The design of accurate and robust analytical methodology is instrumental to developing orally inhaled and nasal drug products
(OINDPs) and their appropriate control programmes. Analytical methods generate data that determines the selection of APIs
and the screening and selection of suitable excipients and container closure systems that form the OINDP. They are a key part
of the quality management system that underwrites the quality, safety and efficacy of clinical and commercial products. Analytical
methods, including on-line and in-line systems, monitor and control the manufacturing process for the API and finished OINDP,
and perform the required end product specification testing.
A Quality by Design (QbD) development programme uses a systematic approach that utilizes designed experiments and multivariate
statistical tools to assemble a product and process design space and, where possible, link any defined critical parameters
to the demonstrated product safety and efficacy.1,2
Appropriate measurement systems will be required to gain greater understanding of the product and process, and to establish
this product and process design space. The greater understanding, enhanced knowledge and increased ability to control product
and process more efficiently, will ensure consistent and high quality OINDPs, may help gain regulatory flexibility and will
facilitate continual improvement.3 A comprehensive method development programme that generates the required analytical knowledge to support the quality management
system and design space establishment is, therefore, integral to this QbD effort.
On the go...
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To gain full understanding of the capability of analytical methods, a life cycle approach to their development and validation
is recommended where a core set of initial development and validation information is augmented throughout the method life
cycle to demonstrate its continued fitness for purpose in all of the different environments and situations encountered in
OINDP manufacture and control.
Analytical methods suitable for their intended purpose, and rugged and efficient in their normal operating environment, are
a critical element of a quality management system. These methods are used to select and monitor critical process parameters
during manufacture, as well as the critical quality attributes in the resulting pharmaceutical product. For these reasons,
the advantages of applying QbD to the development, validation and life cycle management of an analytical method during the
overall development programme should be considered. Identification of critical method parameters and demonstration of how
changes in these influence the method outcome aid the establishment of the analytical method design space (the boundary values
for the combination of method parameters inside which the method performs as intended). An understanding of the variability
associated with an analytical method will also provide insight into the contribution this makes to the overall variability
of the OINDP. Key to this approach is the process of distinguishing between analytical robustness testing and analytical ruggedness
testing. This has been very well described by Borman.4 Analytical method robustness testing typically involves evaluating the influence of small changes in the operating conditions.
Ruggedness testing identifies the degree of reproducibility of test results obtained by the analysis of the same sample under
various normal test conditions such as using different laboratories, analysts and instruments.
The types of tests conducted for an OINDP vary widely from delivered dose uniformity and aerodynamic particle size distribution
(APSD) measurements, to foreign particles and microbiological testing. These requirements are elaborated in regulatory and
pharmacopoeial guidance.5–8 This paper discusses some general points applicable to most methods, but mainly focuses on issues unique to OINDP that arise
because of the combination of the drug formulation and user-operated delivery device in one pharmaceutical product.
Figure 1
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The development process for OINDPs integrates the usual proof of concept, safety and clinical efficacy development phases
with medical device design control requirements.9,10 This can be illustrated in terms of a method development life cycle (Figure 1) where validation criteria are aligned with
the typical product development phases, and elements of the design control and device development life cycle. The design control
aspects will ideally link to critical development milestones, but this may not always be the case. The entry point in the
design control life cycle is different depending on whether formulations use an established delivery platform design or a
new design. More than one iteration through design control process steps may occur.
