Introduction
Nowadays, chemotherapies are prepared by pharmacy technicians or pharmacists in centralized production units under the responsibility of the pharmacists. The preparation of medications is a fundamental part of the pharmacist's profession.
For these preparations, hospital pharmacists need stability data to assign a shelf-life to the compounded products. The needs of stability data concern the administration of injectable infusions and also the administration via Y-sites where knowledge about physical compatibilities are required.
The objective of this work was to evaluate if information given by pharmaceutical companies in the Summary of Product Characteristics (SmPC) or in published articles about the stability of reconstituted and diluted solutions, in the field of oncology, is sufficient to the daily practice of hospital pharmacists.
Methods
The first step was to establish a list of the main needs about stability data on the basis of our daily practice at the hospital.
The second step was to search through information given by pharmaceutical companies in the SmPC or published in pharmaceutical journals. Then, data were compared with hospital pharmacists’ needs. Different examples were presented to illustrate this research.
Results and discussion
Needs for stability studies and the information given by pharmaceutical companies
Long-term stability of infusions
In the field of oncology–hematology, approximately 75% of patients are admitted to hospital to receive their chemotherapy on a 1-day basis. The administration can be different for each patient, with sometimes 4 infusions (e.g., R-CHOP regimen) and sometimes just a single subcutaneous injection (e.g., bortezomib or azacitidine).
- From the patient's point of view, the priority is to obtain appropriate and high-quality care as soon as possible.
- From the nurse's point of view, the objective is to optimize workload and to reduce the waiting time for the patient.
For these reasons, the preparation in advance of chemotherapy is often considered as the best option. This practice requires the pharmacist to use a set of relevant stability data to highlight the professional decision.
The information given by pharmaceutical companies can be different, depending on the status of the product: originator, generic, or biosimilar.
Originators
For originators, the SmPC often limits the stability data with typical sentences such as “from a microbiological point of view, the product should be used immediately.”[1,2] The main reason is related to the potential risk of microbiological contamination if the preparation is not carried out under a biosafety cabinet or isolator.
Financial aspects could also be a reason for this short-term stability. An extended stability data allow the preparation in advance and cost savings for the hospital pharmacy and therefore money lost for the pharmaceutical company. For these reasons, long-term stability is often not included in the SmPC of originator products.
Exceptions can be observed and related to the marketing of generic or biosimilar competitors. For example, Mabthera (rituximab) was commercialized at the beginning of the 2000s and the stability of infusions was limited to 24 hours. However, at the beginning of 2018, the stability of Mabthera in its SmPC was increased to 7 days.[1,3] This modification can be related with the launch on the market of a rituximab biosimilar in the same period with 1-month stability. The hypothesis is that the market of the originator had to be protected.
A second example concerns another monoclonal antibody, Herceptin (trastuzumab), with an extended stability from 24 hours to 7 days. This increase of stability was first presented in an international publication performed by the pharmaceutical company which markets it and then included in the SmPC. This modification can be related for the same reason as Mabthera.[4,5]
A counterexample of this comment is subcutaneous rituximab (Mabthera 1400 mg) which is alone in the market. The SmPC gives a 2-day stability for the solution stored in polypropylene syringes.[6] These data are not enough for the preparation in advance. In 2015, the pharmaceutical company published a 1-month stability for this subcutaneous solution in syringes.[7] This stability study seems to aim to promote subcutaneous injection to facilitate the preparation in advance and to progressively put forward this new product: patients who will receive the subcutaneous injection will not use the biosimilar of intravenous infusion.
Generics and biosimilars
For generics, the situation is different. Several examples highlight that for the generic of a drug, the stability specified in the SmPC is more extended than for the originator (except if the drug is really chemically unstable like azacitidine or bendamustine). Many examples in the pharmaceutical products can illustrate this hypothesis.
Since the first commercialization of the originator of paclitaxel (Taxol), stability data remain unchanged with 27-hour stability: 3 hours for the preparation and transportation and 24 hours for continuous infusion after dilution. Currently, all generics of paclitaxel have long-term stability up to 28 days after dilution, depending on the solvent and temperature.[8]
The hypothesis is that the market must be conquered by generics and stability information has to be included in the marketing strategy.
Biosimilars of monoclonal antibodies have been introduced in the market more recently but the same observation can be done. As previously observed, the stability of Mabthera was 24 hours at room temperature, and for the biosimilars of rituximab, the data were extended to 28 or 31-day stability.[3,9]
Stability of reconstituted vials
The extended stability of reconstituted solutions is fundamental for hospital pharmacists to generate cost savings if the vials can be reused. In the SmPC, short-term stabilities of reconstituted vials are indicated with typical sentences such as “the product contains no preservatives and should be used immediately.”
For example, the originator of bortezomib (Velcade) is available as a 3.5-mg vial without the launch on the market of generics. In France, one 3.5 mg vial costs around 1065 euros in 2018 and the mean dose for a patient with a body surface area of 1.7 m2 is around 2.2 mg (1.3 mg/m2). For 1 cycle, 4 injections are administered at the patient. The cost of 1 cycle if we used 4 vials for 1 patient is 4260 euros. The SmPC indicates that “the total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration.”[10] This short-term stability does not allow reusing the vial for the next day. If we used extended stability data, the cost for 4 injections is 2700 euros and allows a total cost saving for 1 cycle of around 1560 euros for 1 patient.
Sometimes, the SmPC can contain suggestive sentences. This example is about cabazitaxel (Jevtana). This anticancer drug needs an initial dilution of the concentrated solution with a specific solvent. The SmPC indicates 1-hour stability at room temperature and 24-hour stability at 2 to 8 °C. A sentence is added after these data: “unless dilution has been taking place in controlled and validated aseptic conditions” suggesting that the solution can be stored for a longer period. However, no information is given about a preservation of stability after 24 hours.[2]
Stability of ready-to-dilute vials
The same observation for reconstituted vials can be done for ready-to-dilute vials. The reuse of an open vial is essential to save money, especially for monoclonal antibodies because these drugs are very expensive. However, the reuse of a solution is not mentioned in the SmPC of the originator and typical sentences can be included to urge the user to discard the unused product: “do not store any unused portion of the infusion solution for re-use”[11] or “discard any unused portion left in the vial.”[12] The financial aspect for the pharmaceutical company is the main reason for these recommendations.
For ready-to-use generics, the situation is different and the same comment applied for long-term stability data for infusion can be made. For example, a generic of paclitaxel indicates a long-term stability of a partially used vial in its SmPC: “from a microbiological point of view, once opened the product may be stored for a maximum of 28 days at 25 °C.”[8]
Unopened vial storage outside the recommendations
Many products have to be stored between 2 and 8 °C, but accidental excursion outside these recommendations can occur. In daily practice, the vials may be stored at room temperature for a period before being stored in the refrigerator or accidentally frozen because of refrigerator's malfunction.
In these cases, limited information is available in the SmPC. The only information found for drugs which must be stored in the refrigerator concerns nivolumab. The pharmaceutical company specifies that “the unopened vial can be stored at controlled room temperature up to 25 °C with room light for up to 48 hours.”[11]
Preparation of mixtures
For some regimens, mixtures can be prepared to facilitate the administration. For example, in the past, the treatment of myeloma used the VAD protocol which is an association of vincristine and doxorubicin. These 2 anticancer drugs were administered as continuous infusion over 4 days associated with dexamethasone by oral route. Another example is a mixture of cyclophosphamide or ifosfamide with mesna to avoid cystitis. Another one is EPOCH regimen which consists of vincristine sulfate, doxorubicin hydrochloride, and etoposide phosphate. These drugs are typically administered by continuous infusion over 4 days in patients for the treatment of non-Hodgkin lymphoma.[13]
For all these mixtures, hospital pharmacists need to be aware of the physical stability of the preparation and the chemical stability of each molecule. In the SmPC, data are once again very limited in this type of case, except if the drugs are from the same pharmaceutical company. The well-known example is the stability of mesna with ifosfamide with 28-day stability in 0.9% saline solution at room temperature.[14]
Sometimes, useful information for the patient can be found concerning the use of injectable solutions for oral route in mixture. For example, the SmPC of cyclophosphamide indicates that “after reconstitution in Aromatic Elixir USP for oral administration at a concentration of 2 mg cyclophosphamide per ml in Aromatic Elixir USP, chemical and physical stability has been demonstrated for 14 days at 2–8 °C.”[15]
Outside the SmPC, the stability of the mixture of trastuzumab (Herceptin) and pertuzumab (Perjeta) has been investigated for the treatment of breast cancer. The authors are from Genentech Company affiliated to Roche Company which produces the 2 originators, trastuzumab and pertuzumab.
The authors have demonstrated 24-hour stability for this mixture. These data are not included in the SmPC but published in a pharmaceutical journal.[16] This example shows a way used by the pharmaceutical company to protect their own product. If hospital pharmacists want to use these data to prepare the mixture, they have to use Herceptin, the originator of trastuzumab and not the biosimilar. This example illustrates once again that the pharmaceutical industries are performing stability studies only for their own interest and for their own molecules.
Y-site compatibilities
In intensive care units for example, intravenous access is often limited and a large number of injectable drugs can be administered to 1 patient. This context can lead to concomitant administration of several drugs. Information about compatibility or incompatibility of drugs is fundamental to avoid precipitates in the infusion lines.
Some information is available mainly for incompatibility studies but the content of the SmPC can be different from 1 generic to another for the same molecule. For example, 3 SmPCs of doxorubicin specify the incompatibilities with heparin and 5-fluorouracil[17,18,19] and another SmPC specifies the incompatibility of doxorubicin with aminophylline, cephalotin, dexamethasone, fluorouracil, and hydrocortisone.[20] Little information is available about physical compatibilities.
Unusual and off-label uses
Different examples are presented to illustrate this part.
For intraperitoneal hyperthermia chemotherapy, the administration is performed at 42 °C during around 1 hour. Different molecules have been investigated in scientific publications such as mitomycin C, paclitaxel, cisplatine, carboplatine, and oxaliplatine.[21] This route of administration is off-label; therefore, there is no information in the SmPC.
For the treatment of macular degenerescence, bevacizumab (Avastin) can be administered by intravitreal injections. One 100 mg vial could be used to prepare more than 20 syringes. However, in the SmPC, bevacizumab is not allowed for an administration by intravitreal injection. Bevacizumab is authorized only for the treatment of solid tumors and no information on the stability in polypropylene syringes is indicated in the SmPC.[22] However, a publication has demonstrated that bevacizumab solutions in syringes are stable up to 1 month.[23] The stability limit has been included in the recommendation of the French Agency permitting this off-label use of bevacizumab (recommendations of temporary use).[24]
In intensive care units, physicians often want to reduce the infusion volume injected to the patient with fluid restriction resulting from highly-concentrated solutions. According to the manufacturers, the diluted solution of etoposide should not exceed 0.4 mg/ml because precipitation may occur. For the treatment of non-Hodgkin Lymphoma, the dose of etoposide may increase up to 300 mg/m2 administered by intravenous infusion (IV).[25] For patients with a body surface area of 2 m2 (slightly above the mean value for women and men), the dose of etoposide will be 600 mg. This solution should be diluted with 1.5 l of solvent so as not to exceed a concentration of 0.4 mg/ml. This fluid intake is not always feasible for patients. A recent publication has proved the stability of etoposide solutions at 1.75 mg/ml in polyolefin bags diluted in G5% up to 28 days.[26]
Proteins are sensitive to agitation with the possibility of aggregation. The question of using a pneumatic system for monoclonal antibody infusions is relevant. As this mode of transport is still little used for infusions, its influence has not been studied by pharmaceutical companies.
From a stability point of view, it can be said that information given by pharmaceuticals companies are not sufficient for the daily practice of hospital pharmacists and nurses.
Stability information for off-label uses cannot be given by industry. Compatibility studies for the administration depend on the country, are numerous, and cannot be taken into account by the pharmaceutical industry.
Stability data of infusions obtained in the SmPC are often limited to 24 hours for microbiological reasons. Pharmaceutical companies carry out stability studies for different reasons:
- (1) to obtain the marketing authorization and, in this case, only minimal information is necessary;
- (2) to protect the market of the originator and in this case, long-term stability can be presented;
- (3) to conquer the market for generics and biosimilars and, in this case, stability studies are part of the product's promotion.
What can be done for hospital pharmacists and nurses?
In this context, many needs stability data are not covered: stability in mixtures, long-term stability of originators, Y-site compatibility, stability for off-label use, etc. In most cases, the hospital pharmacists do not find the stability data they need.
In 2011, Lawrence Trissel, who wrote the “Handbook on injectable drugs” described in an article the history of his handbook. He deplored the decrease of the number of stability studies published in international literature, especially by American teams.[27] In this article, L.A Trissel recalled the fundamental role of hospital pharmacists in this type of research: “Whose job is to protect patients from harm from drug instabilities and incompatibilities and other aspects of clinical pharmaceutics? Nurses and physicians? Not likely. Drug companies or the US Food and Drug Administration? Even less likely. If not pharmacists, the self-declared drug experts, then who?.”
Concerning the different examples presented above, hospital pharmacists have performed stability studies to save money with long-term stability, to bring solutions for off-label uses, or to perform compatibility studies for the administration by intravenous infusions.
For example:
- Long-term stability of bortezomib has been demonstrated for 42 days instead of 8 hours as recommended by the manufacturer.[28]
- For rituximab (Mabthera), a published study demonstrated 6-month stability instead of 24 hours.[29] These data allow preparation in advance and dose banding resulting in important cost savings.
- Studies were performed to facilitate the production of unstable drugs such as azacitidine with stability studies at the frozen state.[30,31,32]
- The stability of ready-to-dilute solutions of nivolumab and infusions has been demonstrated over a period of 1 month.[33]
- Mixtures were studied and a sufficient stability was demonstrated to administer the VAD or the EPOCH regimen by continuous infusion over 4 days.[34,35,36,37]
- The use of a pneumatic conveying system has been studied. The possibility to use it has been demonstrated if the air is removed from the infusion bag before injecting the monoclonal antibody. The interface air/liquid being considerably reduced, the agitation is nil and no aggregation was observed.[38,39,40,41]
- Concerning compatibility studies, many publications have been published in pharmaceutical journals and are presented in various databases.[42,43,44] Stabilis database is an international database which has given information of incompatibilities in monograph. Stabilis allows performing a search on incompatibilities between molecules with the function ‘Search for incompatibilities.’ A function ‘Table of incompatibility’ allows creating incompatibilities tables for care services.
From a stability study point of view, pharmaceutical companies work for their product and hospital pharmacists work for the patient.
Stability studies are a scientific part of our profession and are essential for the quality of the preparations, the organization of the production, and for the patient.[45] In France, this aspect is included in the Good Manufacturing Practices for hospitals. The first chapter “Preparation” specifies that “the shelf life of finished preparations is fixed following bibliographical studies and/or stability tests.”[46]
This scientific aspect of our profession should be maintained and encouraged. To this end, initiatives have been taken by learned societies, national[47] and international authorities[48,49,50,51] to propose guidelines to perform stability studies. The European Society of Oncology Pharmacists realized a Quality Standard for the Oncology Pharmacy Service (QUAPOS) which includes a specific part about stability of the preparations and the questions of stability data.[52]
The French Society of Oncology Pharmacists also organizes every year since 2013, a 2-day Masterclass in Paris: “Stability studies in Oncology.” This formation helps pharmacists to perform a stability study, to read, and to use stability data. The objectives of this seminar are to give the participants the scientific basis on the degradation of drugs, the methodology to carry out a stability study, and the regulatory environment. An extension to a European level could be interesting as Europe is now the main zone for publishing stability studies.
Conclusion
Pharmaceutical companies perform stability studies to obtain approval of their products from sanitary regulatory agencies and for their own interest. In many cases, the results of these studies are insufficient and do not meet the need for information that hospital pharmacists are waiting for. Conducting stability studies by hospital pharmacy teams should be encouraged. These studies are a necessity and are a scientific issue of our profession.
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