PAT & QbD SUPPLEMENT
between the suitability of the eventually chosen analytical method and the manufacturing process and product requirements. It is proposed that the ATP is submitted to and approved by regulatory authorities, and not an individual analytical procedure: Any analytical procedure conforming to the defined ATP criteria can be applied. This may range from changes of method parameters such as mobile phase composition or gradient in LC up to application of a different analysis technique, as long as the ATP requirements are fulfilled. Of course, the challenge consists in an adequate definition of the ATP (see next section). With
EXAMPLE 1 As part of the control strategy for a drug substance, present as a monohydrate with a theoretical water content of 4.19 per cent, an acceptance range between four and five per cent was established. The determination is required to allow the calculation of assay on an anhydrous basis. The limit shall ensure a consistent drug substance quality, allow discrimination of a potential dehydrate form and avoid stability issues by limiting excessive adhesive moisture. Based on these requirements, the ATP is established (see Figure 2).
strictly handled according to the internal change control management of the company3 The application of the ATP concept is also
.
feasible retrospectively for marketed products. Here past and current process and product information and knowledge can be summarised in order to establish explicitly the requirements to define an ATP. The second concept described in the
Figure 2Analytical Target Profile for water determination in drug substance
respect to regulatory approval, the ATP would be the equivalent to the process design space. Working within this space is not considered as a regulatory change1
. The current method for each
CQA would be included in the dossier as an example procedure in order to allow official control laboratories to implement the testing. As such, an example procedure may include many more operational method and handling details without facing the risk of regulatory constrains, this approach would also facilitate the work of official control laboratories, as requested8
. Of course, any change must be
position paper is focused on robustness and reliability of the individual analytical procedure adapting QbD tools such as risk analysis, design of experiments, robustness studies etc.1-3
to
development and optimisation of analytical procedures as well as to the analytical lifecycle management. Of course, traditionally developed and validated methods are also able to provide reliable data. However, the Working Groups are convinced that a full realisation of the opportunities is only achievable by consequent application of the QbD concept. The implementation of the two concepts
described in the position paper would benefit both industry and regulators: The focus on the very aim of the analytical measurement by the ATP will facilitate the definition of suitability of the applied individual analytical procedure. It is well
Table 1 Method performance and operational requirements influencing analytical technique selection. For evaluation, classification was performed as H = high, M = medium, L = low (for cost and analysis time, the reciprocal was classified, in order to have a uniform ‘sense’)
Performance requirements
Analytical method
Karl-Fischer GC Loss on drying NIR
Specificity Precision Accuracy H
H
volumetric titration by reaction stoichiometry
H
By appropriate resolution
L H
chemometric model
*: including equipment qualification and method development #: including preparation of sample, reagents, mobile phases, factor determinations etc.
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European Pharmaceutical Review Volume 16 | Issue 3 | 2011
M
Interference due to residual solvents, degradation
H H M M Model validation H
no sample preparation
M / L H H M / H H H H M M / L H
Operational requirements Availability 1/Cost*
H H
1/Analysis time #
M
suited to serve as a ‘focal point’, not only in the development phase, but during the whole lifecycle, such as validation, transfer, adjustment and changes
By means of the ATP, criteria for the classification of analytical changes can be simplified, resulting in a facilitation of continuous improvements and technological progress and consequently a more efficient use of resources in both industry and regulatory authorities
An increased robustness and reliability of analytical procedures is achieved throughout the lifecycle by adaptation of the core elements of ICH Q8, Q9 and Q10, resulting in less investigations caused by method deficiencies, such as out-of- specification results, system suitability tests failures etc. Better knowledge and understanding of the performance of the analytical procedures would lead to more smooth analytical transfers
Analytical Target Profile The ATP can be regarded as the analytical counterpart to the Quality Target Product Profile1
. It has to be established for each Critical
Quality Attribute (CQA) and must describe the general analytical requirements to the measurement of the respective CQA. Therefore, the ATP will consist of a list of essential performance characteristics the specific method has to conform with. These performance characteristics will often correspond to the well known characteristics described in the validation guideline9
, such as specificity,
precision, accuracy, and range. However, the fundamental difference will be that these are general instead of method-specific performance parameters. In addition, the ATP must include acceptance criteria in order to guarantee that the requirements to the CQA are met. Obviously, the challenge in establishing an appropriate ATP consists in covering all performance requirements as well as ‘thinking method independently’ (as far as possible).
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