Leachable/extractable issues in a pharmacy setting

The incidence of cancer is increasing worldwide mainly because of increasing average lifetime. More than half of the cancer cases in Denmark involve people over 65 years. In addition, there is also an increase due to the influence of smoking, alcohol, physical inactivity, obesity and sun damage.

This leads to an increased compounding activity at the hospital pharmacies, where the main bulk of chemotherapies is prepared. In an attempt to overcome this increased workload with the same resources available, hospital pharmacies are going to transfer the traditional patient individual production of chemotherapies at the hospital pharmacies to a production scheme resembling industrial manufacturing. This is carried out by, for example, by introducing robot technologies in the cytostatic units.

This semi-serial production pre-supposes extended shelf-lives compared with shelf-lives stated in summary of product characteristics for the compounded drug and dose-banding. Dose-banding and exact stability data for specific drugs are subjects in numerous papers used in daily practice at hospital pharmacies.

In literature pertaining to extended stability data of the cytostatic agents, the influence from the container in the form of chemical contribution to the drug solution due to increased contact time between packaging and drug is an aspect that is generally overlooked. Usually this is not included in the considerations of the safety of the compounded drug, consisting of the drug solution and the packaging chosen by the hospital pharmacies. This issue is the so-called migration or leachables/extractables from the container. As in the case with extended stability, it is also the responsibility of the hospital pharmacies to show that leachables/extractables pose no toxicological risk for the patient.

Leachables are compounds that migrate from the container/closure system of the drug product under normal in-use storage condition which a patient can be exposed to during intake of the drug. Extractables are compounds that can be extracted from the individual components of the container/closure system (CCS) under appropriate solvent and temperature conditions – thereby simulating a ‘worst case’ leachable situation. Potential sources of leachables and extractables are additives, for example, antioxidants and plasticisers, reaction/degradation products of additives, unreacted monomers and oligomers, processing aids, for example, mould release agents and lubricants and many more. In principle, all chemical entities not covalently bonded to the polymer network have the potential to act as a leachable/extractable and these entities can be incorporated in the polymer network through all the process steps from monomers to the final plastic container.

It is obvious from the above list of leachables/extractables that they will appear in a very small scale compared with the API in the drug solution. Hence it also requires methods other than high performance liquid chromatography (HPLC) to detect these entities and that is also playing a role to the fact that leachables/extractables are not necessarily ‘caught’ in stability studies. Some of the appropriate tools for measuring leachables/extractables are gas chromatography-flame ionization detector) and MS (mass spectrometric detector) detector, liquid chromatography coupled to MS/(MS), ICP-MS (inductively coupled plasma mass spectrometry) and ICP-OES (inductively coupled plasma optical emission spectrometry) for metals and ion chromatography for cations and anions.

No explicit European regulation or guideline for leachables/extractables testing exists for the unlicensed production in hospital pharmacies. This could be because the need now only really occurs as a result of the attempt to extend the shelf-lives for the cytostatic agents.

Instead, the ICH guideline on plastic immediate packaging materials, intended for industry¹ is used, and is the most applied guideline regarding leachables/extractables for the hospital pharmacies. The problem is that the treatment of leachables/extractables is not up to date because it presumes that all leachables will be found in an extractable study. This is not the case as the so-called secondary leachables resulting from reaction between leachables and the drug, diluents or excipients can then be formed. These secondary leachables will not necessary appear in an extractable study. For example, butylated hydroxytoluene (BTH) reacts in water by hydroxylation of BHT to BHT-OH.² BHT-OH is rarely seen as an extractable, but is often seen as a leachable.

An argument for not being concerned about leachables is when the patient is receiving chemotherapy in which the cytostatic agents are so toxic that leachables are not the main concern.

It is necessary to have control over leachables for a number of reasons:

Moreover, leachables are often also compounds that the human body is not able to metabolise or degrade. This means that the leachables accumulate in the human body over time and the intake needs to be minimised. For cancer patients, it is extremely important to minimise the intake of the toxic products.

The above methods used to detect and separate the leachables/extractables are not necessarily standard techniques available in hospital pharmacies in Europe. It is also rare that papers concerning stability studies state clearly in which packaging the stability has been is measured. For example, if the stability study has been undertaken in a syringe, it is often only mentioned as a polypropylene syringe without giving the name of the supplier or the name of the syringe.

Hospital pharmacies do not have resources to undertake leachable/extractable studies. There is also the question of whether these studies are worth the effort if it is a CE marked device because there is no guarantee that the process step in the manufacturing, or the components of material for the packaging, remain constant.

Hospital pharmacies are in a special position because they are the link between the drug supplier and the patient. It is the hospital pharmacies’ responsibilities to reconstitute as much medication as needed, and it is this demand that now triggers the need for extended shelf-lives.

One way to treat leachables/extractables with a minimum number of tests is to perform a risk assessment for the combination of the drug solution and the container. The methodology is to score the drug solutions from (for example) the following factors:

From the score, approximately ten drugs with the highest score are chosen. These ten drugs are then analysed further. If the ten chosen through the risk approach are assessed as safe, the remainder can also be considered as safe. For these ten risk drug solutions, the analytical estimated value (AET value) is calculated. The calculation of AET value is based on the work of the Product Quality Research Institute,³ using the value for safety threshold concern in the relevant Cramer class. If no information is available regarding the toxicity of the potential leachables, a worst-case approach is applied and the lowest value, 1.5μg/day, in Cramer Class III is used.

The formula for AET is shown in Box 1.

As can be seen from the formula, the AET value is not an exact entity for the drug, but rather a relative value depending of the actual container size and the concrete number of doses used in the treatment regime.⁴ The AET value is now the limit for how many μg/ml of one specific leachable the drug solution can contain. This value can be compared with the μg/ml of extractable/leachable for the container.

The risk assessment approach is only an option if the data for extractable or  leachable studies are available. In principle, it is the supplier who should provide the extractable/leachable data for the container. In practice it is rather difficult for the hospital pharmacies to get this relevant information. One of the most frequently used infusion bags in Denmark for cytostatic agents is Freeflex® from Fresenius Kabi. Freeflex® consists of:

These infusion bags are registered as a drug. It is not possible to obtain the exctractable/leachable data, because the data is part of the drug master file and cannot be shared with other than regulatory authorities. This causes problems when the hospital pharmacies have the full responsibility for the leachables/extractables when extending the shelf-lives of the compounded cytostatic agent. It is necessary that the level of details for the extractables/leachables studies are so detailed that it would be possible for the hospital pharmacies to verify the study themselves, or at least have full insight in the studies.

If information regarding the material composition and leachables/extractables is not provided by the packaging supplier, hospital pharmacies have to carry out screening of leachables themselves. This is a resource-consuming task, and most of the European hospital pharmacies do not have the required capacity. Keeping the cytostatic agents in CE marked containers such as, for example, infusion bags from Baxter, elastomeric pumps and some syringes for stock preparation, adds to the complexity due to the fact that changes in a CE device can take place without informing.

As the hospital pharmacies are the necessary link between the patient and the medication packaging, it is surprising that the packaging supplier are not making a bigger effort to meet the hospital pharmacies wishes regarding leachables, which is information they, at least in some cases, have available.

The information that hospital pharmacies need are details regarding which exact chemical leachables have been found, in which amount, and which methods have been applied in these studies. Hospital pharmacies have numerous different preparations and the risk approach could be helpful in reducing the number of leachables tests. The biggest packaging supplier already has these results but is afraid of sharing it with the hospital pharmacies.

It is possible that new solutions targeted to the new reality for the hospital pharmacies in forms of increased automated production are necessary. This could, for example, be an official authorisation, which keeps all the confidential information about the leachables made by the packaging supplier. The burden of documentation would then not be on the hospital pharmacies.

Different working groups concerning leachables/extractables are formed, for example, ELSIE, PolymerForum PF, and PQRI, but these are groups targeted to industry.

A new group – L/E group for Hospital Pharmacies in Europe – has started aiming at cooperation among the hospital pharmacies in Europe. The aim is to gather knowledge of the area and make concrete results concerning leachables/extractables of the plastic packaging, for example, elastomeric pumps, syringes and infusion bags. For more information about this new group, please contact the author on [email protected].