FDA has very recently issued a warning letter to the manufacturer of warfarin sodium tablets. The main finding was that the content of active substance in the product was not under control: The product had in more cases been out-of-specification (OOS) with regard to potency and conformity of dose – and the root cause investigation performed by the manufacturer was inadequate.
Warfarin is a product used as anticoagulant for prevention of formation of blood clots and has a very narrow therapeutic window. This implies that very small changes in content of the active substance will potentially be very dangerous to the patients.
In the warning letter, it is specifically mentioned that lack of control of particle sizes could be a major issue! Why is this?
It is well known that the particle sizes have a large impact on the behaviour of the solid products (powders) during development – and this includes both the particle sizes of the active substance of the product and all the excipients. During mixing of the ingredients, the particle sizes should “fit” the production process: For example, if a larger fraction of the particles suddenly have become smaller/larger, a risk of sedimentation or “phase separation” will occur. A lack of control of the particle sizes might therefore have caused an uneven distribution of the active substance in the final product, which might lead to a too low content as well as a too high content.
Mixing oat with sugar and raisins: Distribution is very dependent on sizes.
When an OOS result is observed, following should be taken into consideration in relation to particle sizes:
- Was particle size measured at all?
- Was particle characterization performed on the other solid materials (excipients), not just the active substance?
- Are the particle size results OK – or are any obvious trends/variations observed compared to historical data?
- Are all particle size results generated with the same method and is the method validated?
- Is the shape of the particles unchanged?
- Has something changed in the manufacturing, drying or handling of the API?
Even though the particle sizes have been run as a routine test, an OOS result can reveal that an old method is no longer working sufficiently well – or that something was overlooked during product development. A formal method investigation is important to identify any possible variations in analyses, or to identify obscure issues, such as sedimentation before sampling.
Of course, particle sizes might not be the only reason for such OOS results – it might also be “unknown factors” affecting the product, such as changes in surface area/shape, content of amorphous material, impurities affecting water content – and many others. All these variations might lead to different behaviour of the materials during manufacturing. If all other indications do not show a clear root cause, it should be investigated if there is an unknown (not routinely measured) physical aspect influencing the quality parameters.
At Particle Analytical we can help you in evaluation