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
- 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.
Analysis of the data assists in determining the parameters that have a known effect upon a CQA of the drug product. These
parameters are referred to as being critical process parameters (CPPs). Furthermore, data obtained creates a picture of the
product and process, how its design has evolved, what is critical and must be controlled, and proven acceptable ranges (PARs)
around specific process parameters.
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