From The Editor | June 4, 2024

The Key to Regulatory Innovation? Global Harmonization

By Fran DeGrazio, executive editor, Drug Delivery Leader


When it comes to innovation in the biopharmaceutical industry, many companies focus primarily on developing innovative approaches in technical areas, such as drug delivery. In the meantime, their ability to prioritize and adopt regulatory innovation typically occurs at a much slower rate. Why is that?

Frankly, a significant factor is the substantial diversity in regulations when viewed from a global perspective.

Although the goal around the globe is to deliver safe and efficacious products to patients, the “how” of regulatory compliance from country to country can be very different. These differences can create challenges for pharma companies in their efforts to hit project deadlines, achieve compliance, and avoid wasting resources on unnecessary duplication of efforts. Clearly there is a need for global harmonization. Once global alignment in guidance is in place, each pharmaceutical organization will need to embrace opportunities to realize the impact of harmonization on regulatory innovation.

Design for Quality, Gain Regulatory Control

Fortunately, several organizations are actively working to address the diversity of regulations and encourage best practices in regulatory innovation. However, regulatory innovations instituted by organizations such as the International Council for Harmonization (ICH) or the International Organization for Standardization (ISO) can take years to develop. They may then be adopted by agencies such as the FDA. Although standards may take years to bring to completion, the results can be quite impactful. A key to maximizing the benefits is for pharma companies to have a nimble internal regulatory organization open and prepared to adopt best practices and leverage innovation as soon as possible.

Currently, ICH is focused on harmonizing scientific and technical requirements for human pharmaceuticals through technical guidelines. As an example, there are several key guidances that form the basis for the best practice of Quality by Design (QbD) in drug development. QbD being a science-driven, risk-based approach that expands product and process knowledge and understanding. The FDA encourages the implementation of all ICH guidelines; however, they are not codified into law.

The following guidelines have helped best practices evolve in the area of QbD:

ICH Q8 (R2) – Pharmaceutical Development

ICH Q9 – Quality Risk Management

ICH Q10 – Pharmaceutical Quality System

ICH Q11 – Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

ICH Q12 – Lifecycle Management (Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management)

Among the key aspects these guidelines reinforce is the concept of “risked-based” approaches to the development of drug products. This concept aligns quite nicely with Design Controls, which are defined in FDA 21 CFR Part 820.30. Design controls are regarded as the quality system that helps to ensure that devices meet user needs and related, specified requirements. Understanding both facets ̶   the drug and the device ̶   is fundamental to combination product development.

Manage Change with ICH Q12

One of the most significant challenges for the industry is change management. The FDA and other regulatory agencies are concerned about the conservative nature of the industry in incorporating needed improvements and changes. How can we leverage regulatory innovation to better manage change? ICH Q12, in particular, offers tools to help the industry address the challenge.

Published in its final version in November 2019, the Q12 document and related training materials enable the industry to institute changes more easily. Some of these tools were developed in an effort to clarify the meaning of Established Conditions (EC) and to provide guidance on utilizing a Post-Approval Change Management Protocol (PACMP), as well as on using a Product Lifecycle Management (PLCM) document, to mention a few of the intended outcomes. The Q12 document came about because there was a mutual interest between the regulators and industry to enable enhanced scientific development and controls, reduce unnecessary regulatory oversight of CMC changes, and maximize the utility of existing tools to reduce reportable changes – all of which help to expedite regulatory approvals. Prior to the release of the Q12 document, the FDA had provided draft guidances in 2003 and again in 2016 that contained the agency’s then current thoughts on the use of a comparability protocol (CP). The final document, released in 2022, is entitled Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA. Comparability protocols are, per the FDA guidance, “well-defined, detailed, written plans for assessing the effect of specific CMC changes in the identity, strength, quality, purity, and potency of a specific drug product as these factors relate to the safety and effectiveness of the product.” These protocols are used to manage changes as they are instituted. Historically, industry has not used this innovation option as proactively as it could in helping to manage change.

Prepare Now for FDA QMSR Implementation

One of the most significant recent steps made by the FDA in relationship to global harmonization and best practice is now codified into law. Released in January 2024, the FDA’s revised Quality System Requirements for Medical Devices established requirements that clarify certain aspects of ISO 13485:2016 that are being adopted by reference into the 21 CFR 820 regulations for medical devices. This activity was originally announced in 2018 by FDA, which then published a proposed rule in 2022. With the rollout of the final rule, there is a two-year transition period. The rule will be fully effective on February 2, 2026, and will be a compliance expectation, not just a best practice. The revised requirements will be known as the Quality Management System Regulation (QMSR).  Every company producing medical devices or combination products should already be working on making this transition.

 This update harmonizes quality management system needs for medical devices with requirements used by other global regulatory agencies. Risk Management is explicitly mentioned in Part 4 combination products requirements relating to product realization and expands the scope of risk evaluation to include safety, performance and meeting regulatory demands.

The various standards organizations do not make these ideas become reality alone. All these organizations need active industry participation to bring perspective, expertise and to highlight necessary practical struggles with current regulation. It’s imperative that pharma provide knowledgeable resources to participate. For example, a guidance relating to combination products should include technical and regulatory resources from the pharma industry and from suppliers since many devices are purchased from third party organizations and then leveraged as part of the final combination product.

The ability for the pharmaceutical industry to encourage, participate, and institute regulatory innovation will yield many benefits in respect to drug, medical device, and combination product execution.

Frankly, the key to gaining benefits from guidances and standards is eagerly adopting and actively leveraging these concepts in day-to-day business practices.