6 Takeaways from the FDA’s Complex Generic Drug Product Development Workshop

Key Points

• Complex generic drug product development comes with challenging scientific and regulatory considerations, but the FDA is taking steps to simplify the process
• By publishing additional product-specific guidances and establishing a Pre-ANDA Program, the FDA has improved communication with ANDA applicants
• Q1/Q2 sameness and Q3 similarity requirements for complex ANDAs vary depending on the product and may include specialized characterization techniques
• The FDA is investing resources in modeling and simulation to help simplify bioequivalence evaluations and improve the complex ANDA application process

Why Host a Complex Generic Drug Product Development Workshop?

In September of 2018, the FDA hosted a two-day Complex Generic Drug Product Development Workshop. While the name doesn’t exactly roll off the tongue, the FDA organized this event to help simplify the development process and shed light on the need for generics in the complex drug product space.

Complex drug products are not only critical to the treatment of many serious medical conditions, but they are also valuable to the pharmaceutical industry. Multiple complex drug products have $1B+ markets (see Table 1 for examples of high-value complex drug products). Despite this, these products have little to no generic competition due to the complex scientific, legal, and regulatory challenges associated with complex generic ANDAs (see Table 1 for examples of high-value complex drug products). This is particularly concerning to the FDA because it has resulted in limited patient access for many of these drug products.

Table 1: High-Value Complex Drug Products

The FDA is working to simplify the path to market for complex generic drug products, as we addressed in a previous blog post. In this workshop, presenters focused on addressing the scientific challenges associated with characterizing and proving equivalence for products like liposomes, microspheres, and other complex formulations. If you couldn’t attend the workshop, here are six key takeaways from the presentations.

1. The FDA is Getting Specific with Complex Drug Products

The Generic Drug User Fee Act (GDUFA) was introduced in 2012 to create an evidence-, research-, and science-based standards setting program for the FDA. Since then, it has been a tremendous success story. Because of GDUFA, the Agency has been able to approve more ANDAs and provide better guidance for the development of future generic drug products. Under the program, approximately 800 product-specific guidances (PSGs) were published, and about 40% of those were for complex drug products. Before GDUFA, unclear regulatory expectations often led to incomplete ANDA applications and delays in complex drug product approvals. The Agency’s push to provide clarity on ANDA development requirements has generated more complete applications and helps reduce the number of review cycles required to obtain approval.

2. Communication is Key

As part of GDUFA II, the FDA has established the Pre-ANDA Program to facilitate discussions with the Agency around regulatory expectations for complex generic drug products. While PSGs have contributed to more complete ANDA applications, additional meetings are required for some complex generics. These meetings allow ANDA applicants to gain clarity when there isn’t a PSG available or when an applicant wishes to introduce alternative study approaches that are not covered in the PSG. There are three types of meetings that may occur:

1. Product Development Meetings: Provide for discussion of specific scientific issues or questions, such as an alternative bioequivalence approach. Give applicants the opportunity to receive targeted advice from the FDA on their development plan and early stage data
2. Pre-Submission Meetings: Provide an opportunity for prospective ANDA applicants to discuss and explain the format and content of the ANDA to be submitted. Allow the FDA to identify items or information that need further clarification before the submission takes place
3. Mid-Review Cycle Meetings: Afford an opportunity for the FDA to discuss issues identified during review with the applicant.

“Pre-ANDA meetings allow ANDA applicants to gain clarity when there isn’t a product specific guidance available or when an applicant wishes to introduce alternative study approaches that are not covered in the product specific guidance.”

3. Q1/Q2 Sameness Is Not One-Size-Fits-All…

For certain types of drug products (parenteral, ophthalmic, otic), the FDA requires Q1 and Q2 sameness for generics. Q1/Q2 sameness may also be recommended in a PSG when in vitro methods for demonstrating bioequivalence are proposed. Their definitions are as follows:

• Q1 (Qualitative sameness): the test product uses the same inactive ingredient(s) as the reference listed drug (RLD)
• Q2 (Quantitative sameness): concentrations of the inactive ingredient(s) used in the test product are within +/-5% of those used in the RLD

Q1/Q2 sameness may be demonstrated with a formulation table showing the inactive ingredients and their quantities relative to an RLD. However, this approach is not always sufficient for complex generic drug products. Additional characterization may be required for complex excipients such as PLGA (see case study below).

4. …And Q3 Similarity May Be Necessary

While Q1/Q2 sameness provides a good starting point for matching the performance of an RLD, it is not always sufficient when it comes to complex generic drug products. For some complex ANDAs, Q3 similarity must also be considered:

• Q3 (Physicochemical similarity): the arrangement of matter (physical and structural properties) is similar to the RLD

Q3 similarity mitigates the risk associated with physicochemical variations in a generic drug product, including, but not limited to:

• Differences in the polymorphic form of a drug
• Differences in rheology
• Differences in crystallinity that can impact drug diffusion

When evaluating products such as ophthalmic suspensions and multi-phase creams, these physicochemical properties can have a significant impact on the performance of the generic drug product. As a result, many PSGs, especially those for topical ANDAs, recommend Q3 evaluations.

5. Your Bioequivalence Approach Needs to be Robust

For demonstrating bioequivalence, in vitro release testing (IVRT) is critical to measure the rate and extent of dissolution or release of the drug substance from a drug product under a specific condition. For complex products, these methods should be reproducible, sensitive, and discriminating, allowing detection of changes in polymorphic form, physical structure, and other properties. Ultimately, a bioequivalence approach must be able to show how critical quality attributes and manufacturing process variation impact product performance, and IVRT is a valuable tool in achieving that goal.