How To Implement Post-Approval Changes On A Global Level

By Arundhati Sengupta, MS, MBA, RAC, Mirum Pharmaceuticals

Amid constant innovation and technological advances in the pharmaceutical industry, there is high probability that regulatory requirements and expectations will change after a medicinal product is initially approved by health authorities. Modifications made to a medicinal product to implement new knowledge, maintain control, and/or drive continual improvement after an NDA or BLA is approved are known as post-approval changes (PACs).

PACs are a routine part of the product lifecycle and, within a pharmaceutical company, the chemistry, manufacturing, and controls regulatory affairs (RA CMC) functional body ensures that compliance is maintained throughout the implementation of all PACs by notifying regulatory bodies and securing the appropriate approvals. PACs are initiated to:

• enhance product quality
• improve manufacturing processes
• adapt to regulatory changes
• address safety concerns
• modify formulation
• expand manufacturing capacity
• improve analytical methods
• remain in compliance with evolving regulatory requirements.

To manage PACs effectively, it is imperative to determine their importance in product lifecycles. These changes can be implemented to address specific issues or concerns identified during or after the initial approval process to ensure that the manufacturing process remains under control and that product quality is consistently maintained. PACs can also be initiated to implement advanced technologies in manufacturing processes.

In any PAC scenario, proper planning and a thorough understanding of the associated risks, challenges, and proven strategies are vital to successful execution. Additionally, it is critical to harmonize regulatory impact assessments based on regulatory requirements to develop RA CMC strategies that drive timely PAC implementation.

How To Develop Regulatory Strategies

Health agencies around the world issue guidance documents generally classifying PACs and list out submission and document requirements to be completed, pre- and post-implementation. When regulatory authorities follow international standards, a major-risk post-approval variation approved by one country’s health authority should be accepted and/or approved by other country’s health authorities where the product has been approved. Overall, there should be flexibility in the PAC implementation timelines to ensure smooth supply continuity.

Key parameters essential to developing best-fit regulatory strategies include a knowledge of the intended PAC’s risk classification and its review-and-approval timeline. Developing these regulatory strategies requires RA CMC to:

• collect background information, including change description
• describe the reason for the change
• tag all documents impacted due to the proposed change
• gather product impact assessments
• evaluate all affected cross-functional teams
• map out the change actions to implement
• list jurisdictions impacted by the proposed change
• categorize the impact to product quality, as well as safety and efficacy
• record the PAC’s risk classification
• chart the timeline to secure approval from health agency

Depending on the PAC’s risk level, various guidelines recommends prior regulatory approval before implementation. Global evaluation of the PAC, its classification, submission and regulatory documentation requirements as well as approval timelines from health authorities from different jurisdictions should be converged globally. The international regulatory reliance and mutual recognition of PACs approvals for any medicinal product would ultimately support timely access to safe and effective products for patients worldwide.

PAC Prior Approval Depends On Risk Category

PACs are categorized as major, moderate, and minor risk:

Major risk changes are those that affect product quality, safety, and/or efficacy — that is, change to an approved established condition that requires regulatory review and approval prior to implementation. Prior approval from the health agencies is required to implement major risk changes.

Minor to moderate risk

Some PACs do not require approval prior to implementation. Moderate-risk changes may impact product quality and safety, but the risk is not severe. Moderate risk changes require regulatory notification before implementation.

Minor risk changes require regulatory agency notification to be submitted after implementation of the change. In addition, there are PACs for which there is no risk or impact to product quality, safety and/or efficacy. For these changes, no regulatory impact submission or reporting is required, and they can be implemented right away.

Time To Plan For PACs

Planning for the activities to take place before implementation of a PAC comprises of evaluation of the change by cross-functional teams, documentation of impact assessments and creation of change actions, to be executed by the cross-functional teams. Based on the impact assessments and impacted countries, a list of change actions that must be completed before implementation is created. The RA CMC then prepares the regulatory submission package for the countries where the medicinal product has been approved. After securing agency’s approval or submitting notification or annual reporting of the PAC to the heath authorities globally, change activities are completed and closed in the quality management systems. The quality and RA CMC conducts a review of all the relevant change actions and, ultimately, closes out the change control event (Fig. 1).

Fig 1: Risk-based Approach in Determining Regulatory Reporting Category

What Challenges Affect PAC Management?

Global regulatory complexity poses significant challenges to the change management system. Layered regulatory requirements, lengthy review processes, and convoluted submission procedures all can hinder timely PAC approval and increase the risk of supply disruptions.

The need to secure regulatory approvals for a PAC by multiple health agencies prior to implementation can lead to delays, drug supply disruptions and, eventually, drug shortages. Delays in securing regulatory approval also may cause cGMP compliance issues at drug manufacturing sites. However, studying real-world case studies can be fruitful for organizations seeking to avoid PAC implementation pitfalls.

Case Study 1: Low Risk Compendial Compliance

A PAC was initiated for a new chemical entity (NCE) product in which the acceptance criteria of a quality test attribute of the drug substance had been relaxed to comply with the official compendium. This PAC had been categorized as a minor risk because proposed changes to the approved product posed minimal risk to its quality, safety, and efficacy.

The change implementation plan was to file the PAC in an Annual Report to align with U.S. FDA regulations and to file a Type IA variation to align with the EMA regulation. If the same change had not been prompted by the official compendia, it would have been categorized as a major risk and filed as a prior approval supplement (PAS) in the U.S. or Type IB variation in the EU, meaning implementation of the change could take place only after approval.

Case Study 2: Excipient Changes Under Conflicting Rules

A PAC for excipients was initiated for an NCE product to comply with the requirements laid out in the Japanese Pharmacopoeia (JP). As a result, no filing in Japan was required. However, if the same excipients-grade material change had been made to comply with the United States or European pharmacopeias — and not the JP, although the product is still being under approved status in Japan — then the change would have been classified as a major risk and would require submission of a partial change application (PCA) in Japan.

Each country has its own regulatory framework governing PACs, which may have different requirements for submission types, procedures, and review and approval timelines. Regulatory assessment must be documented for all PACs to ensure change evaluation based on applicable regulations. The marketing authorization holder (MAH) is responsible for ensuring that, whenever a change is to be introduced, the facility meets the regulatory requirements of the jurisdiction where the product is approved. The regulatory pathways can vary depending on the product, the nature of the change, and jurisdictional control.

A Game-Changing Approach

There is a growing effort to harmonize PAC regulations and procedures across jurisdictions to streamline the assessment process and facilitate global access to medicines. Another fundamental proposed solution is regulatory reliance. In other words, once one country’s regulatory authority approves a major- or moderate-risk PAC, approval must be mutually recognized by other countries’ regulators. Such harmonization can reduce supply disruptions and thereby reduce burdens on industry.

Harmonizing global regulatory assessment can be achieved via three key strategies. First, industry leaders must create a culture of collaboration and transparency. The industry must allocate resources and prioritize product quality, safety, and the availability of high-quality and compliant medicinal products.

Second, PACs must be assessed globally where the impacted products have been approved. Effective PAC management requires capturing a “Global Regulatory Filing Assessment” for all proposed PACs.

Third, practicing enhanced science- and risk-based approaches to address global regulatory complexity will help effectively manage PACs. A risk-based approach helps drug developers to focus on patient safety and product quality. A science-based approach helps developers to leverage new knowledge, scientific advancements, and technologies to streamline and manage PAC processes.

Conclusion

PACs are essential and unavoidable in the lifecycle of a medicinal product. Health agencies around the world have issued guidance around PAC classification and submission requirements that drug manufacturers are expected to follow. These local regulations must align with international standards, to minimize approval delays for PACs and reduce potential impacts on drug supply.

However, global regulatory convergence aims to use science- and risk- based regulatory frameworks to enable more efficient PAC management by establishing national or regional variation guidelines in line with international standards (e.g., WHO, ICH) in terms of categorization, requirements, and timelines. This will not only expand reliance practices, but it also will allow predictability and consistency in the handling of PACs without the need for additional requirements, resulting in accelerated PAC approval.

About The Author:

Arundhati Sengupta is the regulatory affairs director at Mirum Pharmaceuticals. She specializes in product lifecycle management and oversees applications preparation and submissions for investigational medicinal products, marketing authorization, and post-approval changes. Previously, she held RA CMC roles at Novartis AG and AbbVie Inc. She holds a MS degree in Chemistry from University of Nebraska-Lincoln and an MBA from the University of California-Irvine.