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Published on 20 September 2010

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Pharmahelp for cytotoxic handling

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Automated preparation of cytotoxic medications improves productivity and profitability and ensures the safety of the operator personnel. To these ends, Institut Curie, in collaboration with MDS, has developed the Pharmahelp handling system

A Hurgon

C Giard

A Pelloquin

S Blondeel

J Pauly

F Daoudi

L Escalup

Institut Curie, Pharmacy Department, Paris, France

Centralised preparation of cytotoxic medications in hospital pharmacies and constant growth of this activity requires innovation and development of more responsive and flexible methods of preparation. Improving productivity ensures profitability of expensive facilities, while ensuring operator safety, good quality preparations and a swift and satisfactory medical service to the patient. Dose calculation errors and prescription or drug errors have an extremely high potential to induce adverse consequences for patients, especially in cancer treatment.[1] In addition to sterility concerns and multiple points of drug exposure between the pharmacy and the patient, human handling and compounding of hazardous drugs are associated with many risks. Operator-related difficulties, such as the recruitment of qualified technicians for these activities, or the high incidence of musculoskeletal disorders resulting from the repetitive tasks, are also observed.
In this context of high-level requirements, an automated system coupled with environment protection could help to improve the hospital pharmacy productivity and profitability, together with providing high-level quality control and ensuring technicians’ safety. Automation of complex tasks requiring vigilance and accuracy could reduce the incidence of errors and relieve operators of the burden of repetitive tasks.
Some simple devices have already improved quality and safety aspects and working conditions. For example, filling pumps are available to ensure productivity associated with precision and accuracy for parenteral nutrition, especially for premature newborns.[2] These pumps fill the infusion bags and are driven by preparation and prescription software. These pumps are adapted for the preparation of complex mixtures comprising numerous components, as in parenteral nutrition solutions. However, they are not suitable for a high production rate of chemotherapy with successive complex tasks such as reconstitution, shaking and dilution.
Two types of more complex automated systems developed over the last ten years have similar objectives: automated formulation of personalised hazardous preparations; and protection of hospital pharmacy personnel.

[[HPE52.63a]]

[[HPE52.63b]]

Cytocare Robot (Figures 1 and 2)[3] and Robotic IV Automation (Figure 3)[4] are medical devices developed for hospital pharmacies to automatically and accurately prepare IV syringes and bags with a high level of autonomy and less human intervention. These all-in-one robots integrated in an HEPA ISO 5 air handling system comprise a robotic arm performing filling, reconstitution, shaking of vials for dilution in syringes or IV bags. Loading/unloading are the only tasks performed by the operator. These robots collect all contaminated materials in the waste and automated cleaning is performed by UV decontamination. In-process quality control is ensured by reading barcode labels, weighing vials, syringes and IV bags, and checking IV bag size. These systems, weighing around 1.5 metric tons, must be implemented in a large ISO 7 4x4m² air treatment area with a minimum ceiling height of 2.4m. The acquisition cost of this kind of robot is about 600,000 to 1,000,000 Euros.

[[HPE52.63c]]

Pharmahelp (Figure 4), an automated machine for the preparation of cytotoxic formulations, is the second type of system. This system was designed by the small Netherlands Company Medical Dispensing System (MDS).[5] MDS ensures design, assembly, and software development. The French MDS subsidiary in Lourdes ensures promotion, maintenance and after-sales service in France. The design is simple: a central unit performs operations such as dilution, shaking, dissolution. Solution transfers are performed by filling and emptying syringes driven by the software with accuracy and precision relative to the calibration method. The system weighs about 75kg and must be integrated in a HEPA ISO 5 air handling system (isolator or laminar flow). Cleaning is performed by the usual manual decontamination method. Waste management is also manual. The acquisition cost of this kind of automated system is about 300,000 Euros plus the cost of the air handling system.

Cytotoxic preparation at the Institut Curie
At the Institut Curie, increasing capacities of the day care hospital and complete centralisation of the preparation of cytotoxic formulations for the entire hospital have led to an annual production of 50,000 preparations. This high production rate is approaching the limits of manual preparation. Four operators have experienced musculoskeletal disorders over the last two years. The use of an automated system in our unit would therefore appear to be a very attractive prospect. Because of space limitations, the low ceiling height (2.3m) and the cost of an automated system, we decided to study the feasibility of integrating an automated system such as Pharmahelp in our Unit, and to develop the prototype in partnership with MDS.

[[HPE52.64]]

The equipment
The steel structure (dimensions: 120 x 90 x 90cm) integrates a central automated unit, a 12-position vial shaker rack, a 16-position IV bag rack and a 12-position syringe rack. The process begins by the creation of the batch and collection of the various items listed on a checklist. All items set up in adaptors are weighed and linked to the adaptor tag during the pre-processing phase. Loading is performed manually in the machine. After the processing phase, the items are also unloaded manually. Weight control of IV bags is performed at the post-processing phase. Weighing of vials is automated and ensures volume control during the process. Preparation labels are printed at the end of the process. The machine is driven by software developed in cooperation with a partner of MDS, and the software manages the entire process from batch creation to labelling. Each step in a batch is recorded and reported.

Objective of the study
The objective of this study was to investigate potential technical improvements of the Pharmahelp prototype in order to adapt the machine to our facility’s pharmaceutical needs and to ensure operational qualification. The Pharmahelp prototype was installed in our Oncology Pharmacy Unit between January and July 2009.

Development
During our first visit to the MDS manufacturing site, the main weaknesses of the prototype concerning the process, software and quality system were observed.
The main point to be improved was the filling system (Figure 5). On the prototype, the MDS specific needle was coupled with a pumping system ensuring the isopressure. This system exchanged air between inside vials and environment. This exposes potentially environment to a risk of chemical contamination. To remove this system we have tested quantity of needles and spikes integrating a vented canal. Some needles were too long and generated a lot of residual. Other needles were too short to penetrate through the injection port of IV bags or generated bubbles during filling of the syringe. The machine was not yet adapted to spikes. We therefore use the MDS needle coupled with a simple vented needle with a filter. We required MDS to develop a tool ensuring automation of this new  task (placement of the vented needle) in a standard position, without generating any chemical contamination.
The flexibility of the machine to prepare different drugs was tested. Limits in the size of vial adaptors were studied. Total adaptation to all shapes, sizes, heights and cap depths is essential to allow for changes in conditioning and formulations of new drugs. The prototype was adapted only to the biggest vials, although the development of flexible standard adaptors for all dimensions was proposed to MDS.
The software manages the elements recording in the database for different forms of drugs, solvent IV bags, syringes, needles and perfusion lines. It manages the pre- and post-processing, processing and labelling phases. A release phase, when the pharmacist decides whether or not the preparation is valid, was requested to MDS. The software required optimisation by adding functions such as error management to rerun a batch after a mechanical or weighing error and residual management to reuse the residual of a vial in the next batch. To optimise the productivity, the multifilling option was developed, that is, the transfer syringe filled with multidoses distributes monodoses in IV bags.
The items (vials, IV bags) are set up in adaptors (Figure 6) before loading on the racks. All adaptors comprise a RFID tag which is read, recognised and followed throughout the process. To improve quality, we asked MDS to add a drug label scanning system to be sure of the nature of the drug before loading by comparison with the database.

Operational qualification
To cover all kinds of cytotoxic solutions, the performance of the filling system on aqueous (most drugs), foaming (monoclonal antibodies), viscous (taxanes), and alcohol solutions was tested. Accuracy and precision were calculated from six measures on each of three days for each kind of solution and each volume in the range of 3ml to 60ml. The withdrawing speed for foaming and viscous solutions was modulated. Accuracy and precision were less than 5% for volumes of 3ml to 60ml. For small volumes, the results were limited by the precision of the balance; a balance with a precision of 0.01g was developed by MDS.
To ensure a good quality of reconstitution for powders, we have studied the automated method by modulating the shaking speed of the vial shaker rack (Figure 7) and the time. We validated the quality of reconstitution by a visual method (as we do for manual preparation) and an analytical control (HPLC). We used slow speed for foaming solutions and monoclonal antibodies and faster for poorly soluble powders. The time ranged from 2 to 8 minutes.
Batches were simulated to assess productivity and operator intervention times. Productivity for a standard batch (5-FU bags with simple dilution) was approximately 20 IV bags per hour with one operator from collection of sterilised material to packaging of sterile preparations. Productivity would improve greatly if sterilisation were to be managed by another operator. Otherwise, productivity decreases for complex batches with reconstitution or for drug dosages not adapted to therapeutic doses. In any case, productivity must be assessed within the environment. As isolator ergonomics impact on this productivity, we are working with the isolator manufacturer on the mock-up of the isolator.
The RFID identification system ensures identification and traceability of components. Drug label scanning before loading will significantly improve the quality system.
All materials (PETP, seals, 316 stainless steel) are compatible and resistant to decontamination agents such as peracetic acid and hydrogen peroxide. Pharmahelp could also, in theory, be integrated in an isolator. Full evaluation of the implementation of Pharmahelp in an isolator is studied on decontamination, ergonomics, software, materials, and electromagnetic compatibility is currently underway.

Partnership experience
A partnership contract exists between the Institut Curie and MDS. Monthly meetings with the technical team (three pharmacists from Curie, three engineers from MDS) are scheduled. Curie has identified the previous limits and proposed ideas to improve the functionalities, the ergonomics, the security and the productivity of the machine. MDS has brought technical support for the development of these ideas and the integration of new functions. At the same time, Curie has tested in real time the new versions of these functions by simulating future production.
To create a successful partnership between hospital and industrial teams with not really the same vision, the high availability of the hospital team and the high reactivity of the industrial are required.
Currently, the partnership is wider. The pharmaceutical team of Hospital University of Geneva is performing tests to assess the level of chemical contamination on the machine.[6]

Conclusion
The Pharmahelp prototype was functional but not completely adapted to our pharmaceutical needs. The vision and expertise of oncology pharmacists was essential to optimise this automated system (flexibility to the new drugs and IV bags, robust quality control systems, very low chemical contamination for operator security, no risk of microbiological contamination and productivity optimisation). MDS is currently performing the additional development. The final version of the machine will be installed in our Unit in September 2010. The first qualification study will be completed with the microbiological and chemical validation, productivity assays and staff training.
Automation could be a major technical innovation for hospital pharmacies that produce high volumes cytotoxics products. The simple design of Pharmahelp in technical functions and software, and the collaboration with MDS, instils confidence in its successful integration in our Unit to complement the current manual processes. As the partnership continues, adaptations of the machine to changes in practices will undoubtedly occur.

References
1. Cohen M et al. Am J Health Sys Pharm 1996; 53:213–22.
2. Bonnabry P et al. Qual Saf Health Care 2005;14:93–8.
3. http://www.devonrobotics.com/cytocare/.
4. http://www.intelligenthospitals.com/.
5. http://www.medicaldispensing.nl/mds.
6. Schindler F et al. 13th Congress of the European Association of Hospital Pharmacists.



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