Due to the increasing demand for compounded cytostatic agents, it has become necessary to increase the efficiency of the compounding process by using automated production. Getting the maximum benefit from automated production, ready-to-use cytostatic agents are produced in advance, and then stored for at least one to three months.
Containers for compounded cytostatic agents are made of plastic. Since automated production leads to an increase in storage time—in the range of several months—there is a substantially longer contact period between the storage container and ready-to-use cytotoxic agents, than with cytotoxic agents produced on-demand. As a result, it is important to establish reliable chemical and physical stability of the agent itself , and to also ensure that the storage container permits an extended shelf life.
Table 1 shows the containers employed for ready-to-use cytostatic drugs at two hospital pharmacies in Denmark.
*Table 1 pending to upload.
As seen from Table 1, containers for cytostatic agents may include infusion bags (either empty or containing saline or glucose) pumps or syringes. Some of these containers are registered by the relevant authorities as a drug and some containers are CE marked. It is important to know if a container leaches any chemicals into the cytostatic agents; this may be determined in leachable and extractable testing.
Studies of leachables and extractables
Leachables are chemical entities that migrate from plastic containers into a drug product, while extractables are compounds that are forced out of the individual parts of the container under specified solvent, temperature and pressure conditions. Leachables are typically a subset of extractables, see Figure 1, and have potential to affect the product. Not all extractables are leachables and not all leachables correlate to extractables due to the fact that they are secondary leachables which is explained below.
*Figure 1 pending to upload.
Leachables and extractables are typically antioxidants, e.g. butylated hydroxytoluene, plasticizers e.g. phthalates, and unreacted monomers and oligomers from the polymerization of plastic. An example is bisphenol-A which is the monomer in polycarbonate plastic. Bisphenol-A is thought to have endocrine-disrupting effects and may harm newborns and infants up to 18 months of age. As a result, the Canadian Government has banned the use of plastic baby bottles that contain this chemical.
Plastic materials like polyvinylchloride, polyolefines and co-polymers are complex formulations that contain many impurities and additives representing thousands of possible leachables . A number of analytical methods may be used to detect the presence and type of chemicals in plastics. For organic compounds, LC-UV-MS, GC-MS, GC-Head-space-MS, IEC, LCNMR and TOC may be used, while ICP-MS, ICP-OES and IEC may be used to detect the presence of non-organic compounds. Due to advances in modern analytical methods, it is now possible to detect compounds in the parts per billion to parts per trillion range . This in turn has led to the introduction of acceptance limits of leachables and extractables that may be contained within plastic containers used for orally inhaled and nasal drug products . These limits have been recommended by a working group under the Product Quality Research Institute (PQRI).
While extractable studies are performed under exaggerated conditions, i.e. in the presence of organic solvents, accelerated temperature and pH, leachable studies are done in the presence of the drug product under normal conditions. Secondary leachables, which result from a reaction between leachable chemicals and the drug or excipients, cannot be identified in extractable studies. If the drug is a biological product, e.g. a mono clonal antibody, the interaction between leachables and the drug might lead to loss of activity or the development of neutralizing antibodies.
Infusion bags containing fluid
Infusion bags like Viaflo (Baxter) or Freeflex (Fresenius Kabi) that contain saline or glucose are registered as drugs and are approved by drug authorities to be stored for a designated length of time. The issue of determining whether leachables/extractables from this kind of container might leach into compounded cytostatic agents is assigned to hospital pharmacies. If the drug solution has aqueous properties, it is usually unnecessary to perform leachables/extractables studies. However, special caution should be taken with infusion bags made of PVC since entities such as DEHP may potentially leach into the contents of the bag.
When the container including the container closure system is part of a registered drug, and the compounding procedure at the hospital pharmacies is process-validated, the container would be microbiologically safe. However, hospital pharmacies must test the chemical/physical stability of a cytostatic drug within a particular infusion bag.
Although infusion bags appear to be the safest choice of container for ready-to-use cytostatic agents, they are not always ideal.
Manufacturers might alter the production process of a drug, or change the composition of a container without notifying hospital pharmacies—only health authorities are privy to such information.
CE marked containers
CE marking is a declaration by the manufacturer that the product meets all the appropriate provisions of the relevant legislation implementing certain European Directives. CE marking gives companies easier access into the European market to sell their products without adaptation or rechecking.
CE marked containers, also known as medical devices, include empty containers such as syringes, empty infusions bags like EVA bags from Baxter and pumps like FOLFusor. Although these containers are intended for immediate preparation and use of the drug, it is common practice for hospital pharmacies in Europe to use them for storing cytostatic agents. Syringesin particular are widely-used storage containers for cytostatic drugs. As such, it is surprising that the European Pharmacopoeia (Ph. Eur.) does not contain a monograph for plastic syringes used in this manner. Like infusion bags, changes in the production and composition of CE marked containers may also occur without notice.
It is not necessary to perform extraction studies if the material of the medical device is approved by the Ph. Eur. or in the pharmacopoeia of a Member State. However, if the material is non-compendial, extractable studies should be performed on the container . If the outcome of extractable studies suggests that a migration study—study of the release of leachables—is unnecessary, justification for the omission of this test should be provided .
‘Guideline on plastic immediate packing materials’ , published by EMA, provides a decision tree describing which documentation should be supplied based on whether the drug is solid or non-solid, see Figure 2. As shown in the decision tree, leachables from the container have to be tested, or justified whether or not the material is described in the Ph. Eur. or in the pharmacopoeia of a Member State.
*Figure 2 pending to upload.
Challenges for hospital pharmacies
There are points of similarities between the discussion of how to select the most suitable container and how to assign shelf life of cytostatic drugs. In both cases, hospital pharmacies bear the responsibility of choosing a safe container and assigning a safe shelf life. Further, as discussed earlier, changes in the production of either the cytostatic drug or the container may be made without the hospital pharmacies’ knowledge.
Lack of traceability in the supply chain of medical devices also often makes it impossible to obtain information regarding the formulation of the polymer packaging. This problem goes further back in the supply chain since the suppliers of cytotoxic drug containers often are unaware of the production processes used by their suppliers. It is also difficult for manufacturers of the container to supply hospital pharmacies with technical details because this information is confidential and not publically available, unlike if the information is required of a drug company for a drug registration where the container information is kept confidential.
Increasing shelf lives of cytostatic agents places extra responsibility on pharmacy staff who must ensure drug safety. This is because the drugs begin a ‘new life’ once they have been compounded [5, 6]. This requires hospital pharmacies to behave more like a drug company in that they must employ scientific/analytical procedures. Further, few hospital pharmacies have extensive material expertise or the analytical expertise to undertake material investigations as, e.g. extractables/leachables studies.
This highlights the need for a European centre of knowledge to house information from manufacturers and suppliers, in a way that allows hospital pharmacies access to important information whilst maintaining confidentiality. This solution would satisfy both the manufacturers’ need for maintaining data confidentiality, and hospital pharmacies’ need for recommendations regarding the use of cytostatic drug containers based upon scientific data.
The author thanks the Head of the Danish Research Unit for Hospital Pharmacy Dr Trine Kart for assistance during the preparation of this article.
Iben Larsson, PhD
DK-2100 Copenhagen, Denmark
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