With the increasing interest
in dose banding and dose standardisation of systemic anticancer (SACT) drugs, the stability of these drugs in a ready-to-use form is gaining interest across Europe
In the opening presentation of the session, Mr Johan Vandenbroucke (University Hospital Ghent, Belgium) detailed a number of the reasons as to why good stability data on SACT is so important.
A compounded drug with a reasonable, proven shelf life, can support:
- Preparation in advance
- Workload and work force planning
- The adoption of dose banding
- Reduced wastage
- Batch preparation
- Re-use of returned drugs
- Lessening of the impacts of drug shortages
- Outsourcing of compounding
- Development of licensed products
- Development of a range of ready to use (RTU) dosages.
L to R: Paul Le Brun, Irene Krämer and Johan Vandenbroucke
When assessing drug stability, a number of factors have to be taken into consideration in order to be assured that when the drug is administered to the patient, they will receive the dose that is intended and no harm will come to the patient through that administration.
Generally there are three key areas that need to be studied: chemical stability; physical and structural stability; and microbiological stability.
Product stability will be of interest throughout the the life of the product:
- Stability of the commercial product
- Stability of the drug vial after it has first been punctured by a needle
- Stability of a powder after reconstitution
- Stability of the drug in its final container (syringe or bag).
All of these may impact upon how efficiently a drug may be used, while ensuring that patient safety remains the top priority.
Mr Vandenbrouke discussed the very different approaches taken by regulators in different countries to the re-use of vials. In Japan, a vial of drug can only ever be used for just a single patient – and no sharing is permitted, regardless of storage conditions, or where/how the vial is manipulated. In the USA, when manipulated under sterile clean room conditions, a vial may be stored for up to 98 hours; in the UK, a vial can be held under clean-room conditions for the duration of a working shift; and in Belgium, generally, local rules are applied with the pharmacist taking responsibility for the assignment of a shelf life.
Regulations and legislation
In her presentation, Professor Dr Irene Krämer (Johannes Gutenberg-University Hospital, Mainz, Germany) identified the different approaches taken by different regulators to the issue of assigning a shelf life to a compounded product.
In the EU, the following applies:
EMA CPMP/QWP/159/96 1998. Note for Guidance on maximum shelf life for sterile products for human use after first opening or following reconstitution ‘24 hour rule’.
“Chemical and physical in-use stability has been demonstrated for X hours at Y oC. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2–8oC, unless reconstitution/dilution (etc) has taken place in controlled and validated aseptic conditions”.
Whereas in the US, the US Pharmacopeia takes a different approach and details a number of criteria to be used when determining a ‘beyond use date (BUD)’, or the date/time after which a compounded product should not be stored or transported:
- 90% or more of the labelled active ingredient is measurable in the solution and container specified, under the stated storage and administration conditions, and;
- Sterility limitation according to the risk level
- In the absence of published stability data or analytical studies, a BUD should not exceed 30 days
- The stability-based BUD should be in accordance with the approved labelling or with reliable published stability data.
Both Prof Krämer and Mr Vandenbrouke concluded, however, that the responsibility for the assessment of a drug’s stability has to reside ultimately with the pharmacist responsible for the issuing of that product to a patient under their care. Therefore, when assessing a drug’s stability, consideration has to be given to all the factors that contribute to that drugs stability.
Professor Krämer identified a number of reference sources to support the assigning of shelf lives to compounded products.1–3
It is therefore possible with the guidance available for pharmacy teams, to undertake stability studies to inform the shelf lives to be assigned to products compounded.
Chemical stability testing
The chemical stability of a compounded drug is extremely important. Not only is assurance needed that sufficient drug is available to deliver the desired therapeutic effect, but that any degradation products that form are themselves not toxic or harmful.
Chemical analysis of a compounded drug should include: (1) tests to determine the drug concentration in solution over time; (2) the impact of storage containers; and (3), the impact of storage conditions, on the rate of drug degradation.
Professor Krämer illustrated the impact of light on drug stability with reference to the degradation of irinotecan solution (Figure 1).4
Figure 1: Impact of light on stability of irinotecan solutions
This example clearly shows that the presence or absence of light is a major determining factor in the rate of degradation of the product. Irinotecan injection concentrate and infusion solutions were physicochemically stable (at a level of >90% irinotecan) for four weeks when stored under refrigeration or light protected at room temperature, independent of the vehicle (0.9% sodium chloride, 5% dextrose) or the concentration (0.4, 1.0, or 2.8mg/ml). Irinotecan infusion solutions exposed to daylight exhibited concentration-dependent instability; solutions were stable for only 7 to 14 days.
For other drugs, other factors (for example, starting concentration or storage temperature) may be the factor that has most influence on the rate of chemical degradation.
The physical stability of a drug is of equal significance to that of chemical stability and all speakers referenced the fact that as the size of drug molecules increases, from conventional SACT agents to monoclonal antibodies, the impact of physical testing becomes ever more important. Physical instability might present in a number of different ways, such as:
- Colour changes
- Formation of aggregates
- Formation of sub-visible particles
- Denaturation – (proteins)
- Adsorption to surfaces (proteins)
The physical stability of etoposide is a very well-known example of how the concentration of a drug in solution can affect its stability. Etoposide is physically stable at concentrations below 0.2mg/ml; it will precipitate out of solution at mid-range concentrations, but then will remain in solution at higher concentrations (>8mg/ml).
Monoclonal antibodies, being more complex molecules, have the potential to be more unstable and, in particular, might be more sensitive to changes in temperature, light, shaking and shearing; this was demonstrated using the analogy of an egg. While an egg following vigorous shaking may exhibit the same chemical properties prior to it being agitated, physically it may take on very different characteristics that will not return to the initial state after cessation of the shaking.
Figure 2: Viability of microorganisms in carboplatin solutions
Figure 3: Viability of microorganisms in idarubicin solutions
Both presenters identified the complexities associated with trying to assign a microbiological shelf life to a compounded cytotoxic agent. A number of studies have demonstrated that cytotoxic drugs in solution are bacteriocidal/bacteriostatic. Professor Krämer referenced three studies showing the viability of microorganisms in different cytotoxic drugs (carboplatin; idarubicin; and nab-paclitaxel;
Figs 2 and 3).5,6
The lipid component present in formulations of nab-paclitaxel does support microbial growth (Fig 4).
However, just because a cytotoxic agent does not generally support microbial growth, that is not a reason to prepare solutions under anything other than cleanroom conditions if any type of expiry date is going to assigned.
Figure 4: Viability of microorganisms in nab-paclitaxel solution
Given the very different structure of monoclonal antibodies, it is likely that they would not exert the same antimicrobial properties as more conventional SACT agents.
Newer SACT agents, such as monoclonal antibodies, gene therapies and advanced therapy medicinal products, present further challenges when trying to derive expiry dates for these compounded products. By virtue of being complex molecules or biologics, they actually lend themselves to different methods of administration and potentially administration either closer to home, or in the patient’s own home. The cost of these agents mean that every effort should be taken to minimise waste through both vial sharing and the use of extended expiry dates to ensure that maximum opportunities are taken to ensure that all doses are used.
However, the particular challenge with these drugs is how to assess their chemical and physical stability and be assured that their biological activity remains after periods of storage.
The answer has to lie in undertaking a range of tests, which may include the following:
- Examination for particles (visible and sub-visible)
- Turbidity, colour
- pH, osmolality
- UV absorption
- Size exclusion high-performance liquid chromatography (HPLC)
- Ion exchange HPLC
- Biological activity assays.
The future and conclusions
In the closing presentation of the session, Dr Paul Le Brun (Central Hospital Pharmacy of The Hague, The Netherlands) did some horizon scanning of the future for preparation services.
Without doubt there is going to remain, for many years to come, a need for hospital pharmacy departments to aseptically compound products. It might well be that the mix of products changes, as potentially will the environments in which they are administered.
Having access to better stability data for products should lead to longer expiry dates being assigned to compounded products; the greater use of dose banding for cytotoxic agents means that the potential exists for greater levels of batch preparation, which, in turn, could lead to greater levels of automation.
Support for the production of this report was provided by Sandoz
- Bardin et al. Guidelines for the practical stability studies of anticancer drugs: A European consensus conference. Annales Pharmaceutiques Francaises 2011;69:221–31.
- Williams LA, Hastings MB. Identifying the criteria of a valid stability study. Int J Pharm Compound 2009;13:32–6.
- Vigneron J. Stability studies: ten pieces of advice. EJHP Sci 2008;14:2.
- 4. Thiesen J, Kraemer I. Physicochemical stability of irinotecan injection concentrate and diluted infusion solutions in PVC bags. J Oncol Pharm Pract 2000;6:115–21.
- Kramer I. Viability of microorganisms in novel antineoplastic and antiviral drug solutions. J Oncol Pharm Pract 1998;4:32–7.
- Sarakbi I, Federici M, Kramer I. Viability of microorganisms in novel chemical and biopharmaceutical anticancer drug solutions. Eur J Parenteral Pharmaceut Sci 2015;20:5–22.