Top Ten Mistakes in Setup of Leachable Studies
Just back from presenting at Smithers European Conference on #Extractables and #Leachables. Whilst presenting on the subject of simulated leachables there it was clear we are in danger of confusion over the terms we use in this topic area. During the conference we ran a poll with three definitions of simulation leachable study. No one definition achieved more than 40% of audience vote.
This time I wanted to talk a little about Leachables not Extractables. So, first a quick definition; Leachables are the substances you find in your drug product from various sources, packaging, devices or manufacturing process so to they could end up in a patient when the patient takes the drug product. Analysing for leachable therefore involves an analysis of the drug product. So that leads to my list of top ten mistakes.
In 10th Place: Mistaking an extractable study for a leachable study
Extractable studies are very useful (See my October Blog) but they are not leachable studies, they are designed studies normally conducted on materials or systems other than the final drug product. Therefore, they run the risk of missing substances which turn up as Leachables
At 9th in my list: Not planning your leachable study
This perhaps should be higher in my count-down. There are many books, articles and even blog entries about the need to plan and this is just as true when in comes to leachable studies. A badly thought-out Leachable Study is worse than no Leachable Study at all.
Why? Because you run the risk of generating misleading information. If badly put together, you will generate information (and potentially submit to regulators) which is inaccurate and therefore leads to the wrong conclusions. So, what can go wrong?
8th on the list: Not having the right samples
A well-designed Leachable study thinks carefully about which samples to include. You must have samples which are representative of the to be marketed product if you are conducting a study for a marketing application. Sounds obvious doesn’t it? However, it sometimes very hard to get hold of samples early in the project which will be the same as the to be marketed product. Therefore, perhaps you will have to settle for samples which from a leachables point of view are representative of the marketed product but not the same. So, what might be representative? That leads to my next few entries.
7th: Not thinking about the inputs into the study
The sources of substances found as leachables are various but there are a number which high risk when it comes to contributing to Leachables in a drug product. High up on the list is the primary container closure system. So, when it comes to designing the leachable study it is important to think about the primary container closure system and how it might interact with the drug product. After all it might be in contact with the drug product for a very long time (up to and including the shelf-life)
6th: Not thinking about the number of batches included in the study
If you are looking to determine the variation you see in leachables from one batch to another, you need to consider where the variation is derived from. For example, if the leachables you see are from an elastomeric syringe plunger, how many batches have you looked at in your studies? Unless you have taken special care. Its possible that your three drug product batches might contain a single input syringe plunger batch so variation you see will not be due to batch to batch variation in syringe batches and will tell you very little about long term variation you might expect to see from this source
5th: Not having the correct Orientation during Storage
Orientation is a strange one, sometimes makes no different at all and on other occasions you can see completely different leachables and complete difference amounts of leachable when a product is stored in different orientations. I’ll refer you back to points in 9th and 8th and on to 1st place.
4th: Not thinking about the in-use period
As well as think about the period during storage you should also consider the in-use period. Why? – because during the in-use period leaching might change significantly. I’ll give you a couple of examples. Firstly, consider a freeze dried parerental. It is stored as a solid for its shelf-life but is re-constituted prior to use and then either injected directly into a patient or infused. Both of these systems are different from the storage period, both of these systems introduce new risks which might increase the risk of leachables. This should be considered in study design.
Second example, a Dry Powder Inhaler (DPI). During, its in-use period it is exposed to a potentially different set of conditions and use patterns to the shelf-life period. Perhaps it has a secondary over-wrap removed, or the temperature range is different or humidity. The device used to deliver the dose is certainly in-use whereas before it was not.
These are only two examples of how an in-use period might affect leachables.
3rd: Not having the correct storage temperatures
Before you start your leachable study what storage temperature are you going to use?
As many leachables are derived from materials in which substances diffuse out of the material by action of the formulation, temperature will play a central role in determining the rate of leaching and the final concentration of a leachable.
You also need to consider the storage temperatures which are relevant to your drug product. If the drug is to be stored refrigerated then a long term study at 2-8°C might be appropriate but if your product is going to be sold into a Zone IV country (as defined by ICH) then a much higher temperature of 30°C or even 40°C might be more appropriate. You also need to think about time, do you have time to study leachables to the end of the registered shelf-life?
If you don’t what are you doing to do about that? One approach is using higher temperature still to “accelerate” the study, but you need to consider carefully if that is the right approach for your study.
Higher temperatures might mean degrading the substances you are studying or enabling an interacting with the drug which at a lower temperature doesn’t occur.
It might mean your container starts to leak or your secondary packaging starts to contribute leachables.
All these things and more might occur without proper consideration.
2nd: Not choosing the right analytical method(s)
The analytical methodology (GCMS and LCMS, with ICP-MS for elemental impurities) used in leachable studies is similar but certainly not the same as the methods used for extractable studies. There are a number of important differences which need to be considered. Firstly, there is the formulation to consider and then the drug itself. The formulation can be a challenge to the development of suitable leachable methods, it takes care and skill to develop methods which are accurate and precise and operate to the correct and required sensitivity. A formulation can interfere with this, different formulation types can have a greater of lesser effect.
Secondly, the drug itself can interfere with leachable analysis, it is sometimes OK to use placebos to avoid this interference but needs to be done carefully because some leachable might be formed from drug – substance interaction to form leachables which are only present when the drug is too.
Another special case is in systems such as Cell & Gene Therapy where drug product is the patient’s cells or genes (See my presentation I gave at 2019 Smithers conference for discussion on Simulated Leachable Studies).
To obtain the correct qualitative and quantitative analysis leachable methods should be validated, this includes a check on matrix interferences and is particularly important in LCMS analysis where this can have a profound effect on results.
1st (and top place): Not Conducting a Pre-leachable Study Technical Risk Assessment
A properly constructed technical risk assessment is number one on my list because without it, it is very hard to get 10-2 correct. The risk assessment provides the inputs into each and every one of the other process steps in have listed and a few more too.
The risk assessment gives you the what and how of where the leaching might occur and therefore predicts and guides what studies you might need (both extractable and leachable). If correctly done it provides a justification for the leachable study or perhaps the reasons why a study is not required. The technical risk assessment should and can score risk from each unit operation; Manufacturing, packaging or device then decide whether the risk from the sub-operations within each unit operation and their associated materials need to have that risk reduced. Reducing the risk might include gathering information from a well-designed leachable study.
I hope I have convinced you that a technical risk assessment is worth the effort and of course Maven E&L Ltd can help you with that!
Equally I hope that my Top Ten Tips has provided something useful. Comments are most welcome, and I would be interested to hear your feedback on your experiences in designing leachable studies and perhaps the regulatory responses you have received (nothing confidential please – just the general direction and requests)
As all ways looking for topics for a future blog…Next Time: LCMS vs GCMS as a method of analysis for Extractables and Leachables