Kathryn Bethune
BSc(Hons) MRPharmS
Specialist Pharmacist in Clinical Nutrition
Pharmacy Department
Great Ormond Street Hospital for Children NHS Trust
London, UK
Robert Duncombe
MSc MRPharmS
Pharmacy Department
Broomfield Hospital Chelmsford, UK
Parenteral nutrition (PN) has been administered to infants and children with intestinal failure at Great Ormond Street Hospital for Children (GOSH) since the early 1970s.(1) The indications for PN are many and varied – it can be used for short periods of time when complete gut rest is required, or for longer periods in patients suffering from prolonged episodes of intestinal failure.
In 2001, 463 patients (4% of total inpatients) received PN for a total of 8,513 days (mean 18.38 days), and 50% (232) of patients were less than six months old when PN was commenced. Although 62% (288) of patients received PN for less than 14 days, 12% (60) received PN as inpatients for over a month (six of these were discharged on home parenteral nutrition).
Since the 1970s, the methods of compounding PN have changed and developed. Initially PN was administered directly to the patient from source containers of the nutrient solutions (glucose, amino acids and lipid) using a complex arrangement of lines joined by two- or three-way taps. Electrolytes were added to the glucose solution by medical or nursing staff on the ward before the start of infusion. Administering PN in this way was not without its complications – electrolyte incompatibilities were likely to occur, and the prevalence of line infections was high, often exceeding 20%.(2)
In an attempt to reduce the risk of infection it was recommended that PN solutions should be manufactured by qualified pharmacy staff within a dedicated aseptic preparation unit using a laminar flow hood.(3)
It is now standard practice in the UK for PN to be prepared in dedicated cleanroom facilities. In most of these units, one of two methods of manufacture are used:
- Manual process The PN solution is prepared manually by measuring the volumes required for the formulation using either syringes or a burette system.
- Two-stage process An automated compounding device is used to add the large volume solutions (eg, glucose and nitrogen solutions) to the final container with electrolytes, trace elements and vitamins added by hand using syringes.
Before February 2001, the two-stage process was used at GOSH to manufacture individually prescribed PN for over 20 patients a day. This process was time-consuming and it was becoming increasingly difficult to meet the demands for PN, which had increased by 25% since 1996. Consequently it was necessary to investigate alternative methods for manufacturing PN.
Automated compounding devices
Fully automated compounding devices (FACD) for the manufacture of PN have been widely used within the USA(4,5) and mainland Europe(6,7) for a number of years. The devices used include the Nutrimix (Abbott), MicroMacro 23 (Baxa) and Micromix (Clintec). These deliver fluid to the final container using either a volumetric or gravimetric fluid pumping system. The FACD is usually linked to dedicated software that electronically transfers information about PN formulations. A number of researchers have compared the accuracy of preparations of PN using FACD and manual methods,(8,9) and found that using a FACD for preparing PN solutions resulted in significant savings in personnel time, lessened costs and improved accuracy.
Validation of FACD
Before introducing a FACD (the Baxa MicroMacro 23 [MM23]), into the MCA (Medicines Control Agency) licensed pharmacy manufacturing unit at GOSH, it was necessary to perform extensive validation of the compounding equipment and operating systems. These validations were performed in accordance with the Good automated manufacturing practice guidelines,(10) and details given in the Rules and guidance to pharmaceutical manufacturers and distributors.(11) As part of the validation work, studies were performed comparing methods of compounding PN (the old two-stage method and the MM23). The results demonstrated no significant difference in terms of precision and accuracy between the two methods. However, PN solutions prepared using the MM23 had an increased number of particles present and did not fully meet the British Pharmacopoeia requirement for particles in the size range greater than 5.0mm.
The difference in the quantity and type of particles found in the PN solutions compounded by different methods may be due either to the plastic compounding apparatus used in the MM23, or to the lack of filtration of the electrolyte solutions in PN manufactured using this method. These results provide more evidence for the use of filters during the administration of PN to patients.(12,13)
Introduction of the MM23
The Baxa MM23 was introduced in February 2001 to manufacture the amino acid/glucose/electrolyte PN solutions. To ensure the smooth introduction of this compounding device, a number of training and operational issues were considered:
- The cleanrooms were redesigned to place network connections for the operating computer.
- All the staff within the PN manufacturing unit were trained and validated in the use of the FACD.
- The order of additions was decided and programmed into the compounder, ensuring that phosphate-containing solutions were added at the beginning of the process and calcium-containing solutions added at the end of the process.
- Filters (1.2mm) were added to the administration set for amino acid/glucose/electrolyte PN solutions.
- Broth validations were performed on bags with administration sets and filters to allow an expiry of five days to be allocated to PN solutions with giving sets attached.
- Nursing staff underwent training in the techniques required to administer PN via administration sets.
Daily operation of the MM23
The introduction of the MM23 has required significant changes in the routine within this busy pharmacy production unit.
Morning
- The MM23 is set up by a technician, who attaches the compounding apparatus to the source containers.
- Solutions with a source container volume of less than 20ml are prepared in syringes before they are placed on the MM23.
- An authorised pharmacist then checks the MM23 setup against the fixed additive configuration.
Afternoon
- A qualified technician operates the MM23.
- A supervisor (pharmacist or accredited technician) operates the computer and checks the setup whenever a source container is replaced.
- The actual total bag weight is compared to a calculated expected weight. A range of ±2.5% is accepted.
- Biochemical and microbiological validation bags are prepared at the end of each manufacturing run.
- Lipid bags are manufactured in a second cleanroom using the old two-stage method.
- Administration sets with filters are attached to the final bags in the second cleanroom.
- The final product is labelled by a member of staff before release by a pharmacist.
Conclusion
The Baxa MicroMacro 23 has been used in this hospital to manufacture approximately 10,000 PN bags over the last year. The introduction of this fully automated compounding device has resulted in a significant improvement in the pharmacy-delivered PN service.
Fully automated compounding devices provide an accurate, fast and safe method of manufacturing PN within busy manufacturing units.
References
- Harries JT. Intravenous feeding in infants. Arch Dis Child 1971;48:855-63.
- Allwood MC. Pharmaceutical aspects of parenteral nutrition: from now to the future. Nutrition 2000;16:615-8.
- Heird WC, et al. Intravenous alimentation in pediatric patients. J Pediatrics 1972;80:351-72.
- Driscoll DF, et al. Automated compounders for parenteral nutrition admixtures. JPEN 1994;18:385-6.
- Santell JP, Kamalich RF. National survey of quality assurance activities for pharmacy-prepared sterile products in hospitals and home infusion facilities – 1995. Am J Health-Syst Pharm 1996;53:2591-605.
- Blok D, Vermelj P. Automated dispensing and mixing machines in the preparation of parenteral nutrition. Experience with the MicroMacro compounder. Eur J Hosp Pharm 1995;1:150-4.
- Combeau D, et al. Baxa MicroMacro compounder for parenteral nutrition solutions in a pediatric hospital. PDA J Pharm Sci Technol 1999;53:226-30.
- Johnson R, Coles BJ, Tribble DA. Accuracy of three automated compounding systems determined by end-product laboratory testing and comparison with manual preparation. Am J Health-Syst Pharm 1998;55:1503-7.
- Dickson LB, et al. Automated compounder for adding ingredients to parenteral nutrient base solutions. Am J Hosp Pharm 1993;50:678-82.
- International Society for Pharmaceutical Engineering and the GAMP forum. Good automated manufacturing practice guide for validation of automated systems in pharmaceutical manufacture. Florida: ISPE; 1998.
- Medicines Control Agency. Rules and guidance for pharmaceutical manufactures and distributors. London: HMSO; 1997.
- Bethune K, et al. Use of filters during the preparation and administration of parenteral nutrition. Position paper and guidelines prepared by a British Pharmaceutical Nutrition Group working party. Nutrition 2001;17:403-8.
- Food and Drug Administration. Safety alert: hazards of precipitation associated with parenteral nutrition. Am J Hosp Pharm 1994;51:1427-8.
Resources
International Society for Pharmaceutical Engineering (ISPE) European Office
PO Box 18
B-1040
Brussels 4
Belgium
T:+32 2 7434422
F:+32 2 7431550
W:www.ispe.org
GAMP Online
For Validation of Automated Systems
W:www.gamp.org/
