Strategic Approaches to Process Optimization and Scale-up - Almac

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• Defining the target product profile as it relates to quality, safety and efficacy, considering, for example, the routeof administration, dosage form, bioavailability, dosage, and stability• Identifying CQAs of the drug product, so that those product characteristics having an impact on product qualitycan be studied and controlled• Determining the quality attributes of the drug substance and excipients, and selecting the type and amount ofexcipients 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 theoutset of formulation development, can produce quality data from an early stage, which can minimize lengthy and costlyrepetition of manufacturing and subsequent studies and analysis. Nevertheless, before manufacturing registrationbatches, it is usual to invest additional time and effort in challenging, and, where necessary, optimizing the existingmanufacturing process. This is achieved by making additional development batches at laboratory-scale, pilot scale, andpossibly even at production scale. The output from the above development efforts provides the basis for justification thatscale up can be achieved without a consequent loss in quality and/or efficacy and provides the link between formulationand 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 apicture of the product and process, how its design has evolved, what is critical and must be controlled, and provenacceptable ranges (PARs) around specific process parameters.This article presents three approaches that a CDMO can consider in designing development and process optimizationstudies that will provide useful data on scaling up a product.Approach 1: Quality ensured by end-product testingThis method of manufacturing is a minimal approach to the mechanistic understanding of a process. The development ismainly empirical with research often conducted one factor at a time (OFAT). Following manufacture, there would be littleor no 'design space' defined, resulting in a strict manufacturing process that should be adhered to in order to minimizeany variability in product characteristics and thus the CQA profile. Validation will primarily be based on initial full-scalebatches. 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 afilm-coated tablet.Example 1: Blend, direct compression, and coating scale-up operation. A blending operation at a specified scale isperformed using a standard tumble blender. The drive unit is set to a fixed speed. The excipients are added to theblending shell and tumbling is initiated. The blend is mixed for a set period of time. Following this mixing time, the blend issampled to determine blend uniformity and bulk assay values. If the blend is determined to be uniform, the time andspeed used is recorded and would be used for future batches. If the blend is found to be nonuniform at this stage, anadditional mixing period is used, followed by further sampling for uniformity and bulk assay. This procedure is repeateduntil 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 compressionparameters 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-upsand continually assessed with appropriate adjustments made. Intensive in process checks continuously monitor productquality characteristics in order to maintain an acceptable product.Pharmaceutical Tech ‐ Sep 10 ‐ Process Opt & Scale‐Up
The tablet cores are progressed for coating using a batch coating process. The coating parameters are initially set usingprior knowledge of the equipment being used and coating at a particular batch size. Intensive in-process checks, inaddition 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, andwould likely invite greater scrutiny from regulatory authorities following submission (3).Approach 2: Full design of experimentsAn enhanced QbD approach to product development would additionally include a systematic evaluation, understanding,and refining of the formulation and manufacturing process, including (3):• Identifying–using prior knowledge, experimentation, and risk assessment–the material attributes and processparameters that can have an effect on product CQAs• Determining the functional relationships that link material attributes and process parameters to product CQAs• Using the enhanced process understanding in combination with quality risk management to establish anappropriate control strategy that can, for example, include a proposal for design space(s) and/or real-timerelease.Figure 1: An Ishikawa (fishbone) diagramthat identifies all potential parameters thatcan have an impact on the desired qualityattribute. (ALL FIGURES COURTESY OFTHE AUTHORS)higher level of process understanding.Risk-assessment tools can be used to identify and rank potential parameters deemedto have an impact on product quality based on prior knowledge and initial experimentaldata. The initial list of all possible parameters can be quite extensive, but is likely to benarrowed, as process understanding is increased, to a smaller list of potentialparameters. Narrowing the list has the advantage of reducing the number ofexperiments necessary in the modeling of a design space. The list can be refinedfurther through screening experimentation to determine the significance of individualparameters and potential interactions. Once the significant parameters are identified,they can be further studied (e.g., through a combination of design of experiments,mathematical models, or studies that lead to mechanistic understanding) to achieve aExample 2: Full design of experiments. Using prior scientific knowledge, the projectteam experts will use the target product profile to establish CQAs, and, in turn, CPPs.An approach could follow the five steps listed below.Step 1: Cause and effect analysis (Ishikawadiagram). The expert team compiles a cause andeffect (C&E) diagram, also known as an Ishikawadiagram, that maps out all potential parameters in aTable I: The potential parameters in anexample analysis.Figure 2: Example C&E diagram detailingmanufacturing process. The number of parameters can be very extensive. An exampledry-mixing and granulation parameters. analysis performed for a recent project at Almac resulted in 79 parameters, possiblyinfluencing the final tablet quality (see Figure 1). The parameters determined areshown in Table I. Figure 2 shows the potential CPPs making up the dry granulation step of the manufacturing process.Pharmaceutical Tech ‐ Sep 10 ‐ Process Opt & Scale‐Up
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Strategic Approaches to Process Optimization and Scale-up - Almac

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