There is a need for further stability records of chemotherapeutic agents to meet practice needs when used for home cancer therapy and factors to consider when designing stability testing experiments are described
Dahlia Salman BSc MSc AMRSC
PhD Researcher in Oncology Pharmacy Practice – Pharmaceutical Analysis
Julian Swinden BEng MSc PhD
Stephen Barton BSc PhD CChem CSci MRSC
Jean-Marie R Peron BSc PhD
Shereen Nabhani-Gebara PharmD BCOP
School of Pharmacy and Chemistry,
Faculty of Science, Engineering and Computing,
Kingston University London,
Kingston upon Thames, UK
During the last decade, many chemotherapeutic treatments have been moved from the traditional hospital setting into a new and dynamic patient-friendly environment through home chemotherapy. Doxorubicin, 5-FU, ifosfamide and cisplatin are examples of chemotherapy regimens administered via ambulatory pumps successfully introduced to home-based settings.
Despite the popularity of home chemotherapy with patients and their carers, the successful transition of chemotherapy from hospital to patients’ homes should be combined with the right procedures to guarantee the safety and efficacy of the therapy. These may include monitoring the stability of the chemotherapeutic formulations, an assessment of the reliability of elastomeric devices, the compatibility of the drug and the delivery device and the accuracy of dosage for home chemotherapy administration.
This brief review aims to provide an overview of the need for stability records of chemotherapeutic agents to meet practice needs when used for home cancer therapy. It highlights the factors to take into consideration when conducting stability testing following the recent guidelines, and describes methods of improving post-dilution stability through novel formulation and delivery methods.
Despite the advantages of ambulatory chemotherapy, stability records for formulations administered via elastomeric pumps are often incomplete. Most stability tests are conducted at ‘ambient temperature’; however, environmental conditions, particularly temperature, experienced by patients at their homes might vary.(1) Research undertaken by the authors shows that temperature variations affect not only the chemical stability of drugs such as ifosfamide, but also the performance of elastomeric pumps.(2) High temperatures cause many drugs to degrade more rapidly, and alter the viscosity of the formulation and the properties of the pump’s elastomeric membrane.(3) This could affect dosage, rate of infusion and consequently patients’ quality of life and treatment outcomes. In the absence of appropriate post-dilution stability records, it is difficult for hospital pharmacists to ensure that patients are receiving their optimal treatment. Furthermore, it is difficult to move a new treatment to home-based settings because of the lack in stability records.
In addition, the lack of post-dilution stability data does not allow hospital oncology pharmacists to prepare intravenous infusions in advance. This means patients have to wait in hospital while their treatment is arranged, which places extra strain on pharmacists, nurses and centralised chemotherapy preparation units. Moreover, surplus drugs from previously opened chemotherapy vials cannot be shared, resulting in wastage. This has significant cost implications for highly expensive drugs such as trabectedin and bevacizumab.(4,5)
Case study: ifosfamide
One example of a practice-based issue is the use of ifosfamide for the treatment of metastatic soft tissue sarcoma as a home-based infusion for 14 days.(6) In practice, ifosfamide (1g) is first reconstituted with water for injection, mixed with mesna and diluted with saline to achieve the desired dose, which is then administered intravenously using elastomeric devices. The information on the dosage regimen and stability data given by the manufacturer specifies that ifosfamide is stable in water for injection for seven days at room temperature.(7) Hence, when the ifosfamide and mesna regimen was moved to home chemotherapy, existing stability records and published literature were reviewed in order to verify whether the drugs were stable to meet the requirements for home-based administration.(8,9)
However, as the available stability studies were limited to seven days, the infusion has to be administered twice (two pumps for seven days each). This is an example where having extended post-dilution stability of ifosfamide can relieve pharmacy services, as the dose could be prepared in advance and not necessarily on day seven. Currently, patients have to visit hospital three times to receive one treatment, placing extra strain on resources and affecting patients’ quality of life.
Research completed by the authors showed that ifosfamide stability is affected by many conditions, such as temperature, oxidation and pH. The degradation kinetics of ifosfamide are complicated. There is more than one degradation product, their clinical toxicity profiles are unknown and the pH of the infusion was found to decrease over time, which might lead to complications during administration.
Case study: trabectedin
A second example, the anticancer drug, trabectedin, is used for the treatment of advanced soft tissue sarcoma, as a home-based 24-hour infusion using elastomeric pumps. This drug was reported by the manufacturer to be stable for 30 hours; however; its true stability might be much longer. Preparation of this expensive anticancer drug in advance is not possible due to insufficient stability data. This ultimately increases the staff workload and leads to wastage of partially used vials.(10,11)
The above case studies illustrate why it is important to investigate the factors affecting the stability profile of home chemotherapy regimens. Studies to evaluate and summarise the stability of anticancer drugs alone or in combination with other medications are needed. The stability of each anticancer drug should be investigated following the recent SFPO guidelines for the practical stability of anticancer drugs, which state the importance of a full evaluation of chemical and physical stability of chemotherapeutic agents (Table 1).(1,4)
It is important to conduct stability testing on the chemotherapy regimen as a whole rather than on the anticancer drug itself. This means that all conditions that might occur during standard clinical practice should be taken into consideration when designing the stability testing experiment. Hence, it is essential to prepare the regimen to simulate the preparation procedure as performed in practice using same diluents, combined with other medications (if applicable) and using the same delivery device (that is, elastomeric pumps). Once the infusion solution is prepared according to practice needs, then other conditions that might occur while the chemotherapy is delivered should be considered. These conditions may well include covering all temperature ranges as well as light and humidity conditions that patients might experience during their normal daily activities.
Furthermore, microbiological stability of the chemotherapeutic therapy is a vital aspect to consider. Microbial growth can impact the stability of the chemotherapeutic agent; as it’s prepared in aseptic conditions, this would eliminate the concerns.(1) Furthermore, incorporating preservatives (for example, phenol, benzyl alcohol) can improve the sterility of the formulation, which in turn enhances the microbiological stability of the drug. It should be noted that the addition of these preservatives could increase the toxicity of the formulation as they ultimately cause changes in physicochemical properties such as pH, ionic strength and osmolarity.(12)
If a chemotherapeutic regimen does not exhibit the stability profile required by practice, ways of modifying the formulation or of avoiding conditions that promote instability should be researched. An understanding of the physicochemical properties of the active pharmaceutical ingredient is essential, as it could be affected by external conditions such as light, temperature, humidity, pH or ionic strength.(13) Development of new chemotherapeutic formulations with enhanced stability profiles is an option that could be pursued by pharmaceutical manufacturers.
As previously discussed, temperature can have a major effect on drug degradation kinetics as well as the performance of the elastomeric device. Some drugs show accelerated degradation with an increase of only a few degrees in temperature; this problem could be addressed by educating patients to avoid high temperatures before starting their home cancer therapy. Conversely, low temperatures could cause particles to precipitate, which will weaken the bulk solution and may block the pumps’ filters, thereby reducing the rate of the chemotherapy infusion.
If the drug is highly sensitive to an external factor such as light or temperature, alternative formulations of the chemotherapeutic agent will need to be researched. Novel formulation/drug delivery technologies are available to enhance the stability of anticancer drugs. For instance, the stability profile of ifosfamide was recently improved using a solid lipid nanoparticle formulation. This delivery technique enhanced the sustainability in in vitro release, and improved the targeting and permeability properties.(14) Doxorubicin, another chemotherapeutic agent, was reformulated in a novel polymeric nanoparticle colloidal system. It was reported that encapsulated Doxorubicin had significantly delayed drug degradation kinetics and improved its stability profile.(15) Development of both ifosfamide and doxorubicin formulations might enhance their post-dilution stability profile. These various formulation technologies are important in enhancing the overall drug properties and should be considered as a platform of development to be taken into the consideration before reaching the market.
Monoclonals and biosimilars
Monoclonal antibodies/biosimilars are protein-based drugs that are very expensive; therefore, extending their stability is important. It has been reported in the literature that the addition of non-ionic surfactants to the formulation of protein-based drugs stabilises the proteins by preventing aggregation and supporting protein refolding.(16) The stability of monoclonal antibodies and biosimilars could be enhanced through the addition of similar excipients to their formulations. It is important to note that different manufacturers will supply different formulations. Ultimately, various formulations will have different physicochemical stability and compatibility profiles with other medications or delivery devices. The above techniques should be considered by manufacturers in order to enhance the stability profile of expensive cytotoxic chemotherapeutic agents.
To conclude, there is a lack of stability data for anticancer drugs obtained from studies replicating standard clinical practice. Therefore, there is a need to conduct further stability testing for chemotherapeutic agents via applying the bench to bedside approach.
Collaborations between practice, industry and research institutions are needed to generate more data and facilitate home cancer therapy, ensuring patients’ safety, care and quality of life. Evaluation of each factor involved in the delivery and efficacy of home-based anticancer treatment is required for each individual regimen. Stability data should be collated and made readily available to assist in the optimal implementation of home cancer therapy.
- There is a lack of stability data for anticancer drugs.
- Conditions relevant to standard clinical practice should be considered when designing stability testing experiments.
- Temperature can have a major effect on the drug degradation kinetics.
- Novel formulation/drug delivery technologies are available to enhance the stability profile.
- Collaborations between practice, industry and research institutions are needed.
- Bardin C et al. Guidelines for the practical stability studies of anticancer drugs: A European consensus conference. Annales pharmaceutiques françaises 2011;69:221–31.
- Salman D et al. Evaluation of the solubility and stability of ifosfamide in order to answer practice based challenge. www.bopawebsite.org/posters/view/evaluation-of-the-solubility-and-stability-of-ifosfamide-in-order-to-answer (accessed 9 January 2014).
- Ackermann M et al. Evaluation of the design and reliability of three elastomeric and one mechanical infusers. J Oncol Pharm Pract 2007;13:77–84.
- Astier A, Pinguet F, Vigneron J. The practical stability of anticancer drugs: SFPO and ESOP recommendations. www.sfpo.com/IMG/pdf/Recommandation_Stabilite_EJOP_2010_E3.pdf (accessed 9 January 2014).
- Surber S, Yaniv A. Analysis of chemotherapy vial waste, J Oncol Pharm Pract 2013;17 1(Suppl):18:160.
- Salman D, Barton S, Nabhani-Gebara S. ISOPP Newsletter 2012;14:3.
- Ifosfamide. Packaging leaflet. Baxter Healthcare Ltd;2012.
- Radford J et al. The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump. Cancer Chemother Pharmacol 199026(2):144–6.
- Zhang Y et al. Physical and chemical stability of high-dose ifosfamide and mesna for prolonged 14-day continuous infusion. J Oncol Pharm Pract 2013;Mar 19 [Epub ahead of print].
- Schöffski P et al. Administration of 24-h Intravenous Infusions of trabectedin in ambulatory patients with mesenchymal tumors via disposable elastomeric pumps: An effective and patient-friendly palliative treatment option. Onkologie 2012;35(1-2):14–17.
- Favier B, Fliche E, Bressolle F. Economic benefit of a centralized reconstitution unit of cytotoxic drugs in isolator. J Oncol Pharm Pract 1996;2(3):182–5.
- de Lemos ML, Hamata L. Stability issues of parenteral chemotherapy drugs. J Oncol Pharm Pract 2007;13(1):27–31.
- Singh S, Bakshi M. Stress test to determine inherent stability of drugs. Pharm Technol 2000;4:1–14.
- Pandit AA, Dash AK. Surface-modified solid lipid nanoparticulate formulation for ifosfamide: development and characterization. Nanomedicine 2011;6(8):1397–1412.
- Missirlis D et al. Doxorubicin encapsulation and diffusional release from stable, polymeric, hydrogel nanoparticles. Eur J Pharmaceut Sci 2006;29(2):120–9.
- Chi EY. Excipients and their effects on the quality of biologics. www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Sections/Formulation_Design_And_Development_Section/FDDTechCorner May2012.pdf (accessed 9 January 2014).