Implementing ICH Q14’s Enhanced Approach to Analytical Method Development, FDA's Proposed Framework for Human Factor Info in Device Submissions + Warning Letter Breakdown

We present expert insights on ICH Q14's enhanced approach to analytical method development, explore a new framework for human factors in device submissions, and break down a recent FDA Warning Letter.

Mar 3, 2023

Welcome to Insider issue #11.

And welcome to the 116 new life science professionals who joined last month.

Today we’re dissecting the enhanced approach to analytical procedure development (originally mentioned at a high level in ICH Q12) that was presented in the draft of ICH Q14 in 2022. The draft describes the benefits of using elements of the enhanced approach, and we present a framework for deciding if it’s suitable for your organization, and if so, how to implement it.

On the device side, we’re doing a deep dive into FDA’s proposed framework for human factors information in device submissions, which was outlined in a draft guidance issued in December of 2022.

Lastly, we break down and draw lessons from a recent Warning Letter to a generic drugmaker over GMP and laboratory control issues.

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Key points revised and summarized:

Considerations for implementing ICH Q14’s enhanced approach to analytical method development

In the first quarter of 2022, ICH released drafts of two significant changes to the guidance for analytical methods: ICH Q2(R2) and ICH Q14. This is the first time since the release of Q2 in the 1990s that there have been significant changes to the guidance for analytical methods. The ICH is targeting the finalization of these guidelines in May of 2023.

ICH Q2(R2) provides guidance for establishing, submitting, and maintaining evidence that an analytical procedure is fit for purpose, ensuring drug quality.
ICH Q14 describes the scientific principles for development, change management, and submission requirements of analytical procedures for the minimal and enhanced approach.

Background

ICH Q14 describes science-based and risk-based approaches for the development and maintenance of analytical procedures in line with previous ICH guidelines. For the first time in detail, two approaches to analytical procedure development are articulated: a minimal (or traditional) approach and an enhanced approach (originally mentioned at a high level in ICH Q12). There is also information for the development of multivariate analytical procedures and the use of these tests for real-time release testing (RTRT).

Principles are provided to facilitate change management of analytical procedures based on risk management, and a comprehensive understanding of the analytical procedure via adherence to predefined criteria for performance characteristics. Lastly, there is guidance on the submission of analytical procedure development and related lifecycle information in the Common Technical Document (CTD).

A more detailed review of each approach is covered in the video and slide deck.

Impressions

While the enhanced approach offers numerous benefits, organizations with financial constraints, inexperienced analytical personnel, immature or non-existent quality systems, and ineffective vendor management may find it difficult to implement this approach.

However, for organizations capable of taking this approach, the upfront investment in implementing it pays dividends into the future by reducing the effort required for analytical procedure lifecycle maintenance, including regulatory approval or notification. It’s important to note that the enhanced approach is not a one-size-fits-all solution, and organizations can choose to apply elements of the approach to their traditional analytical procedures.

As the guidelines are finalized and implemented, it’s expected that the benefits of using elements of the enhanced approach will become clearer.

One area that may require clarification is method qualification, which is not specifically mentioned in ICH Q14. However, the elements of method qualification are captured as part of analytical procedure development, with the identification of parameter set points and/or ranges through experimentation, risk assessment, and/or review of prior knowledge. By establishing these parameters prior to entering method validation, organizations can ensure that their analytical procedures are fit for purpose and meet regulatory requirements.

Overall, the new guidelines are an important step forward in ensuring that analytical procedures are developed, validated, and maintained in a consistent and scientifically sound manner.

Effectively implementing the enhanced approach

The question most teams will be asking: What steps are actually involved in implementing the enhanced approach?

Practical guidance to implement the key elements of the enhanced approach is provided in detail in the video and slides. Below is a summary.

The enhanced approach is a systematic and science-based strategy for developing analytical methods that meet quality standards. To implement this approach, several key elements need to be considered within the context of each organization. The steps below offer a generic plan that can be used as a general framework to develop an organization-specific plan. See the slides and presentation for a more detailed breakdown.

First, it’s important to evaluate sample properties and expected variability based on manufacturing process understanding. Technical reports that capture process and formulation development activities should be created and forced degradation studies should be conducted. This information should then be used to develop a Quality Target Product Profile (QTPP).
Defining an Analytical Target Profile (ATP) is the next step. This involves capturing information in an ATP document about the molecule from the QTPP, the intended purpose of the analytical method, how the analytical method is linked to the critical quality attribute (CQA) of the molecule, and the characteristics of the reportable results. These include desired or target acceptance criteria and associated rationale.
Risk assessment and evaluation of prior knowledge are then conducted to identify analytical procedure parameters that can impact performance. This risk analysis is done with guidance from ICH Q9 and any number of risk assessment tools. The risk analysis is documented according to quality processes (Risk Assessment SOP). Once analytical procedure parameters that can impact procedure performance have been identified, they are evaluated experimentally by conducting uni- or multi-variate experiments. Document the plan and properly record the results.
Defining an analytical procedure control strategy is the next step. Based on product and process understanding and considering the procedure development data and risk assessment, the analytical procedure control strategy is defined ensuring adherence to performance criteria. This can include system suitability testing acceptance criteria, positive and/or negative controls, and sample suitability acceptance criteria.
Lastly (potentenitally), define a lifecycle change management plan. Develop a change management process within the quality systems to include the appropriate stakeholders in the assessment of any method or other changes that may impact the method. This plan should provide clear definitions and reporting categories of established conditions (ECs), proven acceptable ranges (PARs), or method operational design regions (MODRs) as appropriate. (ECs may be developed based on product and process understanding and development data.) Teams can justify reporting categories for changes including adherence to predefined acceptance criteria described in the ATP and additional performance controls (use the example in Annex A of ICH Q14 as a starting point). For every change, it’s important to perform a structured risk assessment to evaluate potential impact on the performance characteristics and the link to CQA as defined in the respective ATP.

While this guidance is a good first step toward defining a systematic approach for analytical method development, getting organizations to embrace the enhanced approach can be a challenge.

Not all organizations are positioned to take this approach for the reasons stated earlier. Hiring a consultant to lead this effort, internally or externally, is typically the best, most cost-effective solution and should be considered before taking a minimalistic approach. The detailed examples located in the Annexes are very useful tools, as they provide a starting point on which more customized approaches and documents can be developed.

Quick reference links:

FDA proposes a framework for human factors information in device submissions

In December 2022, FDA released a draft guidance proposing a risk-based framework for including human factors information in medical device marketing submissions. The guidance is intended to complement the FDA's earlier guidance document, "Applying Human Factors and Usability Engineering to Medical Devices Guidance for Industry and Food and Drug Administration Staff," issued on February 3, 2016. The new guidance aims to help manufacturers apply a risk-based approach when considering what human factors information to include in a marketing submission.

Background

Human factors engineering is a critical aspect of medical device design. Its purpose is to reduce or eliminate use-related hazards and ensure that the device user interface has been designed such that use errors that occur during the use of the device that could cause harm or degrade medical treatment are either eliminated or reduced to the extent possible.

The new guidance framework explores how to determine the appropriate human factors submission category (1, 2, or 3) and what to include in a marketing submission based on that category. Human factors validation testing — testing conducted at the end of the device development process to assess user interactions with a device user interface to identify use errors that would or could result in serious harm to the patient or user — is a critical aspect of the risk-based approach to human factors assessment described in the guidance.

The guidance document provides relevant human factors definitions and recommends useful preliminary analysis and evaluation tools and validation testing that will enable manufacturers to assess and reduce risks associated with medical device use.

Design modifications made in response to human factors validation testing results to eliminate or reduce unacceptable use-related risks should be evaluated in a subsequent test to determine whether the design modifications were effective and whether they have introduced unacceptable new risks that need to be eliminated or reduced.
Common hazards traditionally considered in risk analysis include physical hazards, mechanical hazards, thermal hazards, electrical hazards, chemical hazards, radiation hazards, and biological hazards.
Medical device hazards associated with user interactions with devices should also be included in risk management. These hazards are referred to in the guidance document as use-related hazards. They might result from aspects of the user interface design that cause the user to fail to perform tasks correctly or to misunderstand device status or the information presented to them.
Manufacturers should analyze test data to determine which part of the user interface was involved and how the user interaction could have resulted in the use error or problem. The primary purpose of the analysis is to determine whether that part of the user interface could and should be modified to reduce or eliminate the use problem and reduce the use-related risks to acceptable levels.

See the slide deck and presentation for a much more comprehensive explanation of key considerations and recommendations in the following areas:

Common Human Factor mistakes/oversights companies make in submissions
Common hazards traditionally considered in risk analysis
Optimizing Human Factors Validation
Risk management
Implications for Human Factors
8 Device Marketing Submission Sections

Recommendations/Considerations

See the slide decks and presentation for more detailed recommendations and considerations.

Device manufacturers should have internal documentation of risk management, human factors engineering testing, and design optimization processes to provide evidence that the device is safe and effective for intended users and uses. (The FDA Group can support a device manufacturer’s internal risk documentation. Contact us if you could benefit from external expert support in this or other areas.)
Submitters should begin with a conclusion stating whether the user interface of the device has been found to be adequately designed for the intended users, uses, and use environments and whether new human factors testing was conducted to support this conclusion. FDA recommends that submitters provide a high-level summary of the human factors engineering assessment.
When modifying an existing device, submitters should compare the new device user interface to their own existing device in their marketing submission. They should list any critical tasks affected by the modification and assess whether the proposed changes warranted human factors validation testing.
In addition to the use-related risk analysis document for the entire device, submitters should include a subset of the use-related risk analysis that isolates tasks and risks associated with the proposed modifications made to the device.
Research user needs to support design input, analyze task and use-related risks, develop intuitive designs that reduce the risk of use errors, and evaluate using formative and summative evaluation at each stage of product development.
Use consulting services to support needed analysis, design research, and formative/summative evaluation to comply with FDA’s updated human factors guidance for use-related risk analysis in 510k or PMA submissions.

See the slide deck for a full list of references and significant supplementary information.

Warning Letter breakdown:

FDA warns generic drugmaker over GMP, laboratory control issues

Read the first full Warning Letter »

The FDA recently warned a foreign generic drugmaker for several GMP violations observed during an inspection of its Goa, India facility last May. The Warning Letter, dated November 22, 2022, cites four violations related to investigating failed batches of drugs, written procedures for production and process control, laboratory controls, and incomplete records. Due to these issues, FDA told the firm that its drug products “are adulterated” under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.

A summary of cited issues

Although you attributed the content uniformity failure to the lack of defined [tablet] compression parameters for Desmopressin Acetate 0.1mg batch 20210776, you failed to test other batches/products that used same (b)(4) process & compression equipment.
Your firm failed to adequately validate the manufacturing process for (b)(4) gel (b)(4)%. Specifically, your process validation lacks an evaluation of inter-batch and intra-batch variability for (b)(4) gel (b)(4)% [1 tube/each of the 3 validation batches tested].
Your analyst manually modified the processing of chromatographic data of (b)(4) impurity peak for (b)(4) tablets batch (b)(4). The impurity results would not have met release specification if the automatic integration processing had been applied in the same manner as they were to the standard and other peaks.
Production operators acknowledged using default pre-set tablet rejection values in the recipes for tablet compression instead of calculating the batch specific rejection limits as required by your procedure … In each of the investigations, since the automatic weight control or compaction force control was turned on, the risk of finding tablets that did not meet specification was low.

The main issues distilled

Four major QMS systems went off the rails:

OOS Investigation: Quarantine vs. Containment
Inadequate Process Validation
Chromatogram “Processing” to Pass/Ship Product
Breakdown in Mfg Procedures, sp. Equipment Setup

Some lessons

#1 — OOS Investigation: Quarantine vs. Containment

Quarantine: Places a suspect lot or product on hold
Containment: Places product brothers/sisters/cousins on hold

A rigorous containment action would probably have resulted in a significantly larger recall.

#2 — Improper Validation

1 tube tested per PQ lot for viscosity
No defensible statistical rationale for finished drug PQ
Either process is not validation-ready or corners were cut due to timeline/cost pressures

#3 — Chromatogram “Processing” to Pass/Ship Product

Appears to be a simple case of data manipulation to pass product
FDA has zero tolerance regarding “Data Integrity”
A case of, “Do Whatever You Need to Do to Ship That Product”

#4 — Breakdown in Mfg. SOPs, sp. Equipment Setup

Equipment setup SOP (testing machine) deliberately ignored
Operators were aware that the correct settings would hit yield
Inadequate or deliberate oversight confirming machine settings

Analysis of QMS Breakdown

Looking at the firm as a whole:

Seems successful ($1.5b revenue), with 13,000 employees and 10 sites, no shortage of talent/resources
These are low-hanging fruit problems
Everything should have been caught during an internal audit
The real question is, “where is quality”? Who is signing off on:
- Inadequate OOS investigations?
- Validation protocols with zero statistical rationale?
- Manipulated chromatograms?
- Incorrect machine setups?

Let’s Apply a 5 Why’s Methodology

Why 1: Why did the goa facility qms go off the rails? Lack of quality/independent oversight
Why 2: Why was there a lack of quality/independent oversight? Inadequate quality resources, capabilities, or oversight mandate
Why 3: Why was there a lack of quality resources/oversight? Failure to adequately manage product and compliance risk
Why 4: Why was there a failure to adequately manage risk? Lack of site-level or corporate-level leadership
Why 5: Why was there such a leadership loss? How could Boeing ship the most successful plane in aviation history, and end up killing 346 people and costing the firm $20b?

The consequences for this firm include a stock hit, suspension of reviews, and costly site remediation. The possible root causes for regulatory distress in a firm likely include a lack of management or technical competency, lack of resources, lack of oversight, and lack of management integrity/commitment. Laser-focused corporate governance is critical , especially for new product development, validation and verification, internal audits, and OOS investigations.

In other industry news…

FDA’s CDER released a new report looking at its actions in support of drug safety in 2022.
FDA has reminded device firms that CDRH is set to unveil several enhancements to its Electronic Medical Device Reporting (eMDR) system on March 17, 2023.
According to a newly published press release, Sanofi, Merck, Astellas, BMS, along with various foundations and advocacy groups, have collaborated to establish the Patient Advocacy Leaders and Drug Development Industry Network (Paladin) to hasten the progress of research and development. This initiative addresses multiple areas of interest to the FDA, including the diversity of clinical trials.
A new paper has been released by FDA discussing the use of AI in advanced drug manufacturing. The document highlights various ways in which AI can be used, such as trend monitoring, process monitoring, fault detection, process controls, design, and scale-up. The report acknowledges potential issues, such as data ownership, data integrity, and the extent to which AI should be regulated by the FDA.
A new webpage has been set up by FDA featuring updates concerning digital health technologies (DHTs). The agency is set to release a framework for DHTs later in March, so keep an eye on it if you’re impacted. Additionally, the FDA has created a DHT webpage for the projects it’s funded.
A new report from Hyman, Phelps & McNamara runs through the pros and cons of the FDA’s new eSTAR Template for medical device submissions through the 510(k) pathway. According to Adrienne Lenz, there are several issues with the eSTAR system, such as the requirement to resubmit certain unnecessary information and the absence of a section for human factors documentation. (Need a 510(k) consultant? We can help.)

A special thanks to this issue’s contributors

Judy Carmody, Ph.D. — Judy is the Founder and Principal Consultant of Carmody Quality Solutions, LLC, a quality solutions provider to life science startups and global Fortune 500 organizations who are as passionate as we are about keeping patients safe and delivering quality products. Dr. Carmody has 25+ years of specific expertise driving vision in quality and operations. She is the former founder and president of Avatar Pharmaceutical Services, an FDA-registered contract research organization and manufacturer which was acquired by Vertex Pharmaceuticals in 2010.
Nancy Angus-Edge — Nancy is a pharmaceutical and medical device Regulatory Affairs, supporting new product development from concept through release, Target Product Profile, Lifecycle Management, supporting regulatory strategies for assigned development projects that result in the on-time submission and approval of new products, and the proper maintenance of existing products.
Jon Wacks — Jon is a medical device SME and healthcare industry executive with startup-to-fortune 500 experience. He brings international QA/RA, engineering, and project management experience with medical devices, electronic assemblies, and supply chain management. His core competencies include Quality System Management, Regulatory Affairs (FDA, ISO, IEC, EHS), Product Engineering & Project Management, Design Control and Risk Analysis, Process Control and Process Improvement (SPC, DOE, FMEA), Verification, Validation and Test, and Contract Manufacturing & Supplier Quality Management.

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