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How to adapt a real time release approach to powder processing during drug-product manufacturing.
Real time release testing (RTRT) relies on a thorough knowledge of the materials being processed and the variables within, and influences of, the manufacturing environment. The attributes and quality of the final product depend on both of these contributing factors, and so it is essential that both are well understood.
For example, running a blender at a different speed for two batches of the same formulation has the potential to influence final product attributes, such as dissolution. The powders that go into the blender may be identical, but the fact that one batch has been subjected to more strain than the other means the properties of the output material are likely to be different. For this reason, in this case, it is essential to understand the influence of strain on the properties of the blend.
Equally important are the properties of the materials in the process. If the raw-material properties vary, but the process is fixed (i.e., the same blender speed and time, as noted in the above example) then the output will vary. Recognizing this dependence underpins the essence of quality by design (QbD) and can be conceptualized as: variable input material + fixed process = variable output. What is required is a variable process that is understood well enough to be adjusted to accommodate the unavoidable variability that exists in every batch of raw material.
Herein lies the RTRT challenge. For many years, at least in the powders- processing sector, particle size and distribution has been the primary specification for the physical properties of the materials. However, although size and distribution are important, these are but two of perhaps 20 physical properties that influence bulk material characteristics, which in turn define how the powder behaves during the manufacturing process, as well as the properties of the final product. Additional physical properties might include particle shape, surface area, moisture content, surface texture, and so forth. Each property contributes to the way the powder behaves and the final product attributes.
Understanding the significance of these variables and their contribution is fundamental, however, this relies on the ability to measure the variables and understand their relationship with the process. In addition, RTRT involves finding a way to quantify these important variables during processing. This quanitification must be done within a short timeframe to confirm that the required quality has been achieved and that the intermediate can move on to the next step in the process, or indeed, that the finished product can be released.
RTRT and continuous manufacturing are examples of initiatives that have been catalytic to better material and process understanding. Both depend on a thorough understanding of material properties, beyond the tradition specification of particle-size distribution and tapped density, for example. However, concurrently, the process must be well understood to ensure that the risk of perturbations can be assessed and that the settings, which have traditionally been fixed by regulation, can be modified to accommodate variation in incoming materials and still achieve output material that satisfies the quality attributes.
Advances in measurement technologies and a broadening mindset (helped by the process analytical technology and QbD initiatives) are driving material and process understanding. There are now GMP suites for continuous manufacturing of tablets that rely heavily on PAT and that function with real-time, closed-loop feedback on parameters, such as size, moisture content, and blend uniformity.
For this reason, RTRT has become much more of a reality in the past couple of years. However, there are many material properties that are still not measured routinely at-line or on-line, even though they can influence final product quality. For example, if particle shape is not being monitored, but particle size is and the shape changes, then the powder will perform differently in the press, causing the tablet properties (e.g., weight, hardness, dissolution, stability) to be affected. Yet, the process and quality system may not have accounted for this effect because the material going into the press was conforming to the inadequate specification of particle size.
RTRT is the future for efficient, safe, and competitive pharmaceutical manufacturing. It relies, however, on capturing more information about the materials being processed and the equipment and configuration employed during manufacturing. A closer relationship between formulators, process developers, and plant operators is essential. In addition, the extensive knowledge that exists in manufacturing, such as which products compress well and which are always capping, can be fed back to development to provide the design space necessary for optimal manufacturing and high product quality.
Tim Freeman is director of operations at Freeman Technology in the United Kingdom.