The US FDA has issued a draft guidance on the established conditions: Reportable Chemistry, Manufacturing and Control (CMC) changes for approved drug and biologic products. The regulator expects the biopharmaceutical industry to provide their comments before July 31, 2015.

The guidance has been developed to address the lack of clarity with respect to what chemistry, manufacturing, and controls information in a marketing application.

Clarifications were needed for the biopharma industry regarding which elements of the CMC information. The industry was keen to have a better comprehension on the established conditions. There was need for a better understanding on whether certain CMC changes could be made solely under the Pharmaceutical Quality System (PQS) without the need to report to FDA. For those changes that required reporting, a better understanding of established conditions would allow for a more effective post-approval submission strategy by the industry.

Specifically, this guidance describes those sections in a Common Technical Document (CTD) which meets the definition of established conditions, and provides considerations to manage and communicate changes during the process of product approval.

This guidance is intended for applicants submitting original New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biologics License Applications (BLAs), said the regulatory authority.

Although the reporting mechanism for many CMC changes is clear, FDA is concerned that there is confusion regarding which elements of an application are considered to be established conditions. This confusion could have a negative impact on change management activities and could discourage continual improvement in product manufacturing processes. It could lead to unnecessary submission of post-approval supplements to FDA for changes that could be managed solely by a manufacturer’s PQS, and lead to Form 483 observations. The recommendations in this guidance pertaining to submission of information about established conditions in original applications, supplements, and annual reports are intended to increase clarity and transparency and help avoid such potentially negative outcomes, said the regulator.

Moreover, a better understanding of which elements of the CMC information constitute established conditions to FDA would enable speedy approvals. It also provides effective use of risk management principles in ICH Q9, and knowledge management as defined in ICH Q10. These could allow for a more effective post-approval submission strategy, said the regulator.

Clarity on what constitutes an established condition will also provide FDA with pathways to better regulate post-approval changes by utilizing more flexibility and risk-based principles, in accordance with the Current Good Manufacturing Practices.

In addition, the bio pharma industry will have a better clarity regarding what parts of an application are established conditions might support a future approach in which an applicant could rely upon. This will see the industry implement many post-approval changes appropriately, resulting in a more systematic reduction in or elimination of certain reporting requirements. Future guidance may be 114 developed to further support such an approach.

Based on current review practices, for complex products which includes many biological and biotechnology products and other difficult-to-characterize products, the level of product and process changes can be more challenging to determine. In these cases, FDA will consider these aspects when assigning allowable variations within the established conditions in the application.