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What performance requirements are needed for analytical procedures to ensure an alignment with the enhanced approach of Quality by Design for product/process?
An analytical procedure should be followed during the life cycle of the product to continually assure that it remains fit for its intended purpose.
Traditional approach followed today by pharmaceutical industry is based on ICH Guideline Q2 considering only the characteristics to be demonstrated during validation and/or transfer exercises[2, 3].
An innovative model of life cycle management more structured and fully embraces the concepts of QbD based on process development as described in ICH guidelines Q8 and Q11.
A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
These QbD concepts could also be adaptable to analytical methods if the analytical procedure is considered as a measuring process and the output of this process as a reportable result.
As process validation, lifecycle management of analytical procedures is proposed in three stages* : Analytical procedure Design, Qualification and continued Verification.
*corresponding to European terminology: Evaluation, Verification and On-going verification
Adoption of the QbD principles in analytical measurements would introduce a new concept “the Analytical Target Profile (ATP)” as the concept of Quality Target Product Profile (QTPP) described in ICH Guideline Q8. An ATP is established for each Critical Quality Attribute (CQA) of the drug substance/product integrated in the control strategy.
The ATP describes the method performance characteristics and the associated performance criteria needed to ensure produced data is suitable for its intended purpose.
As the product CQAs, the precision and accuracy of analytical methods described in ICH Q2 are characteristics to be considered holistically to represent the Target Measurement Uncertainty (TMU) associated with the reportable result generated by the procedure[7, 8].
Then criteria are established based on the final purpose of an analytical procedure, which is generating results upon which decisions about a batch are made, to fit with the initial target.
The ATP is independent of a specific analytical procedure and then any analytical procedure conforming to the ATP would be acceptable.
The ATP is considered as the focal point in the analytical lifecycle model.
The ATP would drive the design and development of an efficient method adapted to the intended use.
After technique selection, a science – and risk-based methodology, is used to develop the method and identify the most optimum operating conditions.
As the concept of product Critical Quality Attribute (CQA) described in ICH Guideline Q8, application of the QbD approach in analytical method development would introduce the new concept of the “Critical Quality Attribute” (CQA) of the reportable result.
A CQA of the reportable result is defined as an element of method performance that must measure to assess whether a method is capable of producing fit for purpose data. A CQA of the reportable result is contributing to the TMU through accuracy and precision.
Analytical procedure variables that could impact the analytical CQA must be identified. The risk analysis strategy allows identifying these CQA and the associated critical analytical procedure variables and understanding their relationship.
Quality Risk Management concept and tools (Process mapping, Ishikawa diagrams, Mindmaps…), described in ICH Guideline Q9 could be applied to analytical procedures.
Once the potential critical analytical procedure variables are defined, then studies by Design of Experiment are performed to determine the MODR (Method Operable Design Region), in parallel to the Process Design Space described in ICH Guideline Q8.
The critical analytical procedure variables must be controlled using a well-defined Analytical Control Strategy (ACS) to ensure CQAs of the reportable result are met.
For that purpose, in addition to the system suitability, the ACS will include planned controls related to reagents, standards, sample preparation, facility and equipment operating conditions, product specifications and frequency of monitoring.
These controls associated to the target and acceptance criteria of variables must be specified in the analytical procedure.
The stages of qualification and continued verification of the analytical method are performed to confirm the analytical procedure is delivering reproducible data that consistently meet the performance criteria defined in the ATP throughout the method lifecycle.
Qualification stage is comparable to traditional validation exercises as described in ICH Q2, including also other transfer activities and implementation of compendial procedures. Continued verification is performed using routine monitoring and implementation of changes may be required to improve the operational performance or the Analytical Control Strategy.
From an industry perspective, taking advantage of learnings from QbD, there are no particular barriers to a successful implementation of an analytical QbD approach. However, the development of analytical methodology aligned with the ATP concept will require an enhanced knowledge and understanding of the techniques and their linkage to analytical CQAs.
From a regulatory perspective, FDA and EMA agreed on the concepts of ATP and MODR. However the flexibility in submissions and the level of details in regulatory filling will need to be agreed and adopted between regulatory agencies.
Health’s authorities (FDA and EMA) and pharmaceutical industries are engaged in productive dialogue regarding QbD approaches applied to analytical methodology. The principles of AQbD were initially introduced in 2010 in a position paper written jointly by experts from PhRMA and EFPIA. In 2013, a Stimuli Article from USP and a presentation from FDA have completed this communication.
A new USP general chapter, <1220>, « The Analytical Procedure Lifecycle” is planned for beginning 2017.
Two new USP stimuli articles have been published in September 2016: “Analytical Target Profile (ATP): Structure and Application throughout the Analytical Lifecycle” and “Analytical Control Strategy”.
Analytics play a key role in the implementation of QbD in pharmaceutical industry. ATP should be considered as a link to the requirement of product and process through CQA of product and CQA of the reportable result. An associated approach of process controls and their analytical controls will ensure an overall and enhanced control strategy through the product lifecycle (Figure 1).
After successful implementation of product/process QbD, the application of analytical QbD appears as essential methodology. However, it is a real challenge for the pharmaceutical industries, the regulatory agency and for the patient.
Isabelle MOINEAU – AKTEHOM
- ICH Q2 (R1): Validation of analytical procedures: Text and methodology
- USP<1224>: Transfer of analytical procedures
- ISPE, Good Practice Guide: Technology Transfer. Tampa, FL: ISPE, 2003
- ICH Q8 (R2): Pharmaceutical development
- ICH Q11: Pharmaceutical development and manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological entities)
- USP-Lifecycle management of analytical procedures: method development, procedure performance qualification, and procedure performance verification – Pharmacopeial Forum 39 (5), 2013
- USP – Analytical target profile: Structure and Application throughout the analytical lifecycle – Pharmacopeial Forum 42 (5), 2016
- Bettencourt da Silva R, Williams A, eds. Eurachem/CITAC Guide: Setting and Using Target Uncertainty in Chemical Measurement. First edition. Leoben, Austria: Eurachem, 2015.
- USP – Analytical Control Strategy – Pharmacopeial Forum 42 (5), 2016
- ICH Q9: Quality Risk Management
- FDA – Considerations for Analytical Methods – FDA Perspective – IFPAC, 2013.
- Schweitzer M. et al. – Implications and opportunities of applying QbD principles to analytical measurements – Pharm. Technol. 2010; 34: 52-59.