliliter for the four contrast media in syringes and the three contrast media in vials are presented in Table 1. In the syringe preparation, 123 particles per milliliter measuring 2 ~tm or greater were found in ioversol, which was much greater than the count of 11 particles per milliliter in iohexol and nine particles per milliliter in ioxaglate. The vial preparations had low levels of particle contamination, although the values were higher for ioxaglate than for the other two contrast media. In all samples, the mean particle counts for particles measuring 25 gm or greater were less than two per milliliter. In our study, the particle contamination in the syringes containing ioversol was greater than that in vials. Two types of particle sources for the syringes containing ioversol were observed with scanning electron micrography and EMAX spectrography. Results of EMAX analysis revealed elements of sulfur and silicone in most particles. For some particles, the element could not be determined because the particles were presumably organic material. To elucidate how the particles were generated, the amount of silicone oil on the inner surfaces and rubber pistons of the syringes was determined (Table 2). The amount of silicone oil on the rubber piston was the lowest for ioxaglate, and the amount of silicone oil on the inner surface was undetectable for iohexol. The injection may be controlled smoothly with silicone on the rubber piston in the syringe containing iohexol. In contrast, comparatively large amounts of silicone oil were shown on the inner surface of the syNlge containing ioversol, which contained more particles than did the syringes for the other contrast media.
445
Table 1 Comparison of the Particle Counts in the Large-Volume Prefilled Syringes and Vials Particle Count (pieces per milliliter) Contrast Medium
Type of Package
Iohexol
Syringe Vial
Ioversol
Syringe Syringe (angiography) Vial
Ioxaglate
Syringe Vial
British P h a r m a c o p o e i a * U.S. P h a r m a c o p o e i a *
>2 gm
>5 gm
>10 gm
11 + 2 6_+ 1
4+ 1 4+1
1+ 1 3+0
0 2+0
123 + 20 116 + 42 7+ 1
41 + 11 43 + 19 5+ 1
16 + 9 17 + 9 5+ 1
0 0 2+ 1
9+5 78+ 11
3 +_2 15+ 1
1+ 0 3+ 1
0 0
500
80
•.
.
.
.
>25 gm
. . . . . .
.
60
6
N o t e . - - D a t a are means + standard deviation of five samples. *Values represent the maximum number of particles a l l o w e d (4,5).
Table 2 Amount of Silicone Oil in the Large-Volume Prefilled Syringes as Determined with Infrared Spectrophotometry Area (cm 2)
A m o u n t of Silicone Oil t
Contrast Material
Inner Surface of Syringe*
Contact Portion~
Rubber Piston (mg)
Inner Surface of Syringe ( m g / c m 2, x 10-3)
Ioxaglate Ioversol (angiography) Ioversol Iohexol
135.6
14,3
2.12
23,2
53.2 78.5 122.8
14.3 10.6 13.5
6.82 5.28 10.79
64.8 68.8 ND
*The inner surface area of syringe was c a l c u l a t e d by using the following formula (12): 2~l(Vrch), w h e r e Vis the nominal volume corresponding to the volume filled with the radiographic contrast m e d i u m a n d h is the height of the portion in the syringe filled with the radiographic contrast medium. tThis area represents the c o n t a c t b e t w e e n the inner surface of the syringe and the rubber piston. tEa.ch value represents the m e a n of three different syringes. ND = not d e t e c t a b l e .
From the comparative evaluation of syringes and vials, the particle contamination in the ioxaglate vials was greater than that in the syringes containing ioxaglate. Elemental analysis of most particles in the vial of ioxaglate revealed some elements (eg, aluminum, silicone, calcium, sulfur, and titanium) that originated from the rubber stopper. The rubber stoppers of all vials examined in this study were made of butyrate rubber, which is essentially the same material except for possible variations in the same polymer, and scanning electron micrographs revealed no difference in the surface roughness of the stoppers in the vials.
446
All preparations could be examined satisfactorily by using the counter system and light extinction technique. The maximal allowable numbers of particles in parenteral preparations are described in the various pharmacopoeias. Contrast media should pass the minimum requirements of both small- and large-volume parenteral preparations. The U.S. Pharmacopoeia shows only the limits determined with the light extinction method for small-volume parenteral preparations (<100 mL) (4). The limits allowed by the U.S. Pharmacopoeia for particles with diameters
of _>10 gm and >25 gm are 6,000 and 600 per container, respectively. For all preparations examined in this study, the number of particles was below these limits. Furthermore, all preparations also passed the regulation of particle limits of the British Pharmacopoeia (>2 gm, 500 per milliliter; >_5 gm, 80 per milliliter) determined with the light extinction method for large-volume parenteral preparations (>_100 mL) (5). The literature contains a number of case reports about possible medical hazards of cerebral angiography owing to intraarterial injection of contrast material contaminated with particles (6-8). In a few animal experiments, attempts have been made to demonstrate the harmful effect of particles during angiography of the kidneys or brain (8,9), but the causal relationship between the harmful effect and number of particles in the contrast medium is practically unknown. Until the clinical importance of particle contamination in contrast medium is resolved, an inline final filter may be of value to patients. In clinical settings, however, an in-line final filter cannot be used for rapid infusion of highly viscous contrast media. Therefore, the contrast medium must be devoid of particles as completely as possible. At present, the practical method for reducing the number of particles seems to be improvement of the manufacturing processes (10). Thus, it is important to clarify the sources of particulate contaminants. The elements of the particulate contaminants from ioversol, which contained more particles than did the other contrast media in the syringes, were considered compositions released from the rubber piston and silicone oil coating on the inner surface of the syringe rather than utldissolved contrast media. From the qualitative study of silicone in various large-volume prefilled syringe preparations, it was suggested that silicone represented a substantial contribution to the particle contamination and that silicone shed from the syringe during loading or storage induced the particle contamination. Use of silicone, however, is absolutely necessary for smooth handling during the manufacturing process and for rapid injection during diagnostic radiology. Results of this study indicate that the amount of silicone used should be as small as possible and that is should be applied only to the appropriate portion in the syringe. In general, rubber stoppers in vials are considered prominent contamination sources in parenteral prepara-
tions because they contain leaching ingredients (11). In our study, we found that the sources of particle contaminants in the vial were rubber constituents. Although the reason is obscure, differences in the manufacturing process might be involved in the differences of the amount of silicone on the inner surface among the syringes and the quality of the rubber after cleaning and sterilization among the vial preparations. Finally, a large-volume syringe prefilled with contrast medium might be recommended compared with a vial preparation because of the dramatic particle contamination induced by transferring contrast medium from the vial to a disposable syringe (3). ~CKNOWLEDGMENT,c
The authors thank Masahiko Kikuchi, PhD, for suggestions and help with the determination of silicone oil. In addition, we thank Osamu Fujishita, PhD, and Ayako Hisazumi, MS, for helpful discussions during this study. !EFERENCE.(
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