In the current environment, the pharmaceutical technologist is faced with an ever-changing series of regulations, difficult to process drug substances and the time to make market entry and reach maximum product potential.
For many drug substance candidates, the inherent physicochemical and pharmacokinetic properties pose unique challenges necessitating the application of advanced solid dosage form technologies. The same is true for innovators as well as generic firms that are manufacturing bioavailable products, which are seamlessly reviewed and reach the market quickly. Imbedded in this technical tapestry is the inevitable question of how large a batch needs to be, or more fundamentally, ‘what scale do I need to achieve?’. In many cases, the need for scale-up and the effort to achieve this are looked at as a major technical challenge.
This discussion will provide alternatives to this aspect by considering the risk in scale-up as opposed to the concept of scaling-out using a batch process which is more aligned with that of a ‘pilot scale’ or carry the pilot/small scale concept through to commercial manufacture. There are many advantages to the use of smaller, more flexible equipment; none the least of which is the reduced risk offered by avoiding scale change and the associated economics of facility requirements and capital equipment cost. The approach requires a fundamental consideration as to the nature of scale or more importantly batch size. It is these concepts which need to be re-considered in the pharmaceutical industry. Based on the literature, it is intuitive that a novel approach to commercialization at smaller scale offers an opportunity for increasing product understanding, product quality, reducing cost, minimizing facility infrastructure and leveraging the early stage knowledge store for not only manufacturing clinical supplies, but to allow this process knowledge to be used to commercialize and launch product. The utilization of early stage knowledge aligns with FDA’s Quality by Design approach as well as conforming with the new process validation guidance issued in January 2011.
If the pharmaceutical technologist is limited to developing a process which must meet a pre-determined ‘batch size’ requirement, his ability to move efficiently through to commercialization will contend with the risk inherent in scale-up. If, however, an unencumbered approach is taken by the technologist where the process will be at a scale that has been well defined in the early stages, then risk is reduced and a successful process intro-duction will be achieved while avoiding resources needed to develop the new scale. To get to this situation, a firm should look to batch size and manage it by applying supply chain concepts such as a ‘just in time’ paradigm where the amount of product to be produced will be a function of the number of smaller ‘batch units’. Then the business case will align with the established knowledge store created early in the product development cycle. Time to market will be reduced, capital costs minimized, technical risk mitigated and a path toward product introduction is set. It also allows time for the potential market to dictate the appropriate increase in scale size, if needed.
WHAT ABOUT THE REGULATIONS?
This is a topic which routinely comes up during the discussion about batch size, or more to the point, what is defined as a batch for pharmaceutical firms to address when defining their commercial strategy. The genesis of the discussion has been around for many years in the industry, as evidenced by a section devoted to scaling changes in FDA’s Scale-up and Post Approval Changes Guidance and has its roots in the debate surrounding continuous or semi-continuous process designs. A literature search on the topic reveals a significant amount of the current thinking on the subject. This is seen in a recent article published in Pharmaceutical Technology, September 2011. In this article, the discussion centers more on the aspect of the use of innovation by industry when designing processing scenarios. When one considers our current topic as it concerns use of scale-out while employing novel small scale approaches and the guarded attitude of industry, the point made appears to lend itself to placing the implementation of ‘batch size’ criteria squarely in the laps of industry and their closely held concept of scale-up and the associated area of ‘what do we define as a batch?’.
According to the article noted above, Moheb Nasr, at the time director of the Office of New Drug Quality Assessment, Center for Drug Evaluation and Research at FDA, speaking at INTERPHEX March 2011 stated, “There are no regulatory hurdles for implementing innovation in pharmaceutical manufacturing." A key point made by Nasr is that current regulations do not distinguish between batch and continuous manufacturing. "The regulations are silent about the mode that must be used," he said. He emphasized that the term "batch" does not denote a mode of manufacturing, but rather defines a specific quantity of a drug or other material that is intended to have uniform character and quality. The regulations specify: "A batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture." Moreover, a "lot" refers to a "batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures it having uniform character and quality within specified limits". It would appear that the use of multiple small batches which have been scaled-out at a ‘pilot scale’, for example, may be managed by the firm using a smaller ‘batch unit’ approach, which is a hybrid of the continuous process being discussed. That being stated it then becomes a matter of the business model used by a firm to take the scale-out rather than the scale-up approach to bring products quickly down the development path on their way to commercial introduction.
WHAT ABOUT THE TECHNOLOGY AND PROCESSING STRATEGY?
The discussion takes a familiar tone, simply stated, we have a long his-tory of events which document scale-up challenges. It is fair to say that failure at scale-up is not so much of a surprise, but rather one of dam-age control after the fact. Scientists have been trying to gather all the key parameters for decades, but, unfortunately, there are still no exact and well-established rules ensuring an accurate transition for solid dosage forms from one scale to another. Industry experience shows that small scale behavior is completely different for most unit operations during a scale change so the obvious question that needs to be asked is why scale-up when the option to scale-out at the proven smaller or pilot scale is less of a risk proposition. So we need to challenge the batch-wise process and look to a hybrid scale and ‘batch unit’ application in a pharmaceutical manufacturing plant. We need to consider some additional factors which are collateral advantages to the use of small and inherently more flexible process scenarios.
One thought leader in the area, H. Leuenberger, states this well in his discussion of “scale-up in the 4th dimension” wherein he outlines an approach using multiple smaller batches to achieve commercial introduction. He describes a quasi-continuous production concept which takes advantage of a smaller batch with some aspects of a continuous process. The concept allows a large batch B which would consist of n subunits of sub-batches (b) such that a batch would for example be equal to B=nb.
Several innovator companies have taken the approach wherein they view new products with limited process experience by minimizing scale and taking advantage of a hybrid processing approach such as smaller batches against the backdrop of a semi-continuous process scenario.
The technology to achieve scale-out is best visualized when reading the description given by Tom Chirkot from Patterson-Kelley, "The equipment required for pharmaceutical processing of a directly compressible tablet is just a couple meters long, including feeding devices. The entire system is small enough to be placed over a tablet press”. This suggests that the use of a hybrid approach such as scale-out as opposed to scale-up is limited only by a firm’s desire to take an innovative step toward product quality and leveraging their knowledge store.
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Read the full article in the INTERPHEX 2012 Pharmaceutical Processing supplement.