Dr Joachim Ermer, Sanofi, Germany
Dr Markus Fido VelaLabs, Austria
Patrick Jackson, GSK, United Kingdom
The aim of this two day course is to provide guidance to apply the principles of the modern concept of lifecycle management to analytical methods, as initiated by the PhRMA/EFPIA Position Paper [QbD Analytics. Implications and Opportunities of Applying QbD Principles to Analytical Measurements, Pharmaceutical Technology, Feb. 2010, 2-8] and further elaborated by USP’s Validation and Verification Expert Panel in a Stimuli Article for a proposed USP General Information Chapter [1220 The Analytical Procedure Lifecycle. Pharm. Forum 43(1)]. The application of Quality-by-Design principles during the whole analytical lifecycle provides opportunities, not only for new development products, but also for drugs already marketed. This course will deal among others with the following questions:
- What is the content of the three stages of analytical lifecycle aligned current process validation concepts?
- What are the opportunities of applying QbD principles to analytical lifecycle management?
- How can the Analytical Target Profile (ATP) help to define the measurement requirements and increase regulatory flexibility?
- Why is it important to have a clear understanding and expectation of method performance?
- What is the benefit of a risk-based method development and establishment of an appropriate Method Control Strategy?
- What is the impact and benefit of an integrated lifecycle approach on method verification, transfer, and changes?
- Why is a continued method performance monitoring important, and how can it be achieved?
During the course an overview of the PhRMA/EFPIA Position Paper and the Stimuli Article for a proposed USP General Information Chapter <1210> will be provided which are based on the Analytical Target Profile (ATP) concept. The ATP defines the objective of the test and quality requirements for the reportable value. It therefore aligns with the ICH definition of QbD as “a systematic approach that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management” [ICH Q8].
Besides serving as focal point throughout the analytical lifecycle, the ATP has the potential to facilitate continuous improvement if regulatory authorities would approve the requirement-based ATP instead of specific methods.
Each method conforming to the ATP requirements could be implemented by the company’s internal change control management system, thus providing regulatory flexibility. First steps into this direction can be seen in the draft ICH Q12 guideline Pharmaceutical Product Lifecycle Management, as, for example, the concept of “Established Conditions”.
The three stages of the analytical lifecycle align with current process validation concepts. In Stage 1, the ATP is used to drive method design and development activities. Risk assessment tools and statistical methods used to facilitate understanding of the method (e.g. robustness, design of experiments) and its performance characteristics (e.g. accuracy and precision) will be discussed in the course, as well as how to establish their acceptance criteria.
Stage 2, Method Performance Qualification, confirms that the analytical procedure, operated in the routine environment is capable of delivering reproducible data which consistently meet the ATP. This includes the finalisation of the Analytical Control Strategy, e.g. a science-based definition of the replication level of the reportable value. This stage includes also holistically analytical transfer and implementation of compendial procedures.
An important aspect in the lifecycle approach is Stage 3, the Continued Method Performance Verification, i.e. the ongoing assurance that the analytical procedure remains continuously in a state of control. This includes an ongoing program for routine monitoring of analytical performance data, as discussed in the FDA Method Validation Guideline from July 2015, and the systematic evaluation of changes.
These three stages are also reflected in the new ICH topic agreed in June 2018, Analytical Procedure Development (Q14), and to revise the Analytical Validation Guideline (Q2). In Q14, the concept and strategy of enhanced approaches for analytical procedures will be discussed, as well as performance criteria needed for analytical validation. In line with ICH Q8 and ICH Q11, a greater understanding of analytical procedure can create the basis for more flexible regulatory approaches. The terms Analytical Target Profile (ATP), Critical Method Attributes, Method Operable Design Region, Analytical Control Strategy are also mentioned. The revision of Q2(R1) will include validation approaches for modern analytical technology such as NIR or ICP-MS, as well as statistical methods and on-going performance verification.
Note: In order to fully benefit from the workshops, attendees should preferably bring a notebook with Excel®.
This course is designed for analytical managers and scientists who are responsible for performing or reviewing activities like method development, validation, transfer, operation of methods in a QC environment, statistical evaluation of method performance, analytical change control etc.
In addition, QA and regulatory affairs professionals will benefit from this course by gaining an understanding in future CMC trends. This will aid more effective multifunctional discussions on these topics within industry.
The three Stages of Analytical Lifecycle Management
- Overview on EFPIA/PhRMA Paper and the proposed USP Chapter <1220>
- Analytical Target Profile: ToReportable value, As focal point during the lifecycle, Potential regulatory flexibility
- Regulatory situation, ICH Q12
- Stage 1 – Method Design
- Stage 2 – Method Performance Qualification
- Stage 3 – Continued Method Performance Verification
- Accuracy and Precision, Target Measurement Uncertainty (TMU)
- Point estimate or statistical acceptance criteria?
- Combined or separate evaluation of accuracy and precision?
- Derivation of acceptable TMU based on probability distributions
- Design intent of the analytical measurement
- Linkage with process control strategy (critical quality attributes)
- Business requirements of method
- Design Intent of the Method
- Business Requirements
- Decision Rules
- Application of statistical simulations
- Gain experience (“feeling”) for the consequences of variability
- Variability of RSD determinations
- Probability of OOS results
- Method design and understanding
- Method selection
- Risk assessment
- Analytical Method Control Strategy
- Knowledge management
- “Translation” of ATP into specific method requirements
- Development and understanding
- Risk assessment
- Knowledge management
- Method Control Strategy
- Use of fishbone diagrams
- Identification of controllable factors, noise factors and experimental parameters (CNX)
- Use of priority matrix and failure mode and effects analysis (FMEA)
- For drug substance assay, degradation products in a tablet formulation, methods applied to biopharmaceuticals
- Design of experiments (DoE)
- Identification of experimental parameters
- Establishment of the Method Operable Design Region (MODR)
- Significance and Equivalence tests
- Precision of the reportable value
- Precision study for the definition of a science-based replication strategy: to average or not to average?
- Experimental confirmation of performance or reference to stage 1 investigations?
- Establishment of appropriate acceptance criteria
- Optimization of precision of the reportable value
- For LC assays and methods applied to biopharmaceuticals
- Selection of a method/technique likely to meet the ATP requirements for example attributes (drug substance assay, degradation products in a tablet formulation, methods applied to biopharmaceuticals)
- Consideration of business needs
- Examples for Methods and Changes
- Evaluation of impact
- Risk assessment
- Definition of appropriate actions
- FDA Method Validation Guidance
- Routine monitoring, evaluation of ongoing performance, suitable parameter and data
- Program for routine monitoring, control charts
- Examples for monitoring of Biopharmaceuticals
- Program for routine monitoring
- Identification of suitable performance parameters for example methods
- Establishment of a monitoring program
The concepts and tools used over the two days will be summarised and future implications and opportunities of the analytical lifecycle approach will be discussed. Delegates will be given time to ask questions on how they can apply what they have learned to their own analytical methods.
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