Revolutionizing Drug Development: The Strategic Role of Biowaiver Studies and DMPK

"With FDA Modernization 2.0 and 3.0 focusing on reducing animal use in pre-clinical studies, there's a shift towards ex-vivo systems that better replicate the disease microenvironment for improved clinical predictability. Similarly, biowaivers offer a transformative opportunity for drug developers and ADME/DMPK service providers. By embracing the biowaiver strategy, they can significantly cut development costs and accelerate time to market, all while enhancing business viability."

In the pharmaceutical industry, ensuring the bioequivalence of off-patent drug products is paramount for both safety and efficacy. Traditionally, rigorous human bioavailability and bioequivalence (BA/BE) studies have been required, which are time-consuming, costly and requires approval by ethical committee. Recent advancements in the Biopharmaceutics Classification System (BCS) have introduced biowaiver studies as a streamlined alternative for human BA/BE studies for ANDA submission and approval for marketing authorization, significantly simplifying the drug development process. This article explores how companies can take advantage of BCS-based biowaiver studies and how service provider companies can drive this vertical through Good clinical practices (GCP) as recommended by USFDA under the umbrella of Drug Metabolism and Pharmacokinetics (DMPK).

Understanding BCS-Based Biowaivers

Amidon et.al introduced the BCS based classification of drugs based on their solubility and permeability characteristics into four categories:

?Class I: High solubility, high permeability

Class II: Low solubility, high permeability

Class III: High solubility, low permeability

Class IV: Low solubility, low permeability

The BCS-based biowaiver approach reduces the need for human BA/BE studies for BCS class I (High solubility and high permeability) and class III (High solubility and low permeability) passive permeable, solid dosage orally administered immediate release drugs with broad therapeutic index by providing a surrogate through satisfactory in vitro solubility and permeability data.

?Advantages of Biowaiver Studies

1.???? Cost-Effectiveness: By eliminating the need for expensive and time-consuming in vivo studies, biowaivers can significantly reduce the costs associated with drug development. This is particularly beneficial for generic drug manufacturers aiming to bring cost-effective alternatives to market swiftly.

2.???? Accelerated Development: The streamlined process facilitates faster progression of brand extensions to market, enabling earlier patient access to essential medications.

3.???? Regulatory Flexibility: Regulatory agencies, including the FDA and EMA, provide clear guidelines for biowaiver applications, smoothing the approval process for qualifying drugs. This is particularly advantageous for post-approval changes and applications for generic drug products.

4.???? Ethical concerns: BCS-based Biowaiver approach significantly reduces the bio burden in humans, specifically for the oncology drug development.

Role of DMPK in Biowaivers

DMPK plays a critical role in supporting biowaiver studies. It provides essential insights into the absorption, distribution, metabolism, and excretion of drug substances, Service provider companies specializing in DMPK can drive this vertical by offering the dissolution, solubility and permeability services:

Comprehensive Dissolution, Solubility and Permeability Studies: Accurate classification of drug substances according to BCS requires detailed solubility and permeability data for API. DMPK service providers can conduct these studies using validated permeability models such as Caco-2 cell assays, to establish the permeability of drug. Further the drug product needs to be immediately released and stable through the gastrointestinal (GI) tract transit. Hence, in vitro dissolution, stability and excipient impact needs to be assessed.

1.???? In Vitro Dissolution Testing: For BCS-based biowaivers, comparative in vitro dissolution tests are essential. DMPK service providers can perform these tests under various conditions to demonstrate the similarity between test formulation/compound and reference products, ensuring they meet the necessary criteria.

2.???? Stability Analysis: Stability of the drug substance in the gastrointestinal tract is crucial for BCS classification. Service providers can perform stability studies in simulated gastric (SGF) and intestinal fluids (IF) to ensure the drug substance does not degrade significantly, thus qualifying for high permeability.

3.???? Excipient Impact Assessment: Differences in excipients can affect drug absorption. DMPK service providers can assess the potential impact of excipients on solubility, gastrointestinal motility, transit time, and intestinal permeability, ensuring the excipients do not adversely affect drug absorption.

Insights from Dr. Ansar Ali Khan

I recently had a discussion with Dr. Ansar Ali Khan, Director of DMPK and Pre-clinical Studies at Aryastha Life Sciences Pvt. Ltd., who holds a PhD in Drug Metabolism from the University of Groningen, the Netherlands. Dr. Khan shared valuable insights into the practical applications of BCS-based biowaiver studies. He has witnessed the approval of several compounds for marketing using the biowaiver approach, underscoring its effectiveness in expediting drug development and ensuring regulatory compliance.

He says “Leveraging the In vitro DMPK capabilities in a CRO set up with regulatory compliance can expedite the generic drug development process to market, thereby decreasing the need for redundant human bio studies”

"With FDA Modernization 2.0 and 3.0 focusing on reducing animal use in pre-clinical studies, there's a shift towards ex-vivo systems that better replicate the disease microenvironment for improved clinical predictability. Similarly, biowaivers offer a transformative opportunity for drug developers and ADME/DMPK service providers. By embracing the biowaiver strategy, they can significantly cut development costs and accelerate time to market, all while enhancing business viability."

Driving the Vertical through DMPK

Service provider companies can drive the BCS-based biowaiver vertical by positioning themselves as experts in DMPK under cGLP by offering comprehensive services such as Dissolution and stability of the finished dosage forms, and solubility and permeability of the API to support the BCS-based biowaiver approach for regulatory approvals for marketing authorization. They can attract pharmaceutical companies looking to streamline their drug development processes. Key strategies include:

Investing in Advanced Analytical Techniques: Utilizing state-of-the-art technologies and methodologies to provide accurate and reliable data for biowaiver applications. This includes dissolution, solubility testing, and validated permeability assays under regulatory compliance.

1.???? Building a Strong Regulatory Knowledge Base: Keeping abreast of the latest regulatory guidelines and ensuring compliance with regional requirements for biowaiver submissions. This can help in anticipating and addressing potential regulatory challenges effectively.

2.???? Collaborative Partnerships: Establishing partnerships with pharmaceutical companies to offer integrated solutions that cover all aspects of DMPK and biowaiver studies. These collaborations can lead to shared resources, knowledge exchange, and innovation.

3.???? Continuous Innovation: Developing new approaches and improving existing methodologies to enhance the efficiency and accuracy of biowaiver studies. This can involve adopting novel in vitro models, enhancing predictive capabilities, and integrating AI and machine learning for data analysis.

Conclusion

By leveraging their expertise in DMPK, service provider companies can significantly contribute to the success of biowaiver studies. This provides pharmaceutical companies with a competitive edge, allowing them to accelerate drug development timelines, reduce costs, and ensure high-quality, bioequivalent products reach patients faster. Embracing the BCS-based biowaiver approach not only enhances operational efficiency but also aligns with regulatory trends towards more scientifically justified and patient-centric drug development processes.

References

1. Amidon, G. L., Lennern?s, H., Shah, V. P., & Crison, J. R. (1995). A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research, 12(3), 413-420.
2. U.S. Food and Drug Administration (FDA). (2017). Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Guidance for Industry. Retrieved from FDA website.
3. European Medicines Agency (EMA). (2018). ICH M9 on biopharmaceutics classification system-based biowaivers. Retrieved from EMA website .
4. Khan, A. A., Aryastha Life Sciences Pvt. Ltd. (2024). Personal communication https://aryastha.com/ansar/ .
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6. Yu, L. X., Amidon, G. L., Polli, J. E., Zhao, H., Mehta, M. U., Conner, D. P., ... & Shah, V. P. (2002). Biopharmaceutics classification system: the scientific basis for biowaiver extensions. Pharmaceutical Research, 19(7), 921-925.
7. International Conference on Harmonisation (ICH). (2018). ICH Harmonised Guideline: Biopharmaceutics Classification System-based Biowaivers M9. Retrieved from ICH website.
8. Lawrence, X. Y. (2005). Biopharmaceutics classification system: the scientific basis for biowaiver extensions. Pharmaceutical Research, 22(1), 11-23.
9. Kesisoglou, F., Panmai, S., & Wu, Y. (2007). Nanosizing—oral formulation development and biopharmaceutical evaluation. Advanced Drug Delivery Reviews, 59(7), 631-644.
10. BCS and Biowaivers: Advances in Pharmaceutical Sciences. (2021). Retrieved from ScienceDirect .