Thank you for attending our webinar. The full questions and answers from the session are available below. Our experts are ready to support you with your formulation challenges, if you have any further questions, please contact us.

- Does the term "biologics" in this seminar include regular antibodies?
- Are these devices relevant to critical care patients, such as those with ARDS? Are they used for self-medication (inhalers) or can they be administered via intubation?
- Can you observe high circulating blood levels that are relevant to the treatment of non-lung diseases?

The majority of the content in this webinar reflects the latest literature, which in turn is dominated by protein-based therapeutics, including antibodies.

However, it should be noted that systemic delivery of a monoclonal antibody (mAb) does pose specific challenges, resulting in very low bioavailability. It is important to consider that the bioavailability may still be higher than that of oral delivery, but this would depend on factors such as the molecule, formulation, etc. 

- I am particularly interested in the effect of degradation of biologicals for respiratory delivery. Could you provide an overview of technologies capable of creating aerosols for the inhaled delivery of biologicals?

In general, the technologies used for creating aerosols for inhaled delivery of biologicals include systems that generate aqueous droplets, such as nebulizers and soft mist inhalers. There are also systems that create an aerosol through the use of a propellant, like pressurized metered dose inhalers. Finally, there are systems that directly create an aerosol in a dry state, known as dry powder inhalers. Each of these technologies has its pros and cons. Several reviews on this topic can be found in the literature:

1. Cataldo D, Hanon S, Peché RV, et al. 'How to Choose the Right Inhaler Using a Patient-Centric Approach?' Adv Ther. 2022;39(3):1149-1163. doi:10.1007/s12325-021-02034-9

2. Sanchis J, Gich I, Pedersen S; Aerosol Drug Management Improvement Team (ADMIT). 'Systematic Review of Errors in Inhaler Use: Has Patient Technique Improved Over Time?' Chest. 2016;150(2):394-406. doi:10.1016/j.chest.2016.03.041

- What are the challenges of conducting clinical trials in respiratory products? What criteria will you use for evaluating CRO selection?

Clinical trials are inherently complex and expensive regardless of the nature of the study. Respiratory products present their own set of challenges, particularly in terms of variability in delivery. In trials involving intravenous infusions, for instance, you have precise control over the contents and dosage of the administered fluid. However, with respiratory products, you not only need to formulate the correct size but also ensure accurate delivery of the formulation at that size. Inhalation devices introduce variability in delivery, making it crucial to understand how patients interact with the device.

A person who effectively inhales medication using a dry powder inhaler (DPI), for example, may receive a drug dose that is 4 to 6 times higher than someone who poorly inhales using the same device. This variability in dosing often poses the most significant challenge. Smart device technology, while not always applicable to the marketed product or trial objectives, can provide valuable orthogonal data during the clinical trial stage. It helps assess the actual drug dose received by patients compared to the intended dose.

Thus, the key challenge in respiratory trials, which sets them apart, is determining the actual dose a patient received. 

- What is the optimal molecular weight for an inhaled antibody for local delivery? And what about monoclonal antibodies (MAbs) where systemic concentrations are also required?

There is no universally optimal molecular weight for inhaled antibodies, as it depends on the specific molecule and delivery system, and potentially even the region of the lung where it is deposited. However, in the literature, there is often a dividing line around 40 kDa. Above this molecular weight, achieving systemic delivery becomes very challenging unless there is a specific transport mechanism that can be exploited. 

- How relevant is the engineering of the particle's size and shape to ensure the robustness of the final formulation?

Aerodynamic particle size distribution (APSD) has long been known to correlate with lung deposition. Although there is some nuance to this statement, it is clear that APSD is a crucial characterization. The shape of particles also plays a critical role in powder behavior, such as flow, as well as the deposition profile. The relationship between geometric particle size distribution (GPSD) and APSD is typically defined as follows:

D_ae = D_g √((ρ_p/(ρ₀.X)) )

Where
D_ae : Diameter (aerodynamic)
D_g: Diameter (geometric)
X : Shape factor
ρ_p/ρ₀: Density (normalized)

However, it should be highlighted that the relationship is not as simple in reality, and APSD should be confirmed experimentally, along with other in vitro tools. If you are dealing with variable morphology in your development, using more advanced in vitro-in vivo correlation (IVIVC) tools may also be warranted at an earlier phase. 

- How does pulmonary delivery of biologics in inhalation therapy enable high bioavailability and reduce off-target toxicity in other organs?

Intravenous administration ultimately offers the highest bioavailability. However, there is often a preference for alternative administration routes to alleviate the burden on patients and healthcare systems. These alternative routes are collectively referred to as patient-friendly dosage forms, and inhalation therapies are one such possibility.

Inhalation is particularly appealing to patients as it is needle-free and can be self-administered at home without the need for a trained professional (with some exceptions). Moreover, the lungs' high surface area and relatively drug-friendly environment, in comparison to the gastrointestinal tract, make it an attractive pathway for both systemic and local drug delivery.

- What is the major manufacturing challenge for respiratory biologics from a regulatory standpoint?

It is somewhat subjective and depends on the specific technology involved. For instance, if you are aiming to deliver an expensive mRNA molecule through a spray-dried formulation, yield could be the primary concern due to the high cost of bio-molecules involved.

In general, based on my experience, handling powders within the size range required for achieving pulmonary deposition poses significant challenges. 

- Please provide further details on respiratory delivery for peptides. 

Peptides and small proteins (typically defined as species containing 40 amino acids or fewer) have been extensively documented in scientific literature. The main challenges associated with peptide therapeutics, in general, include their in vivo instability and low membrane permeability.

That being said, peptides are considered one of the more promising biomolecule classes for respiratory delivery, both for local and systemic administration. Their utilization has been extensively studied and successfully formulated, both in academia and commercial products (for instance, insulin is a small protein).

When considering systemic delivery, the lung offers higher bioavailability. In the case of insulin, this results in more rapid absorption and clearance, facilitating patient monitoring.

Regarding formulation for respiratory delivery, peptides can be stabilized using various approaches, such as incorporating sugar glass technology. Furthermore, depending on their specific structure, peptides can be produced in a crystalline formulation.

- What about powder dosages in terms of mg? Is there any evaluation of capsule filling technology?

Although this topic goes beyond the scope of this talk, we may include it in future discussions.

In brief, various equipment vendors have demonstrated the possibility of achieving very consistent fill masses with powder weights as low as 10 mg, with less than 1% relative standard deviation (RSD) (specific to the formulation). However, there is also a need to work with much higher powder doses, such as in the case of antibiotics.

While the majority of devices are designed to deliver 10 to 25 mg, there are also devices capable of delivering 50 mg or more. However, the use of higher powder masses should be carefully considered at the beginning of a program, as there are risks associated with delivering high doses to the lungs, especially in compromised patients. 

Could you further highlight the use of Soft Mist Inhalers (SMIs) as an alternative solution to nebulizer devices for delivering biologicals? What is your experience in this field?

SMIs offer a gentler aerosol generation mechanism compared to traditional nebulizers, making them an attractive alternative for drugs that may be sensitive to degradation. Nebulizers operate by applying shearing forces, which can potentially harm the molecular integrity of biologics, rendering them particularly vulnerable.

The development of formulations for delivery via SMIs is an emerging area, and as more generic options become available, this trend is expected to expand. The combination of accurate dose metering and fine droplet distribution in SMIs is considered highly beneficial when seeking the most efficient way to administer expensive drug substances. 

- What are the preferred devices for delivering biologics in respiratory applications?

The choice of devices depends on the specific intended use. We will focus on dry powder inhalers (DPIs) as an example:

For some therapies that only require a few doses, traditional multi-dose devices used with asthma or COPD medications may not be as relevant. However, for applications such as antibiotics that often require higher doses, having a device capable of delivering 50mg or more of powder may be advantageous.

In the case of lung cancer treatment, regular daily dosing may be necessary, and a device similar to current asthma/COPD devices, capable of delivering a powder mass of 20mg, could be suitable. In situations where there is a strong dose-response sensitivity or addiction risk, the preference may be for a "smart" device that provides rapid feedback to patients or clinicians (although this may be less relevant for biologics, such as pain medications).

Smart devices can also be advantageous during clinical phases. Price is a significant factor in some regions, but typically, wealthier nations are the first to adopt these technologies, with the vaccine market being an exception.

As you can see, selecting an appropriate delivery device for your development requires careful consideration. Other delivery devices can also be considered, taking into account the intended therapeutic use, dose requirements, patient handling and compliance, research phase (where applicable), and, importantly, the molecule's ability to withstand potential high shear forces involved in the drug delivery system. Structural breakdown and loss of activity should be studied to identify the most suitable delivery device. 

- For excipients that are well established in other dosage forms, such as oral solid dosage, but have not been used for inhalation route, they are considered novel by EU/US authorities. What is the regulatory view in other regions? Are they still considered novel?

This is a good question, and we have local regulatory experts who may be able to provide more specific support on an individual basis if needed. Here is our opinion:

In general, for inhalation products, regions outside of the EU/US tend to follow the lead of the FDA with a similar or slightly relaxed approach, even if the local market is less developed. This trend was also observed in the approval of generic inhalers for asthma and COPD (although I am oversimplifying).

In most cases, even if an excipient has established safety data for oral/parenteral/topical use and is listed on the FDA Inactive Ingredient Database (IID) for those applications, its use in inhalation products will likely require a comprehensive risk assessment, toxicological studies, and, if not monographed, a type IV Drug Master File (DMF) or a local equivalent. This has been observed with excipients such as polysorbates, cyclodextrins, and others (based on internal research).

The regulatory landscape for inhaled biologics is evolving. The approvals of Exubera, Afrezza, and Inbrija have helped establish some precedents, but it's important to note that two of these are very small biomolecules and one is an amino acid, so they may not be fully representative.

Both industry and regulators are learning in this area, so my best advice is to consult early and regularly with the regulators, especially regarding devices, potency assays, in vitro-in vivo correlation (IVIVC) tools, or any novel technologies. Clear alignment on these topics can be very beneficial, especially when responding to a Complete Response Letter (CRL), for example.

When measuring the potency of a drug as a quality control attribute, absorption in the body is not taken into account. It simply reflects the effect of a specific amount of the product in a vial on the bench, not inside the body. Although cellular assays can be used to attempt to model absorption or efficacy in the lung, they are not directly related to the definition of potency.

- Is it common to micronize APIs alone, or do you mix the API and pharmaceutical excipients before micronizing them at the same time? I am wondering if this could have a significant impact on aggregation and size control during formulation. Please let us know which method is more common.

For small molecule APIs, it is common to micronize them alone. However, in some cases, micronization may also be performed in the presence of excipients such as magnesium stearate.

When it comes to biologics, as discussed in the webinar, micronization would not be my preferred approach when developing a technology platform. Biologics are sensitive to stresses like shear and heat, making it unlikely that their potency can be maintained through this process. However, there are some examples where micronization of biologics has been achieved with some success.

- Can sucrose or trehalose be used for inhalation?

Both sucrose and trehalose are non-reducing sugars with a good safety profile. In contrast, lactose is a reducing sugar and can interact with biologics through Maillard reactions, leading to the formation of covalent aggregates.

Trehalose, in particular, shows great promise in protecting and stabilizing biologics during processes like spray drying. However, it is important to note that trehalose is not a magic bullet, and other excipients, such as shell formers, are likely needed to achieve optimal stability and protection for the biologic.