"Analytical Characterization Matters"
During his time in academia, Andrew originally studied biological sciences in Cardiff, specializing in respiratory physics. In 1991, Andrew joined Glaxo Group Research, formulating and analyzing inhaled medicines. Andrew went on to specialize in the physical analysis of raw materials and products, expanding into oral and other formulation types. During his 24 years with Glaxo, Glaxo Wellcome and GlaxoSmithKline, he took on roles of increasing responsibility, ultimately managing a materials science group and representing GSK in various academic collaborations.
Three years ago, Andrew moved to Spain and joined Chemo R&D in Madrid. As R&D Manager - Physical Properties, he is responsible for defining the physical characteristics of API, excipients and formulated materials, across a broad portfolio, to ensure consistent product performance.
As someone who has worked on the development of both generic and innovator drug products, have you noticed any differences between the physicochemical analysis approaches used in the generics industry compared to those used by innovators, and do you see any opportunities for analytical learnings to be shared between the two?
One of the main differences I have seen in generic companies is that there are a greater variety of projects and the pace and throughput is much faster compared to innovators. I encounter a large portfolio of APIs (Active Pharmaceutical Ingredients), excipients and final dosage forms across a lot of different medicines. Method development and validation needs to be efficient. Methods themselves need to be rapid, automated if possible, yet still producing high quality data.
Generics, it would seem, have the advantage of background information on a product, and this is true to some extent; no doubt there will be patents and literature relating to the API and product. But assessing this literature throws up problems. Take polymorphism, for example. There are sure to be patents covering numerous polymorphs – I have seen some materials with in excess of 20 forms reported. Some of these are likely to be mixtures of forms, or duplicates patented by different companies, and there are bound to be huge gaps in the available data. Seeing the wood for the trees is tricky. You need to be a detective and find the clues.
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For innovators the issues are different. Characterization is much more targeted. More effort can be spent on specific molecules. But it is necessary since you are starting from scratch with a new material, perhaps with very little material to work with - just a few milligrams in many cases. It’s likely that each small scale batch will be different to the last, with changes in particle size, shape, form, water content and so on. The challenge of understanding a material that has never existed before is exceptionally rewarding. The use of complementary techniques is key. There is no one technique that will tell you all you need to know. X-ray diffraction, thermal analysis, Raman and IR spectroscopies are the minimum for understanding solid state, with ssNMR and other techniques to try to fill some of the gaps. Then surface technologies like vapor sorption and microcalorimetry if any disorder or amorphous material is involved. As more material becomes available during scale up, particle size and surface area go without saying (but careful development of a particle size method is critical, even at this stage). But at every stage the most important technique of all is microscopy. You have to visualize the material, see it with your own eyes. A picture paints a thousand words, but microscopy underpins a thousand techniques.
You are involved in the development of multiple dosage forms. Could you comment on the challenges of characterizing the physical attributes of such a wide variety of products?
Final dosage forms are often an interesting challenge. The properties of the API are clearly important, but the properties and functionality of the medicine heading for the patient is critical for efficacy and safety. The technologies for examining the properties of these various dosage forms are limited in comparison to those for studying API. Various microscopy-based imaging systems with image analysis are available, as well as chemical imaging technologies based on various spectroscopic techniques. These have improved the situation a great deal, but they have their limitations, particularly the resolution of small particles.
Some of the more tricky formulations relate to creams and ointments. Isolating or characterizing the API, in situ, in complex multicomponent colloidal systems require a variety of different technologies, mainly microscopic, and the choice is highly dependent on API concentration and the presence of additional components. When it is necessary to measure the API particle shape, size and polymorphic form, it helps to have an arsenal of possible techniques at your disposal. Injectable suspensions present a similar challenge. Again, analysis in situ would be ideal, but many techniques are confounded by the dispersion media or the glass container. Some analysis techniques can be used – Raman is always one option as well as optical microscopy, but sometimes isolation from the dispersing medium by drying or filtration is the only approach. But clearly the consequences of either approach include the possibility of damaging or changing the API or crystallizing out soluble components.
Are there any frustrations or areas for improvement you can identify with regard to the types of analytical data required for regulatory submission?
Certain physical techniques appear, almost by default, in regulatory specifications. In the same way that identity, assay and impurities will always feature in a release specification for API, particle size will normally feature as well, for example. I believe this is driven by an assumption that particle size will always influence processability or tablet dissolution, and also by the apparent ease and availability of particle size equipment. In many cases this is right, but particle size is not the only characteristic that is important for a product’s performance, and sometimes it is of very little importance at all. Sometimes particle shape is more important in processability, and, as theory tells us, the surface area of an API should be the main driver in dissolution. Correlation with product performance is the key. It is so important to identify which attributes of a material actually influence the performance of a medicine, be it dissolution or in vivo testing. If, for example, surface area is the better parameter to control tablet dissolution, there is no reason why it shouldn’t be the primary, or indeed only critical quality attribute. I know that regulatory agencies will support this approach if they are provided with a good scientific argument and the data to support it.
Can you comment on the use of any emerging technologies which provide additional information on a product’s physical properties and thus its predicted quality and performance?
There are some amazing new technologies for the characterization of APIs and formulated materials. There have been great strides forward in imaging and related technologies such as Raman and X-ray diffraction imaging, surface analysis technologies such as various gas and vapor sorption techniques, as well as huge advances in computing power, driving modelling and prediction technology. But perhaps we should take time to think about what we are actually analyzing. It is great that we can analyze samples with higher and higher resolution, and greater and greater precision, but if the sample we are analyzing is not representative of the bulk material we are trying to characterize then these advances are missing important information. Something every physical scientist must remember is that the materials they work with are heterogeneous, and as such it is important to understand the entire composition of these materials. For example, the correct sampling of a 10 kg batch of API, is as important as any characterization technology you subsequently apply to it.