Affectors of Laboratory Results: Part II

Following up from last weeks editorial on factors that can affect laboratory results, let me mention that this series applies not only to compounding pharmacies but also to those laboratories that analyze compounded preparations where the results are reported in the media, etc. One should exercise caution when jumping to conclusions about media-reported results unless the complete analytical method is available as well as the complete compounding procedures used in compounding the preparations that are analyzed. This short series is to provide information that should be used in interpreting the results of laboratory tests when compounded preparations are involved. This is primarily of importance when the reported laboratory values are relatively close to the targeted value of 90.0 to 110.0% of label.

This week, let�s look at a potential source of errors in compounding intravenous admixtures. The extent of error involved depends upon whether or not the patient is going to receive the �entire admixture� or is going to be administered a drug at a set concentration rate over time. In other words, if 1 g of an antibiotic is administered in a piggyback over 1 hour there may or may not be a problem as the entire contents of a single vial may be used; however, if the quantity is withdrawn from a multiple dose vial, then there may be a problem. In another case, if the patient is to receive a drug at a concentration of 10 mg/mL at a set rate for 24 hours of each day, then the following definitely applies.

First, the recommended excess volume in commercial products, according to USP Chapter <1151> Pharmaceutical Dosage Forms, for �mobile� liquids is as follows: The excess volume recommended is presented in parentheses following the labeled size of the vial: 0.5 ml (0.10 mL); 1.0 mL (0.10 mL); 2.0 mL (0.15 mL); 5.0 mL (0.30 mL); 10.0 mL (0.50 mL); 20.0 mL (0.6 mL); 30.0 mL (0.80 mL); 50.0 mL or more (2%). For �viscous� liquids, the recommended excess volume in commercial products is as follows: 0.5 ml (0.12 mL); 1.0 mL (0.15 mL); 2.0 mL (0.25 mL); 5.0 mL (0.50 mL); 10.0 mL (0.70 mL); 20.0 mL (0.9 mL); 30.0 mL (1.20 mL); 50.0 mL or more (3%).

It is apparent in the cases above, that the use of an entire vial may result in more drug being used than requested and the analyzed concentration may be higher than what was desired. For example, when removing the contents of an ampule or vial, if the entire unit is to be used for the admixture. and careful attention is not paid to the process since the entire unit is being used, then the following may occur. During the process, if most of the contents of a 0.5 mL ampule or vial (the source of the active drug) was removed and this was about 0.6 mL, then there is about 20% more of the drug being used than requested. If this is placed in a set volume of vehicle, for example 100 mL, then the analytical result may be almost 120% of label which is outside the allowable 90% to 110% used in compounding.

Second, the recommended excess for large volume parenterals (Dextrose Injection, Sodium Chloride Injection, etc.), according to the table, would be 2% but in some cases may be as high as 5-7%. In this case, if a drug such as nitroglycerin is being used and is labeled at 25 mg/mL and the allowable USP requirement for the commercial product is 90.0 to 110.0% of the labeled amount and the commercial product being used assayed at 90.0% and is placed in a large volume parenteral (100 mL) containing at least a 2% or more overfill (at least 102 mL), then the actual concentration of nitroglycerin is below 90.0% when analyzed. This, then, falls outside the allowable 90.0 to 110.0% for compounded preparations.

Third, let�s look at the supplies used in measuring the volumes of additives in preparing intravenous admixtures. If automated systems are not in place, it is common practice to use disposable, plastic syringes. Plastic syringes are designed for administration, not for compounding. If they are used in compounding, it would be best if each lot that was received in the pharmacy was calibrated to confirm that the graduated markings on the syringe are accurate. This can easily be done by using water and an electronic balance, as follows: (1) Calibrate the electronic balance to be used; (2) Place the empty syringe on the balance and tare the balance; (3) Fill the syringe to a designated mark, such as 2.5 mL, with purified water or sterile water for injection; (4) Weigh the filled syringe to obtain the weight of the water; (5) With a specific gravity of approximately 1.0, the weight of the water will be equivalent to the milliliters it contains. In this case, the water should weigh 2.5 grams. If not, the syringes should not be used or adjustments must be made in the volumes used in compounding. Errors in the usage of noncalibrated syringes for compounding may be another prominent source in compounding that goes unnoticed until the headlines are made.

Next week in Part III, we will look at some additional factors that can affect laboratory results.

Loyd V. Allen, Jr., Ph.D., R.Ph
Editor-in-Chief

This week on the Compounder�s Network Listserv, pharmacists discussed:

1. A Marinol Oral Liquid Formulation
2. A Disulfiram Injectable Formulation
3. Equipment for Sale!
4. A Dapsone Suspension Formulation

The list below is a sampling of abstracts related to sterile preparations that were added to CT.COM this week. Search �Sterile Preparations� on CompoundingToday.com�s literature database for a complete listing of the abstracts related to this topic.

• Allen LV, Levinson RS, Martono DD. Dissolution rates of hydrocortisone and prednisone utilizing sugar solid dispersion systems in tablet form. J Pharm Sci 1978 Jul; 67(7): 979-981.
• Beatrice MG, Stanaszek WF, Allen LV, Stanton GK, Covington TR. Physicochemical stability of a preanesthetic mixture of hydroxyzine hydrochloride and atropine sulfate. Am J Hosp Pharm 1975 Nov; 32(11): 1133-1137.
• Carrier MN, Garinot O, Vitzling C. Stability and compatibility of tegaserod from crushed tablets mixed in beverages and foods. Am J Health Syst Pharm 2004 Jun 1; 61(11): 1135-1142
• Chirila TV, Morrison DA, Hicks CR, Gridneva Z, Barry CJ, Vijayasekaran S. In vitro drug-induced spoliation of a keratoprosthetic hydrogel. Cornea 2004 Aug; 23(6): 620-629.
• Dager WE, Gosselin RC, King JH, Christensen CL, Owings JT, Larkin EC. Anti-Xa stability of diluted enoxaparin for use in pediatrics. Ann Pharmacother 2004 Apr; 38(4): 569-573. Epub 2004 Feb 24
• Dvorak J, Hajkova R, Matysova L, Novakova L, Koupparis MA, Solich P. Simultaneous HPLC determination of ketoprofen and its degradation products in the presence of preservatives in pharmaceuticals. J Pharm Biomed Anal 2004; 36(3): 625-629.
• McQuade MS, Van Nostrand V, Schariter J, Kanike JD, Forsyth RJ. Stability and compatibility of reconstituted ertapenem with commonly used i.v. infusion and coinfusion solutions. Am J Health Syst Pharm 2004; 61(1): 38-45. [Erratum: Am J Health Syst Pharm 2004; 61(5): 437.
• Pathmanathan U, Halgrain D, Chiadmi F, Schlatter J, Vermerie N. Stability of sulfadiazine oral liquids prepared from tablets and powder. J Pharm Pharm Sci 2004; 7(1): 84-87.
• Smith DL, Bauer SM, Nicolau DP. Stability of meropenem in polyvinyl chloride bags and an elastomeric infusion device. Am J Health Syst Pharm 2004; 61(16): 1682-1685.
• Tu YH, Stiles ML, Allen LV Jr, Olsen KM, Barton CI, Greenwood RB. Stability of amoxicillin trihydrate-potassium clavulanate in original containers and unit dose oral syringes. Am J Hosp Pharm 1988; 45(5): 1092-1099.
• Wang DP, Tu YH, Allen LV Jr. Degradation kinetics of phentolamine hydrochloride in solution. J Pharm Sci 1988; 77(11): 972-976.
• Wang DP, Tu YH, Allen LV Jr, Cheng FC. Degradation mechanism of nefopam in solution under stressed storage conditions. Acta Pharm Nord 1990; 2(2): 73-82.

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