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Detection of particulate material in parenteral nutrition admixtures
PHARMACISTS
COLUMN
Nutrition Vol. 14, No. 2, 1998
GUEST EDITORS: MICHAEL
C. ALLWOOD, BPHARM, PHD, MRPHARMS University of Derby, Mickelover, Derby, UK DAVID F. DRISCOLL, RPH, PHD Beth Israel Deaconess Medical Center Boston, Massachusetts, USA
TIM SIZER, BPHARM, MRPHARMS Hammersmith Hospital London, UK PATRICK A. BALL, PHD, MCPP University of Otago Dunedin, New Zealand
Detection of Particulate Material in Parenteral Nutrition Admixtures ANDREW R. MINTON, MSC, MICHAEL From the Department of Pharmaceutics,
The problems associated with parenteral nutrition (PN) stability are complex and occur because it is impractical to design a stable “common” regimen to meet the total daily needs of every patient, regardless of status. The potential for physical and chemical incompatibilities in the form of degradation or precipitation is enormous. These problems are further enhanced by the demands for additional supplements given as vitamins and trace elements, along with the necessity for longer shelf-lives to improve pharmacy and patient supply. Central or peripheral administration of parenteral solutions into the human body containing particulate contamination is physiologically undesirable. Debris found in intravenous fluids have been documented in postmortem examinations to cause capillary granuloma, phlebitis, and possibly the liberation of certain pyrogenic substances.’ Furthermore, the incompatibility of calcium and phosphate was thought to be the cause of a fatal microvascular pulmonary emboli in two patients after receiving PN,2 the cause of death being attributed to massive obstruction of the pulmonary arterioles. In this latter case, the formation of calcium phosphate precipitation would not have been seen unless an operator was continuously ob-
Nutrition 14:251-252, 1998 OElsevier Science Inc. 1998 Printed in the USA. All rights reserved.
I. BARNE’M’, PHD, AND ALLAN G. COSSLETT,
PHD
Welsh School of Pharmacy, University of Wales, Card@ United Kingdom
serving the automated filling process. Even if the formation of insoluble phosphates were time mediated and took several hours to evolve, visual detection would have been masked by the inclusion of lipid. Although sophisticated analytical techniques, such as the electrolyte resistivity and light-extinction (blockage) instruments, are available, and particulate limit tests are outlined in the United States Pharmacopoeia and European Pharmacopoeia for small- and large-volume injection solutions, on a day-to-day basis in a hospital, compounding unit testing the multitude of ampules and small-volume injections for particulate contamination is just not feasiadmixtures containing ble. Moreover, amino acids, glucose and micro-macronutrients are potentially less stable, but the inspection of these infusates for extraneous particulate matter using simple inhouse techniques may be inadequate for the detection of certain microscopic contaminates. Although it is beyond the scope of this column to describe ways of limiting extraneous material in PN admixtures and how the use of expensive quantitative analytic test such as scanning electron microscopy (SEM) with EDAX (X-ray dispersive spectroscopy) help identify particulate
ELSEVIER
matter, an update of basic inexpensive methods may prove a more beneficial and practical approach to those staff who assess parenteral products. Two such methods are discussed. Current methods for detection of particulate matter in parenteral solutions in the hospital situation are probably unsatisfactory. One such method is the polarized viewer. This technique of using diffuse light is best suited to detect large (>_50 pm) particles like calcium phosphate precipitates. Operators are unlikely to see fine phosphate precipitation (opalescence), vitamin precipitation,3 trace element precipitation,4s5 and certain drug precipitates.6 This method, when used for viewing small volume parenterals, leads to considerable operator fatigue and error in counting and identification. The use of the dark-ground illumination method (which employs directional fiber optic illumination, for example, the Schott (Wiesbaden, Germany) fiber optic cold light source) is best used for those particles that cannot be seen by examination in ordinary daylight and depends on the efficiency of the light beam being reflected at right angles to the line of observation (Tyndall effect). The light beam is vertically shone through the bottom of the bottle or bag, with the particles viewed
0899-9007/98/$19.00 PI1 SO899-9007(97)00442-S
252 from the horizontal position. If particles are present, light will scatter, described neatly by Garvan and Gunner’ as “similar to that of a shaft of light in a dark and dusty room.” If the sample appears hazy (opalescence), the suspension contains small (up to 1 pm) particles, with the degree of haziness dependent on the concentration of particles. With more particles present, the sample appears more illuminated, with larger individual particulates seen as distinct bright spots. There is evidence to indicate that the addition of trace elements has an effect on the physical and chemical stability of PN admixtures.’ Precipitation involving trace metals has been identified,3-5 but the interactive processes between the compounds involved are still poorly understood. Atomic Absorption and SEM with EDAX identify copper (Ct?‘) as one component of trace element precipitation; there is, however, only theoretical evidence that the sulfhydryl group of L-cysteine is the binding site responsible for the complexation of this red- brown copper- cysteinate precipitate. New evidence has found that during the sterilisation process (pasteurisation or autoclaving) of amino acid solutions, hydrogen sulfide (H-J) is released from cysteine which then binds with specific metal ions within admixtures to form insoluble metal sulfide precipitates (identification made by atomic absorption, SEM (EDAX), amino acid analysis and H,S gas readings; unpublished observations). To complicate matters further this process is influenced by ion concentration, the combination of metal ion additives, the order of mixing, temperature, and the inclusion of dextrose. Derivatives of cysteine (excluding cysteine hydrochloride) such as N-acetyl-Lcysteine and Di-acetyl-L-cysteine are more stable and do not appear to release H,S and therefore do not facilitate in the precipitate forming process. Calcium phosphate precipitation is the most likely chemically-formed precipitate in PN admixtures. It is dependent primarily on the nature of phosphate used and solution pH. Even though monographs are available to the hospital pharmacist, outlining the limits of calcium and phosphate compatibility, there will be occasions in which a potential for precipitation can occur. Calcium as the soluble chloride or gluconate and phosphate as the sodium or potassium salt are added to most parenteral nutrient solutions. If the solubility product for a particular calcium phosphate salt is exceeded, then precipitation will occur;
PARTICULATES however, the use of organic phosphates in the form of glucose-l-phosphates or glycerophosphateg increase calcium phosphate compatibility. The use of these salts greatly improves solubility and is recommended for use in neonatal regimens requiring high calcium and phosphorus concentrations. Patterned plastic bags with lines on the outside surface impede the visual detection of particles; even very heavy contamination may not be detected through the opaque wall of the container. The only efficient way to inspect the solution is to pour a small amount into a thoroughly cleaned glass tube and view using the dark-field method. Some brands of bags are visibly contaminated with debris, most likely arising from the molding or extrusion process. The presence of such material may cause seeding, a process whereby soluble ions bind to extraneous material and accumulate to form solid matter. These pose as much of a risk to the patient as do chemically-formed precipitates. Nephelometry, using for example the Hach Ratio/XR Turbidimeter (Loveland, Colorado, USA), is based on the principle of light scatter and may provide the means for detecting the development of subvisible precipitation.5 Photosensitive detectors are positioned in such a way as to record the amount of light scattered. An increase in particle size and concentration over time increases the value of turbidity. This system, however, does not detect individual particles, such as large (>50 pm) phosphate precipitates, but works best as an early warning system for subvisible particulate growth. Nephelometry values for subvisible calcium phosphate precipitation have a much higher turbidity value than trace element precipitation. Opalescence of the solution for each precipitate has a markedly different turbidity value: calcium phosphate precipitation has a turbidity of around 2 units, whereas trace element precipitation is lo-fold lower at 0.2 units. Microscopy has been used to detect and identify particulate matter of filtered solutions.iO The problems with this method are the arduous nature of counting and the need to inspect many samples. The addition of drugs to parenteral admixtures is becoming a more common practice. As our knowledge and understanding of admixtures increases, there will be scope for the safe addition of certain drugs. To date, there is no standard method for detecting particulates in administration sets, which raises the issue of
IN PARENTERAL
SOLUTIONS
administration of drugs via a Y-site. There are numerous reports in the literature involving precipitation of single dose or multidose additives during such infusions. Our understanding of the physical and chemical compatibility of drugs in PN admixtures and infusion fluids is still in its infancy and our knowledge only appears to increase during trial-and-error experiments. There is still much work to be done in this area to ensure both PN integrity and patient safety. The responsibility to provide particulate-free parenteral solutions inevitably falls on the manufacturer. Compounded PN bags, however, are the responsibility of the pharmacy sterile compounding unit, and as regimens become more complicated with the addition of new and existing products, it is imperative that regular inspection procedures be carried out by the most efficient means possible. Any feasible improvement toward the detection of particles in parenteral solutions ought to be considered. REFERENCES 1. Garvan JM, Gunner BW. The harmful effects of particulates in intravenous fluids. Med J Aust 1964;2:1 2. Hill SE. Heldman LS. Goo EDH. WhiDDo PE, Perkinson JC. Fatal microvascuiar pulmonary emboli from precipitation of a total nutrient admixture solution. JPEN 1996;20:81 3. Allwood MC, Bamett MI, O’SulJivan J, Washington C. Guidelinesfor assessing the physical and physico-chemicalstabili~of parenteral nutritiona&inures. The National Total Parenteral Nutrition Group, University of Derby, Derby, 1997 4 Allwood MC, Greenwood M. Assessment of trace element compatibility in total parenteral nutrition infusions. Pharma Weekblad Sci Ed 1992;14:321 5. Bamett MI, Cosslett AG, Minton A. Poster pm sentation. Eur J Pharm Sci 1996;4(suppl):Sl64 6. Trissel LA, Martinez JF. Turbidity assessment of the compatibility of taxol with 42 other drugs during simulated Y-site injection. Am J Hosp Pharm 1993:50:300 I. Allwood MC, Barnett Ml. Micronutrient stability. Pharm J 1996;256:403 8. Hardy G, Torres NJ. Glucose-l-phosphate in parenteral nutrition. Pharm J 1987;239: 641 9. Raupp P, Kries RV, Pfahl HG, Manz F. Glycero- vs glucose-phosphate in parenteral nutrition of premature infants: a comparative in vitro evaluation of calcium/ phosphorus compatibility. JPEN 1991;15: 469 10 Garvan JM, Gunner BW. Particulate contamination of intravenous fluids. Br J Clin Pratt 1971;25:119
COLUMN
Nutrition Vol. 14, No. 2, 1998
GUEST EDITORS: MICHAEL
C. ALLWOOD, BPHARM, PHD, MRPHARMS University of Derby, Mickelover, Derby, UK DAVID F. DRISCOLL, RPH, PHD Beth Israel Deaconess Medical Center Boston, Massachusetts, USA
TIM SIZER, BPHARM, MRPHARMS Hammersmith Hospital London, UK PATRICK A. BALL, PHD, MCPP University of Otago Dunedin, New Zealand
Detection of Particulate Material in Parenteral Nutrition Admixtures ANDREW R. MINTON, MSC, MICHAEL From the Department of Pharmaceutics,
The problems associated with parenteral nutrition (PN) stability are complex and occur because it is impractical to design a stable “common” regimen to meet the total daily needs of every patient, regardless of status. The potential for physical and chemical incompatibilities in the form of degradation or precipitation is enormous. These problems are further enhanced by the demands for additional supplements given as vitamins and trace elements, along with the necessity for longer shelf-lives to improve pharmacy and patient supply. Central or peripheral administration of parenteral solutions into the human body containing particulate contamination is physiologically undesirable. Debris found in intravenous fluids have been documented in postmortem examinations to cause capillary granuloma, phlebitis, and possibly the liberation of certain pyrogenic substances.’ Furthermore, the incompatibility of calcium and phosphate was thought to be the cause of a fatal microvascular pulmonary emboli in two patients after receiving PN,2 the cause of death being attributed to massive obstruction of the pulmonary arterioles. In this latter case, the formation of calcium phosphate precipitation would not have been seen unless an operator was continuously ob-
Nutrition 14:251-252, 1998 OElsevier Science Inc. 1998 Printed in the USA. All rights reserved.
I. BARNE’M’, PHD, AND ALLAN G. COSSLETT,
PHD
Welsh School of Pharmacy, University of Wales, Card@ United Kingdom
serving the automated filling process. Even if the formation of insoluble phosphates were time mediated and took several hours to evolve, visual detection would have been masked by the inclusion of lipid. Although sophisticated analytical techniques, such as the electrolyte resistivity and light-extinction (blockage) instruments, are available, and particulate limit tests are outlined in the United States Pharmacopoeia and European Pharmacopoeia for small- and large-volume injection solutions, on a day-to-day basis in a hospital, compounding unit testing the multitude of ampules and small-volume injections for particulate contamination is just not feasiadmixtures containing ble. Moreover, amino acids, glucose and micro-macronutrients are potentially less stable, but the inspection of these infusates for extraneous particulate matter using simple inhouse techniques may be inadequate for the detection of certain microscopic contaminates. Although it is beyond the scope of this column to describe ways of limiting extraneous material in PN admixtures and how the use of expensive quantitative analytic test such as scanning electron microscopy (SEM) with EDAX (X-ray dispersive spectroscopy) help identify particulate
ELSEVIER
matter, an update of basic inexpensive methods may prove a more beneficial and practical approach to those staff who assess parenteral products. Two such methods are discussed. Current methods for detection of particulate matter in parenteral solutions in the hospital situation are probably unsatisfactory. One such method is the polarized viewer. This technique of using diffuse light is best suited to detect large (>_50 pm) particles like calcium phosphate precipitates. Operators are unlikely to see fine phosphate precipitation (opalescence), vitamin precipitation,3 trace element precipitation,4s5 and certain drug precipitates.6 This method, when used for viewing small volume parenterals, leads to considerable operator fatigue and error in counting and identification. The use of the dark-ground illumination method (which employs directional fiber optic illumination, for example, the Schott (Wiesbaden, Germany) fiber optic cold light source) is best used for those particles that cannot be seen by examination in ordinary daylight and depends on the efficiency of the light beam being reflected at right angles to the line of observation (Tyndall effect). The light beam is vertically shone through the bottom of the bottle or bag, with the particles viewed
0899-9007/98/$19.00 PI1 SO899-9007(97)00442-S
252 from the horizontal position. If particles are present, light will scatter, described neatly by Garvan and Gunner’ as “similar to that of a shaft of light in a dark and dusty room.” If the sample appears hazy (opalescence), the suspension contains small (up to 1 pm) particles, with the degree of haziness dependent on the concentration of particles. With more particles present, the sample appears more illuminated, with larger individual particulates seen as distinct bright spots. There is evidence to indicate that the addition of trace elements has an effect on the physical and chemical stability of PN admixtures.’ Precipitation involving trace metals has been identified,3-5 but the interactive processes between the compounds involved are still poorly understood. Atomic Absorption and SEM with EDAX identify copper (Ct?‘) as one component of trace element precipitation; there is, however, only theoretical evidence that the sulfhydryl group of L-cysteine is the binding site responsible for the complexation of this red- brown copper- cysteinate precipitate. New evidence has found that during the sterilisation process (pasteurisation or autoclaving) of amino acid solutions, hydrogen sulfide (H-J) is released from cysteine which then binds with specific metal ions within admixtures to form insoluble metal sulfide precipitates (identification made by atomic absorption, SEM (EDAX), amino acid analysis and H,S gas readings; unpublished observations). To complicate matters further this process is influenced by ion concentration, the combination of metal ion additives, the order of mixing, temperature, and the inclusion of dextrose. Derivatives of cysteine (excluding cysteine hydrochloride) such as N-acetyl-Lcysteine and Di-acetyl-L-cysteine are more stable and do not appear to release H,S and therefore do not facilitate in the precipitate forming process. Calcium phosphate precipitation is the most likely chemically-formed precipitate in PN admixtures. It is dependent primarily on the nature of phosphate used and solution pH. Even though monographs are available to the hospital pharmacist, outlining the limits of calcium and phosphate compatibility, there will be occasions in which a potential for precipitation can occur. Calcium as the soluble chloride or gluconate and phosphate as the sodium or potassium salt are added to most parenteral nutrient solutions. If the solubility product for a particular calcium phosphate salt is exceeded, then precipitation will occur;
PARTICULATES however, the use of organic phosphates in the form of glucose-l-phosphates or glycerophosphateg increase calcium phosphate compatibility. The use of these salts greatly improves solubility and is recommended for use in neonatal regimens requiring high calcium and phosphorus concentrations. Patterned plastic bags with lines on the outside surface impede the visual detection of particles; even very heavy contamination may not be detected through the opaque wall of the container. The only efficient way to inspect the solution is to pour a small amount into a thoroughly cleaned glass tube and view using the dark-field method. Some brands of bags are visibly contaminated with debris, most likely arising from the molding or extrusion process. The presence of such material may cause seeding, a process whereby soluble ions bind to extraneous material and accumulate to form solid matter. These pose as much of a risk to the patient as do chemically-formed precipitates. Nephelometry, using for example the Hach Ratio/XR Turbidimeter (Loveland, Colorado, USA), is based on the principle of light scatter and may provide the means for detecting the development of subvisible precipitation.5 Photosensitive detectors are positioned in such a way as to record the amount of light scattered. An increase in particle size and concentration over time increases the value of turbidity. This system, however, does not detect individual particles, such as large (>50 pm) phosphate precipitates, but works best as an early warning system for subvisible particulate growth. Nephelometry values for subvisible calcium phosphate precipitation have a much higher turbidity value than trace element precipitation. Opalescence of the solution for each precipitate has a markedly different turbidity value: calcium phosphate precipitation has a turbidity of around 2 units, whereas trace element precipitation is lo-fold lower at 0.2 units. Microscopy has been used to detect and identify particulate matter of filtered solutions.iO The problems with this method are the arduous nature of counting and the need to inspect many samples. The addition of drugs to parenteral admixtures is becoming a more common practice. As our knowledge and understanding of admixtures increases, there will be scope for the safe addition of certain drugs. To date, there is no standard method for detecting particulates in administration sets, which raises the issue of
IN PARENTERAL
SOLUTIONS
administration of drugs via a Y-site. There are numerous reports in the literature involving precipitation of single dose or multidose additives during such infusions. Our understanding of the physical and chemical compatibility of drugs in PN admixtures and infusion fluids is still in its infancy and our knowledge only appears to increase during trial-and-error experiments. There is still much work to be done in this area to ensure both PN integrity and patient safety. The responsibility to provide particulate-free parenteral solutions inevitably falls on the manufacturer. Compounded PN bags, however, are the responsibility of the pharmacy sterile compounding unit, and as regimens become more complicated with the addition of new and existing products, it is imperative that regular inspection procedures be carried out by the most efficient means possible. Any feasible improvement toward the detection of particles in parenteral solutions ought to be considered. REFERENCES 1. Garvan JM, Gunner BW. The harmful effects of particulates in intravenous fluids. Med J Aust 1964;2:1 2. Hill SE. Heldman LS. Goo EDH. WhiDDo PE, Perkinson JC. Fatal microvascuiar pulmonary emboli from precipitation of a total nutrient admixture solution. JPEN 1996;20:81 3. Allwood MC, Bamett MI, O’SulJivan J, Washington C. Guidelinesfor assessing the physical and physico-chemicalstabili~of parenteral nutritiona&inures. The National Total Parenteral Nutrition Group, University of Derby, Derby, 1997 4 Allwood MC, Greenwood M. Assessment of trace element compatibility in total parenteral nutrition infusions. Pharma Weekblad Sci Ed 1992;14:321 5. Bamett MI, Cosslett AG, Minton A. Poster pm sentation. Eur J Pharm Sci 1996;4(suppl):Sl64 6. Trissel LA, Martinez JF. Turbidity assessment of the compatibility of taxol with 42 other drugs during simulated Y-site injection. Am J Hosp Pharm 1993:50:300 I. Allwood MC, Barnett Ml. Micronutrient stability. Pharm J 1996;256:403 8. Hardy G, Torres NJ. Glucose-l-phosphate in parenteral nutrition. Pharm J 1987;239: 641 9. Raupp P, Kries RV, Pfahl HG, Manz F. Glycero- vs glucose-phosphate in parenteral nutrition of premature infants: a comparative in vitro evaluation of calcium/ phosphorus compatibility. JPEN 1991;15: 469 10 Garvan JM, Gunner BW. Particulate contamination of intravenous fluids. Br J Clin Pratt 1971;25:119