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Q&A: Long-Acting Implants: Design for Durable Drug Delivery

Seth Forster, Merck

Q: Is the implant removable in between time?
A: The implant may be removable during or at the end of therapy. Most currently available biodegradable polymers (PLGA, PLA) degrade throughout the implant over time, so it may be challenging to remove partway through its use. Surface eroding biodegradable polymers retain more mechanical strength over time. Biodurable polymers (EVA, TPU, Silicones) will usually retain mechanical integrity in vivo and can be removed after therapy. 

Q: Can implant be manufactured aseptically using the extrusion process?
A: Implants must be made with low bioburden and endotoxin levels, usually in a cleanroom environment to avoid particulate or biological contamination. If the product is not stable when irradiated for terminal sterilization, it may be feasible to sterilize the product contact parts of an extruder, depending on the equipment’s design, and process in an aseptic environment.

Q: Can you describe the in vitro release assay shown on slide 13?
A: The in vitro release study was using an automated flask shaker incubator with a fixed volume of phosphate buffer saline (PBS). Automated flow-through dissolution and sampling systems like the USP Apparatus 7 can also be used.

Q: How much material do you need for your early investigations when you choose a suitable carrier?
A: Pilot scale extrusion batches require 250 – 500 g of total formulation, but some small scale twin-screw extruders can process with as little 5 – 10 g of formulation.
We continue to work to reduce the amount of API for prototyping. Injection molding and vacuum compression molding techniques can make prototypes for initial testing, but we do not know yet if these will predict performance at scale.

Q: What equipment do you use to cut filaments in the laboratory scale and in the larger manufacturing scale? How reproducible is the process?
A: At the smallest scale, we use a razor blade to cut while a small fixture holds the implant. Fragile rods can be placed in tubing to hold them square for cutting. At larger scale, filaments can be cut using off-line and on-line cutting equipment used for medical tubing

Q: Has the implant mfg process been used for biologics API?
A: Extrusion exposes APIs to high temperatures and high shear. Some peptides and biologics can tolerate this process, especially when isolated as solids. 

Q: For a non-degradable implant, where release is maybe more dependent on a completely connected API network, what is the minimum API loading that is often needed (if there is a minimum)? And how does this depend on the hydrophobicity of the API?
A: In our experience, a non-degradable matrix implant does have a minimum filler loading to establish a complete pore network, roughly 30%w/w. The minimum level is a function of filler size and morphology. The expected volume fraction can be estimated by percolation theory. Note that the “fillers” could be API or API and other excipients.
The loading level required for complete release does not seem to be related to hydrophobicity of the API, though there may be reduction in the release rate related to the API’s affinity for the polymer or if the API dissolves into the polymer and cannot dissolve out when exposed to fluid.

Q: How is the cutting process made? 
A: Refer to response #5.

Q: How is the microstructure of the implant determined and what parameters are used to assess the reproducibility of these microstructures?
A: We have used several imaging tools to characterize the implant microstructure. X-ray computed tomography (XRCT) has been especially helpful.
For more information: Skomski, Daniel, et al. “An Imaging Toolkit for Physical Characterization of Long-Acting Pharmaceutical Implants.” Journal of Pharmaceutical Sciences (2020).

Q: What are some of the API characteristics that would make a long acting implant delivery not a feasible strategy? Would a short half life impact this decision?
A: For a long acting implant to be feasible, the API input rate per day should be roughly 1 mg/d or less. Input rate = Ctrough x Clearance, so it is related to the potency and the clearance of the API. A short half-life, i.e. rapid clearance, means a higher input rate and more difficulty in development.

Q: Which is the better option regarding lubricants
A: Lubricants as process aides should be compatible with the formulation and biocompatible for the duration of use. Compare with other parenteral products and implantable medical devices for examples.

Q: What is the usual preclinical safety/toxicology studies usually required for long-term (> 6 months?) implants?
A: Refer to ISO 10993, Biological Evaluation Of Medical Devices for testing requirements,    depending on location and duration of use. In general, an in-life toxicology test is likely to be      required in addition to local irritation and in vitro safety tests.

Q: What is the best method for terminal sterilization of biodegradable products?
A: The preferred terminal sterilization method is highly dependent on the API and formulation. For long-acting implants, gamma irradiation is probably most often used, though other types of irradiation like e-beam or X-ray may be more compatible with biologics. The dose of irradiation is another important consideration: typically 25 – 40 kGy is used as a default, but lower doses may be justified if necessary to protect the stability of the product.

Q: Would it be great to have In-Situ forming implants compared to solid implants? Can you share a little bit on how in situ forming implants field is growing or not at all?
A: In situ forming implants are attractive, particularly if they are patient administered and biodegradable. Commercial examples are Sublocade (buprenorphine q1m) and Perseris (risperidone q1m), both using PLGA. In situ implants tend to be more porous and higher surface area so they may be more challenging to achieve drug releases beyond a month or two. 

Q: What kind dissolution media is used on slide 11 for in vitro release? And what kind of dissolution apparatus?
A: The in vitro release study shown on this slide was performed in flasks containing phosphate buffer saline (PBS) continuously gently agitated in an incubator shaker at 37°C. Alternatively, USP IV or VII apparatus can be used.

Q: How do you generate first prototypes when you work with NCE with limited availability?
A: We have used small-scale extrusion and molding to make prototypes with 1 – 10 g of API. There is more work to be done to scale this down further and confirm scalability to pilot and commercial scale.

Q: When the duration is long like 3 to 5 years, can the drug release rate decrease due to the growth of fibrous tissues around the implant?
A: Yes, this is described in the literature and occurs as rapidly as a few weeks after implantation. This phenomenon highlights the importance of in vivo testing.

Q: Most of the biodegradable polymeric implants change release profile after sterilization. Any comments?
A: Both biodegradable and biodurable polymeric implants can change drug release profile after sterilization and as a function of radiation dose. It is important to assess the impact of irradiation during development.

Q: Can you please name of all instruments required for formulation and characterization of implants?
A: This depends on many factors. The process described in the talk to make implants uses mills, twin-screw extruders, sieves, single-screw extruders, automated cutting equipment, visual inspection equipment, and device assembly equipment. Characterization involved typical wet chemistry testing, solid state characterization, and, because of the long duration of testing, specialized drug release testing equipment. 

Q: Could you please explain API physical and pharmacological properties?
A: The API’s physicochemical and pharmacological properties can impact the formulation approach in many ways. The ideal molecule would have a low dose and slow clearance. It would be chemically and physically compatible with heat, shear, and the formulation components.

Q: How do you screen for matrix + skin systems?
A: We have used a few approaches, including producing coextruded implant prototypes at pilot scale, filling core material into tubes, or layering between films of the rate-controlling membranes. These have had varying degrees of success in predicting performance of implants made at commercial scale.

Q: How does high drug loading affect in vitro release behavior of PLGA microspheres?
A: I am not an expert in this area. However, there are several literature examples of drug loading limitations for PLGA microspheres, similar to matrix implants. As the drug loading increases past a certain point, generally 10 – 30%w/w, it becomes more challenging to control the release rate with the excipients, and it is dominated by the API properties.

Q: Can you share more on how reservoir type implants manufactured and what are specific controls related to that? Any thought on implants for biologics ?
A: Reservoir systems require an integral, consistent coating without bubbles or gaps. For coextruded products, the position of the core and coating thickness can vary in an individual implant and across the batch and impact the drug release.
Biologic APIs are challenging to formulate using typical processing, though isolation as a solid with stabilizing excipients can help improve the thermal and shear processing. Gentler, lower temperature approaches are needed to effectively deliver biologic APIs over a long period.

Q: What can be the effective strategy for formulating hydrophilic drug implant?
A: Provided it is sufficiently potent, a hydrophilic API can still be formulated as a long-acting implant. For a hydrophilic API vs a hydrophobic one, the drug release is likely to be more sensitive to the drug loading and the water permeability through the matrix or rate-controlling membrane.

Q: Are there specific models of IVIVC (in vitro – in vivo correlation) that you refer to for long-acting implants?
A: An IVIVC can sometimes be made for long-acting implants based on empirical data but, unfortunately, it is difficult to predict a priori what the correlation will be.

Q: Are there differences in ease of terminal sterilization between the degradable and non-degradable implant systems?
A: Terminal sterilization, depending on type and dose, can impact drug release from biodegradable or biodurable formulations. 

Q: How many generic implantable products are on the market?
A: I am not aware of any approved generic long-acting implant products. Several products are novel delivery systems for generic APIs.

Q: What are challenges in matching release profiles developing generic products?
A: Generic long-acting injectible formulation development is challenging. Over the last few years, the US FDA has invested resources to improve technical understanding (reference 1, 2) and build predictive tools for generic development.

Q: What challenges are experienced regarding stability of API in the implants (a) before implantation and (b) once implanted? Is there a risk of degradation or other stability issues with the API molecule under various conditions and lengths of time?
A: The API should be (a) stable in the formulation, in the primary packaging that is selected, before and after irradiation and (b) stable in the subcutaneous space for an extended period of time. Some APIs will degrade at body temperature and may not be suitable for long-acting implants.

Q: What tests are used to determine if an implant is stiff enough to administer but won’t break/bend during use? Is there a range of Young’s modulus that will inform this?
A: Tensile strength and three-point bending testing can help inform the risk of discomfort, breakage, or bending, though more work is required to predict the clinical impact from these tests.

Q: Is there any requirement to generate stability data and do we have to prove bioavailability?
A: Stability data and in vivo drug release data would be required.