Approaches to process optimization and scale-up

Pharmaceutical development activities around the scaling-up and optimizing for pilot- or commercial-scale manufacture should include, at a minimum, the following elements (3):

• Defining the target product profile as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, dosage, and stability
• Identifying CQAs of the drug product, so that those product characteristics having an impact on product quality can be studied and controlled
• Determining the quality attributes of the drug substance and excipients, and selecting the type and amount of excipients to deliver drug product of the desired quality and efficacy
• Selecting an appropriate manufacturing process
• Where possible, identifying a control strategy.

The basis of quality-by-design (QbD) follows that well-designed experiments, carefully planned and thought out from the outset of formulation development, can produce quality data from an early stage, which can minimize lengthy and costly repetition of manufacturing and subsequent studies and analysis. Nevertheless, before manufacturing registration batches, it is usual to invest additional time and effort in challenging, and, where necessary, optimizing the existing manufacturing process. This is achieved by making additional development batches at laboratory-scale, pilot scale, and possibly even at production scale. The output from the above development efforts provides the basis for justification that scale up can be achieved without a consequent loss in quality and/or efficacy and provides the link between formulation and process development, pilot-scale manufacture, and eventual commercial production.

This article presents three approaches that a CDMO can consider in designing development and process optimization studies that will provide useful data on scaling up a product.

Approach 1: Quality ensured by end-product testing

This method of manufacturing is a minimal approach to the mechanistic understanding of a process. The development is mainly empirical with research often conducted one factor at a time (OFAT). Following manufacture, there would be little or no 'design space' defined, resulting in a strict manufacturing process that should be adhered to in order to minimize any variability in product characteristics and thus the CQA profile. Validation will primarily be based on initial full-scale batches. CPPs are determined using only prior knowledge. Proven acceptable ranges for CPPs are not fully determined. A minimal knowledge of PARs is determined. The following is an example of how this approach is used in developing a film-coated tablet.

Example 1: Blend, direct compression, and coating scale-up operation. A blending operation at a specified scale is performed using a standard tumble blender. The drive unit is set to a fixed speed. The excipients are added to the blending shell and tumbling is initiated. The blend is mixed for a set period of time. Following this mixing time, the blend is sampled to determine blend uniformity and bulk assay values. If the blend is determined to be uniform, the time and speed used is recorded and would be used for future batches. If the blend is found to be nonuniform at this stage, an additional mixing period is used, followed by further sampling for uniformity and bulk assay. This procedure is repeated until uniformity is achieved with the mixing time and speed recorded for future batches.

The uniform blend is compressed using a suitable tablet press for the batch size in question. The compression parameters are adjusted in order to obtain the desired product characteristics such as tablet weight, hardness, thickness, disintegration time, and dissolution time. Compression force and compression speed would be adjusted during set-ups and continually assessed with appropriate adjustments made. Intensive in process checks continuously monitor product quality characteristics in order to maintain an acceptable product.

The tablet cores are progressed for coating using a batch coating process. The coating parameters are initially set using prior knowledge of the equipment being used and coating at a particular batch size. Intensive in-process checks, in addition to close visual observations by trained operators, allow adjustments to be made throughout the coating process. The final parameters would be recorded and used for future coating operations at this scale.

With the advent of the guideline ICH Q8 Pharmaceutical Development, this historical approach is falling out of favor, and would likely invite greater scrutiny from regulatory authorities following submission (3).