ICH Q2(R2), Product Recalls & More – June 2022 Pharma Update

Step 3 drafts of both guidelines were published for consultation on March 24, 2022.

Q2(R2) is a complete revision of Q2, which has been unchanged since 1996, although the original Q2A and Q2B were consolidated into Q2(R1) in 2005. The Q2(R2) revision adds multivariate calibration and introduces new terminology, such as “working range,” which encompasses the previous linearity characteristics, detection limit and quantification limit.

The draft Q2(R2) shows how knowledge can be generated during analytical procedure development, as described in the new draft ICH Q14, and can aid the design of a validation study.

Annex 1 shows which validation tests should be selected depending on the objective of the analytical procedure. Annex 2 illustrates how the performance characteristics of 11 analytical techniques could be validated, including high-pressure liquid chromatography for impurity testing, binding or cell-based assays for determining potency, and near-infrared methods for core tablet assay.

The draft of the new Q14 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 analytical procedures’ development and lifecycle management. 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 enhanced approach in Q14, you can establish method operational design regions (MODRs) based on multivariate design experiments. Similarly, you can 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 developing multivariate analytical procedures and 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 for 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 U.S. FDA first issued draft guidance on “quality metrics” back in 2015, and this has been revised and the subject of much discussion ever since. On April 8, 2022, the Office of Pharmaceutical Quality (OPQ) issued a white paper titled “Quality Management Maturity: Essential for Stable U.S. Supply Chains of Quality Pharmaceuticals.”

One of the suggestions made by the FDA’s Drug Shortages Task Force was to develop a rating system to incentivize drug manufacturers to invest in achieving Quality Management Maturity (QMM).

QMM is a state that has consistent, reliable and robust business processes to achieve quality objectives and promote continuous improvement. Gauging QMM requires, in part, determining how well and how thoroughly a manufacturer has implemented the concepts of ICH Q10. A transparent rating system could inform purchasers about the level of QMM at sites from which they purchase drugs. The OPQ paper does not say how QMM will be measured, but it could revert to something proposed in the draft quality metrics guidance.

The FDA surmises that manufacturers with a high QMM rating would benefit from recognition and reward. In turn, the people who buy, dispense and use their products would benefit from improved supply chain transparency and greater certainty of supply.

It is probably not a coincidence that the FDA published a new public docket on the quality metrics program in March. This docket asks for feedback by June 9, 2022, on three areas:

• Reporting Levels: Should reporting be aggregated at the facility level, and would such facility-level reporting facilitate the submission of data on quality metrics by contract manufacturing organizations? How would a product family be defined? Should metrics be aggregated?
• Practice Areas and Quality Metrics: Are there other areas that should be considered? What about an assessment of the quality culture? Are suggestions made by the FDA not appropriate, and what other metrics could be considered? Plus additional questions about practical implementation.
• Other Considerations: Are there special considerations for certain product categories (e.g., generics, over-the-counter medicines or biological products)? What would be the optimal frequency for reporting data on quality metrics (e.g., monthly, quarterly or annually and broken down by quarter, year or month)?

New FDA guidance for the industry on initiation of voluntary recalls was issued in March 2022. The guidance has the following main headings:

How should a firm in a product distribution chain prepare to facilitate the timely initiation of a voluntary recall?

This section states, “It is critical for firms in a product distribution chain to be ‘recall ready.’ [The] FDA recommends that a firm make the following preparations as appropriate and applicable to its operations in advance of when a recall may be needed”:

• Identify appropriate personnel
• Train personnel
• Establish a recall communication plan
• Identify reporting requirements
• Use adequate coding
• Maintain distribution records

The section then describes recommended procedures for initiating a recall and performing actions related to initiating a recall.

• What should a firm do if there is an indication of a problem with a distributed product?
• How should a firm initiate a voluntary recall?
• How does the FDA work with a recalling firm to initiate a voluntary recall in a timely manner?