A Practical Guide to Post-Approval Changes in Drugs
The journey of drugs from development to receiving market authorizations involves extensive research and planning. However, receiving market approval is not the end of its lifecycle. To ensure the ongoing safety, efficacy, and quality of a drug, continuous monitoring is necessary- or post-approval lifecycle management. This also involves monitoring and maintaining changes to ensure continued compliance with regulatory requirements including implementation of post-approval changes (PACs). They refer to changes that occur after receiving market approval. These changes encompass a wide range of alterations, including changes to the manufacturing process, formulation changes, and updates to product labeling. It is important for these changes to align with global regulatory requirements. Indeed, the regulatory framework for post-approval changes varies by region.
Types of Regulatory Submissions for Post-approval Changes
The regulatory pathway varies depending on the country or region. The countries also categorize PACs into several domains based on the nature of the change and its potential impact. These categories require a specific type of regulatory submission.
US FDA: The FDA categorizes post-approval changes into three main types: major, moderate, and minor changes.
Major changes: These are the changes that have the potential to significantly impact the drug’s safety, efficacy, or quality. Changes classified as major, such as changes to manufacturing process, site, or formulation, require a Prior Approval Supplement (PAS), which means manufacturers must submit detailed documentation outlining the change and receive FDA approval before implementing it.
Changes Being Effected (CBE): These are moderate changes and are further divided into 2 subcategories:
Changes Being Effected 30 (CBE-30): changes that have a moderate impact on the drug’s safety, efficacy, or quality and require FDA notification 30 days before implementation. E.g.: Minor changes to the manufacturing equipment.
Changes Being Effected 0 (CBE-0): changes that can be made without prior approval but must be reported when they occur. Examples include minor labeling updates or adjustments in specifications that do not significantly impact the product. CBE-0 changes can be implemented immediately upon FDA submission.
Minor changes: changes that are unlikely to have an impact on the drug’s safety, efficacy, or quality and do not require immediate FDA review. These can be reported in the annual report (AR) submitted to the FDA without prior approval. For example, minor changes in container closure systems or labelling.
EMA: Post-approval changes in the EU are classified into three main types: Type IA, Type IB, and Type II variations.
Type IA Variations: Type IA variations are minor changes that have minimal or no impact on the quality, safety, or efficacy of the medicinal product and follow a "Do and Tell" procedure. Examples include minor administrative changes such as MAH contact details, deletion of a manufacturing site for secondary packaging, or updates to the product quality system with no impact on the product.
Type IA Immediate Notification (IN): Variations that require immediate notification to EMA after implementation.
Type IA: Variations that do not require immediate notification can be submitted within 12 months after implementation.
Type IB Variations: Moderate changes that are not classified as Type IA or Type II and have a moderate impact on the quality, safety, or efficacy of the medicinal product and follow a “Tell, Wait and Do” procedure. Companies must submit a Type IB variation notification to the EMA and wait 30 days before implementing the change. Examples include changes in a product’s batch size, minor adjustments to the manufacturing process, changes in the immediate packaging materials that do not affect the product.
Type II Variations: changes that may significantly impact the quality, safety, or efficacy of the medicinal product. The review process can take anywhere between 60 and 90 days, and these variations require a formal application to be made and prior approval before implementation. Examples include changes to the manufacturing process of the active substance, introduction of a new therapeutic indications, and updates to the product’s dosing regimen or safety profile.
Worksharing Procedure: The EMA provides worksharing procedures for companies with similar changes affecting multiple marketing authorizations. This allows a single assessment of the change, reducing administrative burden. Companies must submit a worksharing application detailing proposed changes and affected authorizations. The EMA coordinates the assessment across multiple national authorities, streamlining the approval process.
PMDA: In Japan, post-approval changes are categorized primarily into two types: Partial Change Application and Minor Change Notification.
Partial Change Application (PCA): changes that may impact the quality, safety, or efficacy of a drug. This is like the "Prior Approval Changes" in the United States and Type II variations in the European Union.
Minor Change Notification (MCN): The MCN is designed for lower-risk changes that do not significantly impact the drug's quality, safety, or efficacy. MCNs can be filed within 30 days after implementing or shipping the change.
The regulatory framework for post-approval changes varies across different regions, impacting the global lifecycle management of products. The regulatory process for managing post-approval changes is necessary for ensuring uninterrupted global supply of medicines. However, the lack of harmonization among global regulatory requirements causes supply chain disruptions due to delayed approvals. To address this issues, countries are adopting reliance mechanisms, leveraging approvals from recognized reference authorities to expedite review processes in other countries. Adopting ICH Q12, a lifecycle management guideline, is a significant step towards standardizing risk-based categorization of post-approval changes. It introduces tools like established conditions, post-approval change management protocols, and risk-based reporting categories, streamlining post-approval change management across different countries.
At DDReg, we provide regulatory services through a multifaceted approach that ensures the safety and efficacy of pharmaceutical products throughout their lifecycle. DDReg’s team of experienced professionals is well-versed in regulatory requirements and guidelines from health authorities, ensuring that all safety assessments comply with the latest regulatory standards. For professional advice and assistance in regulatory-related queries, get in touch with us at https://www.ddregpharma.com/contact-us
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