The US Food and Drug Administration (FDA) has released a new policy document to clarify how agency staff in the Office of Pharmaceutical Quality (OPQ) should apply three international quality guidelines.
The new policy, which went into effect on Wednesday, outlines the responsibilities and procedures FDA expects its staff to adhere to when applying three International Conference for Harmonization (ICH) guidelines: ICH Q8(R2): Pharmaceutical Development, ICH Q9: Quality Risk Management and ICH Q10: Pharmaceutical Quality System.
According to FDA, the new policy comes as the agency is seeing an increase in the number of new and supplemental applications for drugs and biologics featuring Quality by Design (QbD) approaches, which are outlined in ICH Q8(R2).
"Reviewers should ensure that applications contain at least the minimum information on pharmaceutical development described by ICH Q8(R2) as 'at a minimum, those aspects of drug substances, excipients, container closure systems and manufacturing processes that are critical to product quality should be determine and control strategies justified,'" the policy states.
FDA says its reviewers should check applications to ensure that certain elements described in ICH Q8(R2) are included in all applications, including the quality target product profile (QTPP), critical quality attributes (CQAs) of the drug product, CQAs of the drug substance and excipients and that the sponsor has selected an appropriate manufacturing process and control strategy.
Additionally, FDA says its reviewers should be making sure the applications demonstrate that the manufacturer has an understanding of the development and manufacturing processes they've identified in their applications.
If necessary, FDA says that its quality reviewers should "confer with CMC [chemistry, manufacturing and controls] subject matter experts and members of the extended review team (e.g., medical officer, pharmacology/toxicology reviewer) to establish the relevance of CMC information that supports the drug's safety, efficacy, and performance."
Flexible Regulatory Approaches
As described in ICH Q8(R2), manufacturers can justify the use of flexible regulatory approaches in "areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches."
When an application includes information supporting a flexible regulatory approach, FDA says its reviewers should determine whether the application "includes sufficient enhanced knowledge that demonstrates the applicant's understanding of material attributes, manufacturing processes, and controls for product quality to support the proposed flexible regulatory approaches."
FDA gives the following examples of potential flexible approaches a manufacturer can take:
- "Manufacturing process improvements without regulatory notification (e.g., movement within a design space).
- Approaches to reduce post-approval submissions through submission of change protocols.
- In-process tests in lieu of end product testing, including real time release testing approaches.
- Mathematical models (e.g., multivariate models) as surrogates for traditional end product testing."
However, in order to determine whether a flexible regulatory approach is appropriate, FDA says its reviewers should evaluate the risk assessments provided by the manufactures to support the use of a flexible approach in a "scientific and risk-based" manner.
Lastly, FDA says its reviewers should "collaborate with the investigator and compliance officer, as needed, regarding potential risks in the manufacturing process if potential risks are discovered during the course of the review."FDA