ICH Flashcards
ICH Q2(R2) contents
ICH Q2(R2)
The new 36-page ICH Q2(R2) is divided into the following main chapters:
* 1. Introduction
* 2. General considerations for analytical procedure validation
* 3. Validation tests, methodology and evaluation
* 4. Glossary
* 5. References
* 6. Annex 1: Selection of validation tests
* 7. Annex 2: Illustrative examples for analytical techniques
ICH Q14 contents
ICH Q14
The new ICH Q14 comprises 40 pages, including the title page and table of contents, and is divided into the following sections:
* 1. Introduction
* 2. General considerations for analytical procedures
* 3. Analytical target profile
* 4. Knowledge and risk management in analytical procedure
* 5. Evaluation of robustness and parameter ranges of analytical procedures
* 6. Analytical procedure control strategy
* 7. Lifecycle management and post-approval changes of analytical procedures
* 8. Development of multivariate analytical procedures: additional considerations
* 9. Development of analytical procedures for real time release testing: additional considerations
* 10. Submission of analytical procedure related information
* 11. Glossary
* 12. References
* 13. Annex
ICH Q2 update
The Q2(R2) revision adds multivariate calibration and introduces new terminology such as ‘Working Range’, which encompasses the previous characteristics of linearity, detection limit and quantification limit.
The draft Q2(R2) includes Figure 1 that shows how knowledge can be generated during analytical procedure development as described in the new draft ICH Q14 and aid the design of a validation study.
In the draft Q2(R2) a new Annex 1 provides the following figure 2 to show which validation tests should be selected depending on the objective of the analytical procedure:
The draft Q2(R2) Annex 2 illustrates how the performance characteristics of 11 analytical techniques could be validated, including:
* HPLC for impurity testing
* Elemental Impurities by ICP‐OES or ICP‐MS
* Quantitative 1H‐NMR for the Assay of an API
* Binding or cell‐based assays for determining potency
* Quantitative PCR
* Near‐infrared (NIR) methods
* Quantitative LC/MS
ICH Q14 update
The draft of the new Q14, which has some 64 pages, was published on the same day as the draft Q2 revision. This new guideline applies quality‐by‐design (QbD) principles from Q8 and quality risk management concepts from Q9 to the development and lifecycle management of analytical
procedures. Like Q8 and Q11 it describes minimal and enhanced approaches to analytical procedure development. It also draws from the Q12 guideline on product lifecycle management by adopting concepts like established conditions and post‐approval change management protocols (PACMPs).
Using the Q14 enhanced approach, you can establish method operational design regions (MODRs) based on multivariate designed experiments, in a similar way that you establish a design space for manufacturing processes under the ICH Q8 QbD approach.
The Q14 draft:
* Specifies a minimal approach and elements of an enhanced approach for analytical procedure development
* Describes considerations for the development of multivariate analytical procedures and for real time release testing (RTRT)
* Provides principles to support change management of analytical procedures based on risk management, comprehensive understanding of the analytical procedure and adherence to predefined criteria for performance characteristics
* Includes submission considerations of analytical procedure development and related lifecycle information in the Common Technical Document (CTD) format
* Has three annexes
Annex A – Analytical Procedure Lifecycle
Annex B – Validation Strategies for method operational design regions (MODRs)
Annex C – Example of Multivariate Model Lifecycle Components
The analytical procedure lifecycle is shown in the figure below:
Established Conditions (ECs) for analytical procedures could consist of:
* Performance criteria (e.g., in the ATP or as part of SST)
* The analytical procedure principle (i.e., the physicochemical basis or specific technology)
* Set points and/or ranges for one or more parameters
* Procedure parameters which need to be controlled to ensure performance
ICH M7
ICH M7(R2) Mutagenic Impurities
The ICH M7(R2) Guideline on the “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” and the accompanying M7(R2) Addendum “Application of the Principles of the ICH M7 Guideline to Calculation of Compound‐Specific Acceptable Intakes” reached Step 4 of the ICH Process on 3 April 2023.”
This document is intended to provide guidance for new drug substances and new drug products during their clinical development and subsequent applications for marketing. It also applies to post‐approval submissions of marketed products, and to new marketing applications for products with a drug substance that is present in a previously approved product, in both cases only where:
* Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities
* Changes in the formulation, composition, or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products
* Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level
In this Addendum to ICH M7, AIs or Permissible Daily Exposures (PDEs) have been derived for a set of chemicals that are considered to be mutagens and carcinogens and are common in pharmaceutical manufacturing or are useful to illustrate the principles for deriving compound‐specific intakes described in ICH M7. The set of chemicals include compounds in which the primary method used to derive AIs for carcinogens with a likely mutagenic mode of action is the “default approach” from ICH M7 of linear extrapolation from the calculated cancer potency estimate, the TD50.
ICH Q9 update
This revision has been made to address four areas for improvement with the application of QRM:
1. High levels of subjectivity in risk assessments and in QRM outputs
2. Product availability risks
Quality/manufacturing issues that impact the supply chain and product availability can present risks to patients, and management of these risks is important
3. Lack of understanding as to what constitutes formality in QRM work
4. Lack of clarity on risk‐based decision‐making
This revision has, quite rightly, taken the opportunity to change the terminology for the start of the risk assessment process to “Hazard Identification” from risk identification, as shown below:
The main additions to the revised guideline are in section 5, Risk Management Methodology, with additional sub‐sections on:
* Formality in QRM
* Risk‐based Decision Making, and
* Managing and Minimizing Subjectivity
On formality, the new revision gives examples of the factors to be considered to determine the appropriate level of formality:
* Uncertainty; i.e. where there is a lack of knowledge about the risks
* Importance of the decision to be made
* Complexity of the project or subject area
The revised guide then gives characteristics of higher and lower levels of formality.
The new section on Risk‐based Decision‐Making states that “Effective risk‐based decision making begins with determining the level of effort, formality and documentation that should be applied during the quality risk management process.” It goes on to describe highly structured processes, less structured processes, and rule‐based processes when making risk‐based decisions.
On subjectivity, the revision states that this can be introduced through:
* Differences in how risks are assessed and in how hazards, harms and risks are perceived by different stakeholders
* The use of tools with poorly designed risk scoring scales
It goes on to state “While subjectivity cannot be completely eliminated from QRM activities, it may be controlled by addressing bias, the proper use of QRM tools and maximising the use of relevant data and sources of knowledge.”
The revision also adds a new section on ‘QRM as part of Supply Chain Control’ to Annex II on the
potential applications of QRM. This new section is sub‐divided as follows:
* Manufacturing Process Variation and State of Control
* Manufacturing Facilities and Equipment
* Supplier Oversight and Relationships
ICH Q13
ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products.
Endorsed by the ICH Assembly in June 2018 and an expert working group formed. The guideline received final, step 4 approval at the ICH Assembly meeting in South Korea on 16 November 2022.
As the title states, Q13 is intended to apply to both drug/medicinal products and drug substances/APIs
for chemical entities and therapeutic proteins.
Continuous manufacturing (CM) is applicable to new products and the conversion of batch manufacturing to CM for existing products.
The draft guideline describes three different models of continuous manufacturing:
1. A combination of approaches in which some unit operations operate in a batch mode while
others operate in a continuous mode
2. An approach where all unit operations of a drug substance or drug product manufacturing
process are integrated and operate in a continuous mode and
3. An approach in which the drug substance and drug product unit operations are integrated
across the boundary between drug substance and drug product to form a single continuous
manufacturing process
The draft uses the ICH Q7 definition of a batch for both drug substance and drug product. Based on
this definition, the size of a batch produced by CM can be defined in terms of one of the following:
* Quantity of output material
* Quantity of input material
* Run time at a defined mass flow rate
Other approaches to define batch size can also be considered, if scientifically justified. A batch size
can also be defined as a range.
Section 3, Scientific Approaches, has the following sub‐sections:
1. Control Strategy
2. Changes in Production Output
3. Continuous Process Verification
Section 4 is on Regulatory Considerations and Section 5 is a glossary.
Part 2 of the draft, which is actually the majority of the document, is a series of five Annexes, as
follows:
1. Continuous Manufacturing of Drug Substances (Chemical Entities)
2. Continuous Manufacturing for Drug Products (Chemical Entities)
3. Continuous Manufacturing of Drug Substances (Therapeutic Proteins)
4. Integrated Drug Substance and Drug Product Continuous Manufacturing
5. Perspectives on Managing Disturbances
