Navigating Regulatory Challenges for Generic Inhalation Drug Products: A Strategic Approach

Pulmonary drug delivery has been the preferred route for treating respiratory conditions for over 70 years. The efficiency of delivering active pharmaceutical ingredients (APIs) directly to the lungs makes it an attractive option for both local and systemic treatments. However, developing generic inhalation drug products (IDPs) is a more complex process than developing other generic drug products (e.g. ibuprofen tablets), requiring careful consideration of formulation, as well as delivery systems, and careful regulatory strategic planning word wide.

Generic inhalation drug products must not only match the reference listed drug (RLD, US) or the reference medicinal product (RMP, EU/UK) in formulation and equivalence in performance, but also device compatibility, and patient usability need to be addressed. The challenge arises because these products are inherently combination products—integrating drug formulation with a delivery device, such as:

• Pressurized metered dose inhalers (pMDIs)
• Dry powder inhalers (DPIs)
• Nebulizers

Unlike traditional generics, where a waiver for bioequivalence (BE) may be obtained, or BE demonstrated through in vitro studies and/or pharmacokinetic studies, inhalation products require a weight-of-evidence approach combining in vitro, pharmacokinetic, and pharmacodynamic studies to establish therapeutic equivalence.

Challenges of the inhalation drug market are high competitiveness, and constant innovation through significant technological advancements. Developing a successful generic inhalation product involves:

• Matching the device characteristics of the reference product
• Ensuring stability and consistent aerosolization of the drug
• Overcoming formulation challenges related to differences in the physical properties of the formulation components
• Managing complex manufacturing processes during scale-up.
• For MDIs, phasing down of the HFA propellants provides additional challenges associated with the change to low GWP propellants
• Addressing regulatory scrutiny due to safety concerns

Furthermore, patient compliance is a key concern, as improper inhaler technique can impact drug efficacy. This makes user-friendly device design an essential aspect of development.

In the US, the regulatory pathway for generic inhalation products follows the Abbreviated New Drug Application (ANDA) under Section 505(j) of the FD&C Act. To gain approval, generics must demonstrate:

• Pharmaceutical equivalence (same active ingredients, dosage form, strength, and route of administration as RLD)
• Bioequivalence (no significant difference in drug absorption and action)
• Therapeutic equivalence (same clinical effect and safety profile as the RLD)

For inhaled drugs, bioequivalence assessments pose unique challenges, as systemic absorption does not directly indicate lung deposition. The FDA employs a weight-of-evidence model using:

• In vitro studies (comparing aerosol properties, particle size distribution, and delivered dose)
• Pharmacokinetic (PK) studies (evaluating systemic exposure)
• Pharmacodynamic (PD) or clinical endpoint studies (assessing therapeutic effect)

The FDA also provides product-specific guidance (PSG) to assist developers in establishing therapeutic equivalence. However, many generic developers face difficulties meeting PSG expectations due to formulation and device differences.

In the EU, inhaled drug products follow the Directive 2001/83/EC for medicinal products and must be approved under Article 10(1) and 10(2). Unlike the US, the concept of direct substitutability does not exist in the EU, meaning approval depends on demonstrating drug delivery equivalence, which may require:

• Comparative in vitro testing
• Pharmacokinetic studies
• Pharmacodynamic studies or clinical trials

Additionally, inhaled drug-device combinations must meet the Medical Device Regulation (MDR) requirements for device safety and performance.

In contrast to the US approach, the EU relies on a stepwise approach for demonstrating equivalence, beginning with in vitro testing and escalating to pharmacokinetic or clinical studies if necessary. This provides more flexibility but also increases regulatory complexity.

The formulation and device interaction play a critical role in ensuring consistent drug delivery. Key challenges include:

• Device Compatibility: Inhalers must provide uniform dosing and be similar in operation to the reference product.
• Particle Size and Distribution: The drug must deposition into the ling in a comparable way to the reference product.
• Bioequivalence Demonstration: Establishing equivalence beyond systemic absorption is challenging.
• Regulatory Hurdles: Varying requirements in the US and EU necessitate tailored development strategies.
• Manufacturing Considerations: Scaling up production while maintaining batch-to-batch consistency is complex.
• Market Access & Commercialization: Establishing a competitive edge in the inhalation drug market requires strategic planning beyond regulatory approval.

Celegence offers end-to-end regulatory support for pharmaceutical companies navigating the complexities of inhalation drug products. Our expertise includes:

• Regulatory Strategy Development: Tailored pathways for FDA ANDA and EU submissions.
• Combination Product Suitability: Ensuring device-drug compatibility under MDR and FDA requirements.
• GxP readiness: Ensuring GMP Inspection readiness of manufacturing sites through focused QA audits.
• Bioequivalence Study Design: Supporting in vitro and PK/PD study strategies.
• AI-Powered Literature Reviews: Leveraging CAPTIS^® for systematic data extraction and analysis.
• Technical Documentation & Submission Support: Assisting in compiling regulatory dossiers for global submissions.

At Celegence, we combine:

• Regulatory Expertise: Decades of experience in inhalation drug approvals.
• Customized Client Engagement: Supporting clients from early-stage development to post-market surveillance.
• Cross-Functional Team Support: Bringing Pharma and Medical Device experts together in regulatory, clinical, and technical fields.
• Technology-Enabled Solutions: CAPTIS^® AI-powered tools for regulatory documentation and literature reviews.

With evolving regulatory expectations, generic inhalation developers require an adaptable, informed, and technology-driven partner. Celegence provides the strategic insights and hands-on support needed to navigate this landscape efficiently.

The development and approval of generic inhalation drug products require a meticulous approach due to the inherent complexities of drug-device integration and regulatory requirements. With deep expertise in regulatory affairs and a technology-enabled approach, Celegence is uniquely positioned to help pharmaceutical companies streamline their regulatory submissions, ensuring efficient approvals in both the US and EU markets.

As regulatory landscapes evolve and the demand for generic inhalation drugs increases, Celegence continues to support companies in achieving market success with optimized strategies.

For more information on how Celegence can support your inhalation drug product development, reach out to us at info@celegence.com, contact us online or read more about Celegence’s services.