Manufacturing process design and development
Workshop participants noted that process development and formulation design cannot be separated because a formulation cannot
become a product without a prescribed process. Process design is the initial stage of process development, in which an outline
of the commercial manufacturing processes is documented, including the intended scales of manufacturing. The outline should
include all the factors that need to be considered for the design of the process, including facility, equipment, material
transfer, and manufacturing variables. Other factors to consider during process development are the QTPP and CQAs. Depending
upon the product being developed, type of process, and process knowledge the development scientists have, it may be necessary
to conduct preliminary feasibility studies before completing the process development. The selection of the type of process
depends upon the formulation and the properties of the materials.
Identification of critical process parameters and critical material attributes
A pharmaceutical manufacturing process usually consists of a series of unit operations to produce the desired quality product.
A unit operation is a discrete activity such as mixing, milling, granulation, drying, compression, or coating, that involves
physical or chemical changes. A physical, chemical, or microbiological property or characteristic of an input or output material
is defined as a material attribute. Process parameters include the type of equipment and equipment settings, operating conditions
(e.g., time, temperature, pressure, pH, and speed), and environmental conditions such as moisture. The output of a process
depends on the process parameters and the input material attributes.
Process robustness is the ability of a process to demonstrate acceptable quality of the product and tolerate variability in
inputs at the same time. The effects of variations in process parameters and input material attributes are evaluated in process-robustness
studies. The analysis of these experiments identifies CPPs and CMAs that could affect product quality and establishes limits
for these CPPs and CMAs within which the quality of drug product is assured. When the limits on CPPs and CMAs are scale-independent,
they may form the basis of a design space as defined in ICH Q8(R1) (1). Even when a design space is not established, multivariate
experiments are valuable because they identify CPPs and CMAs and support a conclusion of process robustness.
Process parameters and material attributes are critical when a realistic change can result in failure for the product to meet
the QTPP or a CQA that is outside an acceptable range. Process parameters are not critical when there is no trend to failure
and there is no evidence of significant interactions within the proven acceptable range (3).
Although workshop participants generally agreed that it was necessary to conduct process robustness studies for each unit
operation, some viewed this effort as overkill. The primary reason for this claim was that some generic-drug sponsors have
sufficient prior knowledge to determine whether a process parameter or material attribute is critical or not and to know when
process operating conditions will be robust. Workshop participants are generally in agreement that process-robustness studies
should be risk-based, that is, more studies with complex products and fewer studies with simple low-risk dosage forms.