Key Points

• The FDA is taking steps to simplify complex generic drug product development and meet the clinical need around products like long-acting injectables
• The Agency is funding research in the characterization of complex drug products and providing guidelines for how to design and execute analytical test methods
• Efforts to encourage complex generic drug product development include guidance documents focused on biologics, grant funding for PLGA-based generics, and regular updates/improvements to the Inactive Ingredient Database

Introduction

In part 1 of this two-part blog series, we discussed the first two takeaways from the 2019 FDA Complex Generic Drug Product Development Workshop—an event that showcases efforts to facilitate generic approvals in areas such as long-acting injectables and biosimilars. Historically, there has been a lack of generic drug products in these areas, but the Agency has pushed policy initiatives and funded research to address this pressing clinical need in recent years.

Our first post centered around product-specific guidances (PSGs) and the Agency’s pre-ANDA meeting program, which were introduced to clarify the scientific and regulatory requirements around complex ANDA filings. In 2019 alone, over 160 new and revised PSGs were published to assist applicants in developing complete submissions. These documents provide guidance on topics such as in vitro and in vivo release testing, among other scientific considerations. When additional support is needed, the FDA encourages applicants to apply for pre-ANDA meetings which allow for direct feedback on product development or issues identified before or during submission review.

In addition to the improved communication created by these programs, the FDA is also funding research in the characterization of complex drug products and providing guidelines for how to design and execute analytical test methods. Efforts such as the FDA’s Regulatory Science Program for Generic PLA/PLGA-Based Generic Drug Products have made it easier for applicants to ensure Q1/Q2 sameness, even when complex mixtures of bioresorbable excipients are involved.

In this post, we will finish our list of key takeaways from the 2019 FDA Complex Generic Drug Product Development Workshop by discussing complex characterization issues related to APIs, excipients, particles, and in vitro drug release.

Complex API Characterization Requires an Evidence-Based Strategy

API sameness and proving pharmaceutical equivalence are requirements of generic drugs. For well-known small molecules, characterization is often straightforward, and testing is well-described in literature. However, characterization of complex APIs, such as peptides and small molecule mixtures, requires a totality of evidence approach. According to the FDA, a totality of evidence approach is a stepwise process consisting of tests on various material properties to demonstrate pharmaceutical equivalence or biosimilarity. For complex APIs, testing often consists of:

• Structure confirmation or comparative structural signature analysis: For peptides and oligonucleotides, this may include assessment of the primary structure, secondary structure, and tertiary structure
• Comparative physicochemical property analysis: Includes molecular weight distribution and spectroscopic analysis
• Comparative impurity profile analysis: For synthetic peptides, these include peptide-related impurities, and for oligonucleotides, these include (N+1) and (N-1) impurities. With biologics, the risk is generally with process impurities because degradative impurities are expected to match the RLD.
• Comparative biological activity analysis if necessary: For biologics, confirmatory in vitro and/or in vivo biological activity tests (bioassays) are needed.

FDA Guidelines: Injectable Peptide-Based Products

For injectable, peptide-based products, there are currently no published PSGs. However, in October 2017, the FDA put out a draft guidance for industry titled “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin.” This document provides general characterization principles and strategies for the development of complex peptide-based products. But for each peptide, a different set of tests may be needed. Following their totality of evidence approach, the FDA recommends utilizing orthogonal analytical methods to build a comprehensive profile of the peptide in question. Examples provided during the workshop included impurity measurementusing data-dependent acquisition (DDA) LC-MS-MS and data-independent acquisition (DIA) LC-MS^E approaches as well as structural fingerprinting of a peptide through compositional analysis and fragment mapping.

Each complex API has its challenges, so generic drug developers must evaluate each situation individually and apply general principles to generate a complete data package that demonstrates pharmaceutical equivalence or biosimilarity.

… and Complex Excipient Characterization Does Too

Many long-acting, polymer-based drug products have been developed for parenteral and ophthalmic routes of administration (e.g., bioabsorbable microspheres, in situ forming gels, solid implants). These products provide a route to improved patient compliance and significant market differentiation, and interest in long-acting drug delivery continues to grow.

For long-acting products delivered via parenteral and ophthalmic routes, the FDA requires Q1 and Q2 sameness, meaning the excipients in generic formulations must meet the following requirements:

• 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

However, for complex, polymer-based drug products such as bioabsorbable microspheres, achieving Q1/Q2 sameness can be challenging. Many of these products are formulated using poly(lactic-co-glycolic acid) (or PLGA) copolymers, which degrade in the body over time. PLGA is highly customizable and available in a range of:

• Lactide-to-glycolide (LA:GA) ratios
• Molecular weights
• Configurations (linear or STAR-branched)

These features are helpful when designing drug delivery systems, as they allow formulators to adjust degradation rates, drug loading, and drug release. But when developing complex generic formulations using PLGA, these same features introduce significant challenges.

STAR-branched PLGA

STAR-branched PLGA polymers consist of a glucose core surrounded by up to five PLGA branches. For drug products containing these polymers, such as Sandostatin LAR, molecular weight determination is complicated, as standard GPC does not provide information on branch frequency. As a result, the FDA funded a study comparing commercially available STAR-branched PLGA polymers to Sandostatin via GPC-4D. The study showed that, with advanced method development, even complex, branched polymers can be characterized.

Mixtures of PLGA

Some implantable and injectable PLGA-based drug products contain mixtures of LA:GA ratios to achieve a specific sustained-release profile. To develop a generic and match Q1/Q2, formulators must determine the PLGAs that comprise the product and their concentrations. An FDA-funded study showed that by using different solvent systems, the identity of PLGA polymers in Trelstar®, another long-acting injectable, could be determined.

These projects illustrate two main points: the FDA is committed to bridging scientific gaps in complex drug characterization, and the Office of Generic Drugs is open to novel alternative approaches for assessing bioequivalence of complex, long-acting drugs. With these points in mind, complex generic drug product developers should engage the Agency early in the development process and provide sufficient information/data to support their proposals.

A Closer Look: Excipient-Grade Polymers and the IID

As part of GDUFA II, the FDA has committed to the improvement of their Inactive Ingredient Database (IID), which contains information about excipient in previously approved products. The database contains data covering routes of administration, dosage forms, and maximum acceptable levels of excipients. By October 1, 2020, the Agency will add Maximum Daily Intake and Maximum Daily Exposure information where available and continue updating this information every quarter.

In July of 2019, the FDA published a Draft Guidance titled “Using the Inactive Ingredient Database.” The guidance is intended to support IND, NDA, and ANDA submissions by explaining how to use the IID during product development. A key point from this guidance was to always specify the excipient grade of materials in product development and regulatory submissions. Excipient-grade materials should be manufactured under Good Manufacturing Practices (GMP) that adhere to IPEC-PQG Guidelines. Additionally, excipient suppliers can support U.S. regulatory filings by submitting a Drug Master File (DMF), which is provided to the FDA and has a compilation of technical details related to the manufacture of the excipient. An example is Pathway™ Thermoplastic Polyurethane (TPU) Excipients, which are manufactured following GMP requirements and have multiple DMFs on file with the FDA.

Particle Size Analysis is Critical

Particle size is a critical quality attribute across a range of complex drug products, including emulsions, suspensions, and liposomes. It may also be considered a critical property in bioequivalence assessments. For example, PSGs for the development of cyclosporine emulsions and budesonide suspensions specifically call out globule size distribution and particle size distribution as parameters to measure. These characterizations help identify issues such as wide size distributions and multi-modal curves that highlight a lack of homogeneity in a product.

Particle size measurements are valuable because they inform several other evaluation criteria for complex drug products, including:

• Physical stability: changes in particle size over time due to agglomeration or degradation can indicate a lack of stability
• Dissolution and bioavailability: for particle size reduction approaches, particle size distribution has a critical impact on solubility and bioavailability enhancement
• Process capability: accurate particle size distributions provide data on batch-to-batch consistency through measurements of mean particle size, percentiles, modality, and particle size ranges
• Bioequivalence: the FDA lists particle size determination as a parameter on several complex PSGs

There are several techniques to measure particle size, including laser diffraction, optical microscopy, and electron microscopy (just to name a few). Proper particle size characterization requires a method that is sensitive and specific enough for a given product, meaning the method is consistent through formulation changes, process changes, and interference that may occur during measurements. The FDA encourages drug developers to welcome new particle sizing techniques which may provide more complete information, and in some cases, complementary analytical techniques may be required to fully characterize a particle size distribution.

Once a plan is developed for particle size characterization, method validation should demonstrate that the methods are repeatable, reproducible, and robust. Measurements should remain consistent across operators or aliquots of a product, and significant changes to method parameters should be detectable.

Particle size characterization is required by the FDA for many complex drug products, and it is not always a straightforward process. However, if characterization methods are properly designed and executed, they provide valuable information about complex drug products.

Long-Acting Drug Products Require Product-Specific In Vitro Drug Release Testing

In vitro drug release testing (IVRT) models drug release from a product in a controlled laboratory environment. It is not a replacement for in vivo testing, but it does provide valuable information for quality assessments. Changes in IVRT results allow drug developers and quality personnel to:

• Detect variations during routine product manufacturing
• Detect changes during product storage that may negatively impact product performance
• Support minor/moderate CMC changes

The FDA and USP have published various IVRT methods that should be used to characterize drug products when possible. However, many complex products do not have appropriate USP or FDA methods and require product-specific method development. In these cases, methods should be designed with testing conditions, discriminating ability, and acceptance criteria that detect changes in:

• Critical Material Attributes (CMAs)
• Critical Formulation Variables (CFVs)
• Critical Process Parameters (CPPs)

To achieve this goal, testing conditions must be optimized based on the intended route of administration. The release media should be at a temperature and pH that reflects the anticipated in vivo environment. The testing apparatus should create appropriate agitation and flow conditions as well. In our experience at Particle Sciences, USP Apparatus 4 and 7 are the most commonly used for complex drug products such as microspheres and solid implants. Apparatus 4 is more commonly available and has greater flexibility in terms of dissolution volume, but Apparatus 7 may be appropriate when more vigorous agitation is needed or low-volume is required to maximize analytical sensitivity. We utilize both and adjust testing parameters as necessary to ensure meaningful drug release data is obtained.

Testing timelines may also be adjusted to gain a complete understanding of drug release behavior. Real-time testing is evaluated through the intended period of product use to gain a mechanistic understanding of drug release. Accelerated testing, wherein temperature or media is altered to encourage drug release, can also be used as a quality control tool. Accelerated testing must be supported by cross-validation with long-term testing to demonstrate the interchangeability of the proposed tests as a quality control tool.

Conclusion

The second annual FDA Complex Generic Drug Product Development Workshop provided a wealth of valuable information for drug developers, building on the success of last’s year’s event. Complex drug product development remains uniquely challenging, but the Agency continues to promote programs that simplify the process. Product-specific guidances and formal meeting programs with the FDA have improved communication in recent years, and Agency-funded research programs in complex drug delivery have helped answer challenging scientific questions related to release testing and characterization of complex APIs, excipients, and formulations. As the Agency continues to promote complex generic drug product development, there is hope that the clinical need for products such as long-acting injectables will be met.

If you are looking for a partner to develop a complex generic drug product of your own, look no further than the experts at Particle Sciences. We have decades of experience across a range of dosage forms, including microparticle and gel depot injections, implantable systems and combination products, and many sterile ophthalmic products.

Have a project in mind? Contact us today.

Authors: Joey Glassco and Nick DiFranco