Main questions Flashcards
QP LEGAL duties
Each batch of product has been manufactured in compliance with:
National laws
Requirements of Marketing Authorisation
Each batch imported from outside the community
has undergone in the EU:
Full qualitative analysis
Quantitative analysis of at least all the active constituents
(note: exemptions where MRA exists)
All other tests to show compliance with the Marketing Authorisation
Where the product is released for sale, QP must certify in a register or
equivalent that the above requirements
have been satisfied
Note: Certification must precede
physical release to market
Explain ICH Q2 AMV and ICH Q14 AMV updates
ICH Q2(R2) – Groundbreaking innovations in analytical method validation!
The revision of the ICH Q2(R2) guideline represents an important extension to the original Q2(R1). This revision not only updates the approach to analytical method validation, but also sets new standards for precision, accuracy, and consistency in pharmaceutical analysis.
The main changes include:
- expanded Validation Scope
Emphasis on cross-life cycle evaluation and monitoring of analytical procedures.
Inclusion of new and revised analytical methods for the release and stability testing of medicinal products.
2. detailed Validation Tests
Requirements for performing specific validation tests, including precision, accuracy, and specificity.
Guidance on the evaluation of detection and quantification limits, linearity, and range.
3. risk-based Approach
Promotion of a risk-based approach to validation for improvement of analytical procedure’s efficiency and effectiveness.
Adaptability to technological developments and regulatory requirements.
4. promotion of the robustness of analytical processes
Development Support for reliable analytical methods that ensure consistent product quality.
Facilitation of analytical methods conversion and amendment after approval through clear guidelines.
The introduction of ICH Q2(R2) supports the pharmaceutical industry in developing and applying analytical procedures that meet high quality and safety standards. By providing a clear framework for validation, the guideline contributes to a more efficient and scientifically sound approval practice.
Standards that have long been set by regulatory authorities, e.g. with regard to linearity, are now officially included in the ICH standards.
Through direct reference to the ICH Q14 guideline, the development of analytical methods is already decisively integrated as a qualitative course-setter.
Tell me about IPC during packaging?
See picture
Discuss the updated ICH Q2 objectives
Guideline Objectives – ICH Q2
* Presents elements for consideration during the validation of analytical
procedures included as part of registration applications.
* Provides guidance on selection and evaluation of the various
validation tests for analytical procedures.
* Includes a collection of relevant terms and their definitions.
* Bridges the differences that often exist between various compendia
and documents of the ICH member regulatory authorities.
* Provides an indication of the data which should be presented in a
regulatory submission
Expected Benefits – ICH Q2(R2)
- Encourages the use of more advanced analytical procedures leading to
more robust quality oversight by pharmaceutical drug manufacturers. - Adequate validation data, resulting in reduction of information requests
and responses, which can delay application approval. - Modernisation of general methodology to include analytical procedures
and data evaluation for biotechnological products, future modalities and
statistical/multivariate data evaluations. - Enables efficient use of prior knowledge to support analytical procedure
validation.
ICH Q2
**Chapter 3 - Validation Tests, Methodology and Evaluation
Chapter 3.1 - Specificity/Selectivity
* The specificity or selectivity of an analytical procedure can be
demonstrated through
* absence of interference
* comparison of results to an orthogonal procedure
* inherently given by the underlying scientific principles of the
analytical procedure.
* Selectivity could be demonstrated when the analytical procedure is
not specific.
* For identification tests, a critical aspect is to demonstrate the
capability to identify the analyte of interest based on unique aspects
of its molecular structure and/or other specific properties.
* The specificity/selectivity of an analytical procedure should be
demonstrated to fulfil the accuracy requirements for the content or
potency of an analyte in the sample.
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ICH Q2(R2): Validation of Analytical Procedures
Chapter 3.2 - Range
* Depending on the sample preparation (e.g., dilutions) and the analytical
procedure selected, the reportable range can lead to a specific working
range.
* Linear response : Alinear relationship between analyte concentration and
response should be evaluated across the range of the analytical
procedure.
* Non-linear response: The suitability of the model should be assessed by
means of non-linear regression analysis (e.g., coefficient of
determination).
* Multivariate response: Algorithms used for construction of multivariate
calibration models can be linear or non-linear, as long as the model is
appropriate for establishing the relationship between the signal and the
quality attribute of interest.
* Validation of lower range limits: Detection and Quantitation Limits can be
validated through signal-to-noise, Standard Deviation of a Linear
Response and a Slope or through Accuracy and Precision at lower range
limits.
Chapter 3.3 - Accuracy and Precision
* Accuracy and precision can be evaluated independently, each with a
predefined acceptance criterion.
* Accuracy should be established across the reportable range of an
analytical procedure and is typically demonstrated through reference
material comparison, a spiking study or an orthogonal procedure
comparison.
* Precision: Validation of tests for assay and for quantitative
determination of impurity (purity) includes an investigation of
precision. Repeatability and intermediate precision are typically
determined. Investigation of reproducibility is usually not required for
regulatory submission.
* An alternative
to a separate evaluation of accuracy and precision is
to consider their total impact by assessing against a combined
performance criterion.
Chapter 3.4 - Robustness
* The evaluation of the analytical procedure’s suitability within the
intended operational environment should be considered during the
development phase and depends on the type of procedure under
study.
* Robustness testing should show the reliability of an analytical
procedure in response to deliberate variations in analytical
procedure parameters including stability of the sample preparation
and reagents.
* The robustness evaluation can be submitted as part of development
data for an analytical procedure on a case-by-case basis or should be made available upon request.
Common tablet defects, list 8.
Capping, lamination,cracking, chipping, sticking, picking,binding, double impression
Wet Granulation End point determination
Popular End Point Observations in Wet Granulation
- Visual Inspection
Description: Observing the appearance and consistency of the granules during and after granulation.
Key Indicators: Granules should appear uniformly wetted without excess liquid, and they should have a consistent size and shape.
- Granule Cohesion Test
Method 1:
Steps: Squeeze a handful of granules. If cohesion lumps form, and these lumps can be easily separated into individual granules, the end point is reached.
Observation: Proper cohesion without excessive wetness indicates the right balance of moisture.
Method 2:
Steps: Withdraw a handful of granules, shake off large granules, and examine the fine granules sticking to the glove.
Observation: Minimal fine granules and a small amount of sticking indicate an appropriate end point.
- Torque and Power Consumption
Description: Monitoring the power or torque consumption of the granulator’s impeller motor.
Key Indicators: A stable plateau in the power consumption curve indicates that the desired granule consistency has been achieved. A sharp increase or decrease suggests over- or under-granulation.
- Moisture Content Measurement
Description: Measuring the moisture content of the granules at various stages of the granulation process.
Key Indicators: The moisture content should be within a predefined range suitable for the specific formulation.
- Granule Size Distribution
Description: Analyzing the particle size distribution of the granules.
Key Indicators: A consistent and narrow size distribution indicates proper granulation.
- NIR (Near-Infrared) Spectroscopy
Description: Using NIR spectroscopy to monitor the moisture content and uniformity of granules in real-time.
Key Indicators: Consistent NIR spectra throughout the batch indicate uniform granulation.
- Effusivity Measurement
Description: Measuring the thermal effusivity of the granules to determine their thermal properties.
Key Indicators: Stable thermal effusivity values indicate uniform wetting and granulation.
- Acoustic Emission Monitoring
Description: Using acoustic sensors to detect changes in the granule formation process.
Key Indicators: Specific acoustic signatures correlate with different stages of granulation and can indicate the end point.
Examples of End Point Determination
Visual and Cohesion Tests
Example: During the pre-blend stage, the blade is set at low speed without the chopper to avoid excess dust. After adding the granulation liquid, visual inspection and cohesion tests are performed to ensure the granules have the right consistency without over-wetting.
Torque and Power Consumption
Example: In high shear granulation, the end point is often determined by monitoring the power consumption of the mixer motor. A stable power consumption curve plateau indicates that the granules have reached the desired size and density.
Moisture Content and NIR Spectroscopy
Example: In fluid-bed granulation, real-time NIR spectroscopy is used to measure the moisture content of the granules. The process is stopped when the moisture content reaches the target range, ensuring consistent granule quality.
Summary of Key Focus and Common Issues
Key Focus
- Granule Appearance: Granules should appear uniformly wetted and have consistent size and shape.
- Granule Behavior: Granules should have the right balance of moisture and cohesion without forming lumps.
- Equipment Settings: Proper settings for blade speed, chopper speed, and spray rate are crucial for achieving the end point.
- Process Control: Monitoring parameters such as torque, power consumption, and moisture content ensure consistent granulation.
Common Issues
- Over-Granulation: Excessive moisture or binder can lead to large, dense granules that are difficult to process further.
- Under-Granulation: Insufficient moisture or binder results in powdery granules that lack cohesion.
- Inconsistent Granule Size: Variability in granule size can lead to poor tablet formation and inconsistent drug release.
- Moisture Variation: Inconsistent moisture content can affect granule quality and stability.
By employing these popular end point observations and addressing common issues, the wet granulation process can be optimized for consistent and high-quality pharmaceutical products.
EU pharmaceutical legislation revisions
Commission adopted a proposal for a new Directive and a new Regulation, which revise and replace the existing general pharmaceutical legislation.
Q1 2023
Reduced baseline regulatory protection for non-orphan, orphan, paediatric and repurposed medicines, but with potential extension based on factors such as level of unmet need, trial design, indication expansion, or pan-EU launch within two years
Improved medicine availability safeguarding procedures, including monitoring and earlier reporting of shortages, and temporary emergency marketing authorisations (TEMAs)
Transferable data exclusivity voucher for novel antimicrobials
Streamlined EMA committees and processes, including reduced MA procedure length from 210 to 180 days, regulatory sandboxes, and ability of EMA to update labels based on data submissions independent of MA holder
Strengthened enforcement of current environmental requirements.
Windsor protocol impacts on Malta
29/08/2024
End of derogation for Marketing Authorisation holder, batch release site and batch testing site established in the United Kingdom. The Marketing Authorisation Holders having products that are still not in line with Directive 2001/83/EC in terms of Marketing Authorisation Holders, batch release sites and batch testing sites still located in the United Kingdom, are being reminded that the Marketing Authorisations will become invallid at the end of 2024. To ensure that MAs continue to be valid, these activities must be moved to the European Union. The necessary variations are to be submitted in good time for their review and approval. The Marketing Authorisation Holders will be contacted again in the coming weeks with a list of the products requiring regulatory action. It is the responsibility of MA holders to ensure that their dossiers and products are in line with Directive 2001/83/EC
Windsor Framework (WF) and how this will impact the Maltese market
The Windsor Framework addresses certain issues between the UK and NI relating to the movement of medicines (and other goods) between the two territories. Article 7 of Regulation (EU) 2023/1182 introduces a new provision which states that medicinal products should not be moved from NI to the EU or be placed on the market in a Member State of the EU. In this regard, joint packs with UK will no longer be possible after 1 January 2025. Packs manufactured for the UK market will no longer be allowed to bear the safety features and will also have the wording ‘UK only’ included on the packs once the Regulation comes into force.
Nationally and centrally authorised products which are in accordance with the Maltese/EU Marketing authorisation can continue to be released on the Maltese market using the packaging (including UK information) approved before the Windsor Agreement comes into force on 1 January 2025. The expectation is that this is a transitional period, and the outer labelling should be updated when other changes to the packaging are required. Therefore, the provisions of the WF are only applicable to medicinal products batch released after 31 December 2024. Administrative information relating to UK market must have been removed from the product packaging by 31 December 2027. This applies to the outer carton shen the immediate label and/or package leaflet is shared with the UK.
For nationally authorised products (National, DC and MR procedures), it is not necessary to submit an article 61(3) notification application when removing or amending the administrative information which does not affect any other aspects of the product, such as layout, font size, labelling and package leaflet text.
Whats new (ICH Q9)
ICH
ICH Q9 Guideline Quality Risk Management published as revision 1
In January 2023, the revision of the guideline10 reached stage 4 and went into implementation. A concept document11 set out the direction of the changes in 2020.
The concept document identified four areas where the current application of QRM could be improved:
- A high degree of subjectivity in risk assessments and QRM results
- Inadequate management of supply and product availability risks
- Lack of understanding of what constitutes a formality in QRM work
- Lack of clarity on risk-based decision making
The now published revision contains guidance on each of these four topics
The latest updates in GMP Annexes.
Annex 1
New - Manufacture of Sterile Medicinal Products - The deadline for coming into operation of Annex 1 is 25 August 2023, except for point 8.123 which is postponed until 25 August 2024
Manufacture of Sterile Medicinal Products (previous version)
Annex 2
New - Manufacture of Biological active substances and Medicinal Products for Human Use (into operation since 26 June 2018)
Annex 2 is no longer applicable to Advanced Therapy Medicinal Products to which applies the Commission guideline on Good Manufacturing Practice for Advanced Therapy Medicinal Products, published in Part IV of Eudralex Volume 4 and operational as of 22 May 2018.
Annex 17 New - Parametric release (Deadline for coming into operation: 26 December 2018)
Further information on the consultation can be found here.
not ICH Q9
Recent ICH updates
Final versions of the Q2(R2) and Q14 Guidelines adopted
On October 31 and November 01, 2023, an ICH Assembly Meeting was held in Prague. At this meeting, the final texts of the ICH Guidelines Q2(R2) “Validation of Analytical Procedures” and Q14 “Analytical Procedure Development” were adopted after the drafts of March 2022 had each received around 3000 comments.
ICH Q2(R2) describes the aspects to be considered in the validation of analytical procedures in the context of marketing authorization applications and the parameters necessary for the validation of various analytical methods. The scope of the revision of ICH Q2(R1) also includes principles of validation related to the analytical use of spectroscopic or spectrometric data (e.g. NIR, Raman, NMR or MS). ICH Q14 addresses the scientific basis for the development, change management and submission requirements of analytical methods. The new guideline is intended to improve communication between industry and regulatory authorities and facilitate more efficient, science-based and risk-based approval and post-approval change management of analytical methods.
Brexit
U.K./ Brexit
“Windsor Framework”: a new agreement for Northern Ireland
The European Commission and the government of the United Kingdom (UK) reached an agreement on special arrangements for Northern Ireland at the beginning of 2023 (the so-called “Windsor Framework”)15. Part of this is also a possible solution for medicinal products. In this regard, “Regulation (EU) 2023/1182 of the European Parliament and of the Council of 14 June 2023 laying down specific rules for medicinal products for human use to be placed on the market in Northern Ireland and amending Directive 2001/83/ EC” was published in the Official Journal of the EU.
Here are some important aspects:
Centrally authorized products (CAPs) in the EU can no longer automatically be placed on the market in Northern Ireland. A marketing authorization from the MHRA will be required.
The MHRA can allow the import of medicinal products from Great Britain to Northern Ireland by wholesale authorization holders (even without a corresponding manufacturing authorization).
Verification by the wholesaler is no longer required: “Wholesale authorization holders are not required to verify medicinal products under Article 1(1) of this Regulation in accordance with Article 80(1)(ca) of Directive 2001/83/EC”.
The requirements of the EU Falsified Medicines Directive (FMD) and the associated Delegated Regulation (EU) 2016/161 in relation to safety features for medicinal products are repealed for Northern Ireland. This means that packages placed on the market in Northern Ireland may no longer bear EU safety features on secondary packaging (features must be completely removed or covered). See also the relevant MHRA document.
The packaging of all medicinal products placed on the market in Northern Ireland must clearly state “UK only”.
