Post-approval changes (PACs) – changes made to the drug substance manufacturing process after receiving market authorization from regulators – have become routine across the industry.
PACS, or variation filings (the European Medical Agency, or EMA, refers to post-approval changes as ‘variation filings’), are submitted for various reasons. These include:
- enhancing the robustness and efficiency of the manufacturing process
- ensuring timely supply in case of increased demand
- improving quality control techniques
- responding to changes in regulatory requirements
- upgrading or changing facilities or sites
- modifying the strength or potency of a drug substance
- filing for an extension of shelf life
- changing the formulation of the drug
- modifying batch size.
“Tightening drug specs is easy, widening them is not.”
The long-term success or failure of an approved drug often depends on its post-approval changes. There are multiple post-approval pathways that can be used, and choosing the right one is critical for drugmakers. The wrong selection can result in time-consuming resubmissions or even recalls.
To assist submitting entities, the FDA has provided Scale-Up Post-Approval Changes (SUPAC) guidance, which has been amended since it was first introduced in 1995. Guidelines are in place to govern revisions to approved new drug applications (NDAs) or abbreviated new drug applications (ANDAs), along with applications for biological products and approved applications for synthetic biological products and specific biotechnology.
In addition to scale-up, changes to the drug composition, ingredients, production site, packaging, and production equipment may require post-approval. Certain modifications, such as the assumption of a new manufacturing site, are particularly impactful, potentially affecting the purity, strength, and quality of the pharmaceutical product.
To ensure safety, inspection of resulting changes must confirm compliance with the current Good Manufacturing Practice (cGMP) guidelines.
Impact of Post-Approval Changes Dictates Specific Regulatory Submissions
Post-approval changes can vary in impact. Process or product modifications are categorized based on the risk associated with the change. The chosen pathway will impact how long post-approval authorization takes and what is required. The 3 primary types of PACS are:
Significant drug composition or ingredient changes require a careful inspection and the filing of a Prior-Approval Supplement. The omission or addition of a drug component can negatively impact the final product’s dissolution profile. Changes that display significant potential to negatively affect the drug products’ quality, strength, potency, or identity generally require prior approval. These changes are considered substantial because of their possible effects on product safety and efficacy. Thus, the drug’s distribution with the changes in place must be FDA-approved.
Among the types of change submissions, prior-approval changes are often the most time-consuming. Moreover, due to the potential need for resubmission, prior-approval changes are associated with a greater risk of hindering innovation and adversely affecting business plans.
Other changes only have a moderate potential for adverse effects on the drug product. These moderate changes, which are termed Supplement-Changes Being Effected (CBE), are submitted as CBE-0 or CBE-30 applications. With a CBE-0 application, the distribution of the product is permissible upon the FDA’s receipt of the application. A CBE-30 allows product distribution 30 days after the FDA receives the application.
Minor changes have little impact. These can be reported annually with no delay in product distribution.
NDA and ANDA holders must follow the FDA’s guidelines concerning post-approval changes. Whether the effects of a change are expected to be significant or not, the FDA still maintains final say concerning the most appropriate path of regulatory approval. A careless approach to PACs, paired with the failure to wait for the FDA’s response, can result in avoidable adverse incidents such as drug recalls.
Effects of the FDMA on Reporting Changes
The Food and Drug Modernization Act (FDMA), which was enacted in 1997, reduced the requirements for reporting manufacturing changes. Many changes that were previously designated as requiring prior approval could subsequently be filed as CBEs. Nevertheless, over the years, changes in the types and numbers of drugs being developed have caused a rise in prior-approval supplements.
Need for Post-Approval Guidance for Complex Generics
Many generic drug industry leaders consider the current versions of post-approval guidance for complex generics to be incomplete and outdated. During a conference in November 2022, panel participants voiced concerns that current guidelines fail to fully address filing categories and data requirements for post-approval changes. Additionally, the existing policies offer no post-approval guidance for the scale-ups, transfers, or component changes of dry powder or metered dose inhalers.
Case in point: the guidance that the Scale-Up Post-Approval Changes (SUPAC) regulations offer was established in 1995, and guidelines governing new drug applications (NDAs) were released in 2004. There have been a large number of significant pharmaceutical developments which have occurred since the creation of the SUPAC and NDA guidance.
Reducing Risk Potential
The FDA tends to be cautious regarding accepted risk. Drugmakers should assume a similar approach when determining the best filing category for submission.
There are multiple strategies to reduce the risk potential while employing a suitable, less taxing reporting category.
- Comparability protocol (CP)
A CP is a comprehensive, prospectively written plan for assessing the effect of chemistry, manufacturing, and controls (CMC) changes to a drug that may impact safety or effectiveness. A comparability protocol indicating the specific testing, analysis, and acceptance criteria for the proposed modification can lower the risk associated with the change’s implementation and may result in a less burdensome submission category. CP can be applied to a single change or several related CMC changes.
- Intra-organizational filing criteria
Applicants can develop and apply their standards for filing based on the information available in previous applications, whether original or supplemental. Strong scientific knowledge of the potential impact of the change may lower implementation risks and result in an easier submission.
- Process improvements
As process controls improve, the risk of an undesirable product lessens.
Avoiding Post-Approval Resubmissions
Post-approval changes should be based on evidentiary data generated from the drug product’s performance. The thorough review of multiple product batches—typically 25 to 50—is crucial. As an alternative, a commercial history spanning three to five years may be used.
LGM has a dedicated regulatory team that reviews data to determine the need for a specific type of post-approval submission. The experience and expertise of the team help facilitate a careful and thorough approach to the submission process, increasing the likelihood of FDA acceptance and ensuring regulatory compliance. As a result, our clients’ submissions are approved as rapidly and safely as possible.
Contact us today to discuss how LGM Pharma can help with your post-approval changes.