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Criticality Management of a Drug Product and its Manufacturing Process
Criticality management combines pharmaceutical product, process, and material knowledge and risk management in one approach, which is reflected in a single document.
Figure 1 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
The literature describes the criticality management of the API-synthesis process (6). This article describes the criticality
management of the drug product and its manufacturing process using a direct-compression tablet as an example (see Figure 1).
Drug-product criticality management
The drug-product criticality-management process translates the target product profile into a list of potentially critical
quality attributes of the drug product. The formulation is designed and selected based upon these quality criteria and further
optimized by studying and managing the criticality of the composition and material properties, the packaging design, shipping,
stability, and the in-use procedure.
Table I: Quality attributes of a drug product (tablet).
Translating the target product profile into critical quality attributes (CQAs) is the initial step. It is important that the
right attributes be defined with proper measurement methods. These quality attributes are initially chosen based upon the
requirements of the target product profile, prior knowledge of this type of product, the manufacturing process, and the sensitivities
of the API. The attributes are further refined during development, based upon the characterization of the product, relationship
with in vivo behavior (when possible), or new findings. Table I defines the quality attributes, which tests are used to check the fulfillment
of these quality attributes, and whether a quality attribute is critical for the safety, efficacy, and usability for the patient.
The last column defines whether the CQAs are controlled by the process, by the materials, or by GMP systems. If the control
relies on GMP systems, criticality management of the attribute is not pursued.
The next steps—criticality in product, materials, and package—are similar to those in the manufacturing-process criticality
management, which is described below.
Materials play a role both in the drug product and in the manufacturing process. Therefore, they can be part of either the
drug-product criticality management or the manufacturing-process criticality management.
Manufacturing-process criticality management
Figure 2 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
Figure 2 outlines the steps in the manufacturing-process criticality management. The list of end-product CQAs and a detailed
process map are the starting points.
Table II: Potentially influential steps and process parameters or material attributes for a direct-compression tablet.
In the first step, a team of experts identifies factors that might influence these CQAs and which process steps, process parameters,
material attributes, and attributes of the pharmaceutical intermediate or in-process product are worthwhile to investigate
further. This evaluation is based on prior knowledge and thus is a science-based risk assessment. This assessment is represented
in a tabular format that provides a clear overview of the parameters and attributes that will be investigated further (see
Table II).
Filip Vanhoutte is an associate director of drug-product development at Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium, tel. +32 0 14 60 39 58, fax +32 0 14 60 5333
Articles by Filip Vanhoutte
Guy Smans
Guy Smans is a principal scientist in drug-product development at Johnson & Johnson Pharmaceutical Research and Development.
Articles by Guy Smans
Luc Janssens
Luc Janssens is senior director of global regulatory affairs at Tibotec.
Articles by Luc Janssens
Marc Vanstockem
Marc Vanstockem is senior director and chemicalpharmaceutical team leader at Tibotec.
Articles by Marc Vanstockem
Survey
How does your company apply quality-by-design (QbD) principles to manufacturing processes?
To all processes for both new and legacy products
21%
To all process for new products only
11%
To select process for new products only
25%
To select processes for both new and legacy products
