Given that particle formation and spheronising technologies play such an important role in preparing oral solid dosage (OSD) active pharmaceutical ingredients (APIs) for delivery and therapeutic action, I ask the panel what solutions are being applied and whether certain methodologies can be used to improve the efficacy of emerging formulations.
SR: To improve the opportunities and potential for drug candidates with low solubility or bioavailability, we’ve seen the increased utilisation of techniques such as spray dried dispersions (SDD).
Pelletised and particalised API formulations are also serving developers and helping to manage a broad range of delivery challenges presented by today’s potent drugs.
These API formulation techniques allow for very effective fixed dose combinations as well as blends of particles engineered to control and extend release times.
All of this helps to keep dose frequencies and the number of medications required to achieve therapeutic and patient performance goals to a minimum. Inherently functional for capsule delivery, pelletised API technologies are practically purpose-built for the fill and finish of encapsulated dose forms.
JR: Multiparticulate (MP) dosage forms are increasingly favoured because of benefits such as predictable gastric emptying, a reduced risk of dose dumping, flexible release patterns and increased bioavailability with less inter- and intra-subject variability.
Within the MP “family,” minitablets are emerging as a preferred route because they are easy to manufacture and present few stability problems. Therapeutic benefits include dose flexibility and combined release patterns.
Also, the narrower particle size range and lower incidence of shape variation gives them a more predictable substrate for subsequent polymer coating and drug layering.
They are also patient-friendly systems, particularly for paediatric and geriatric populations who may have difficulty swallowing (dysphagia), as they can be mixed with soft foods. They can also be used when rapid or flexible dose adjustments are required.
KSR: Dose-form finishing requires a broad range of operations to manufacture and successfully commercialise a finished product. Increasingly, developers are seeking flexible production environments that can cope with smaller batches, higher potency APIs and other issues. What is your organisation doing to institute flexibility and resiliency into processing and manufacturing?
ML: Many traditional contract development and manufacturing organisations (CDMOs) typically produce large volumes of product and lack the expertise that Idifarma has to handle products requiring low manufacturing volumes and specific containment needs.
Safety and flexibility are our main advantages. Many highly potent drugs — most of them for oncology treatments — require the production of small batches because of low demand requirements.
In continents such as Europe with fragmented markets, our clients sometimes require a very low number of packs for smaller countries. We are able to optimise the process by customising the order during the final stages, allowing our clients to order just a few packs in each SKU.
The growing demand for highly potent and non-potent drugs is fuelling the need for high potency handling capabilities owing to the increased exposure risk, meaning that facilities must be equipped with specialist equipment, infrastructure and expertise from preclinical development through commercial manufacture.
Companies are increasingly seeking partners such as Idifarma with specialised HPAPI handling capabilities to help them develop and manufacture medicines in the safest possible conditions.
The capacity to handle highly potent compounds, including spray drying for highly potent drugs, the flexibility to manufacture small-scale batches and the ability to provide packaging — all under one roof — means that we are increasingly important for many of our drug developer customers and their products.
SR: Lonza’s CHI business division’s reputation for quality operations and advanced manufacturing environments is well established. We have tremendous capsule manufacturing experience and this extends to our filling equipment lines and the systems we engineer and sell as well.
From a supplier standpoint, our global footprint allows us to quickly respond to changing demand. Our filling technologies also provide the automation and control needed to support the flexible manufacturing environments that pharma needs to be agile, control costs and remain competitive.
New ICH guidelines1 (Q8–Q11) that incorporate Quality by Design (QbD) principles have encouraged the search for process efficiency and cost effectiveness, no matter what the dosage form, and we’ve seen a very conscious effort by developers to reduce unnecessary complexity.
This is, in part, to reduce quality risks … but also to help produce better production economies overall. Encapsulating formulations fundamentally accelerates OSD drug development because it eliminates the necessity of validating tablet form processes such as pressing and coating.
In fact, most early clinical phases are supplied with capsules because they are the fastest and most economical route to market.
Once the API and excipient formulation are validated, they’re virtually ready for human trials. The API can be directly filled into capsules and then supplied clinically. This makes capsules faster than tablets to first-in-human trial.8
Alternatively, capsules can be filled with suspensions. This may be an effective strategy to evaluate and optimise the formulation characteristics of low bioavailable formulations and another way to speed development and get promising investigational new drug (INDs) to first-in-human trial faster.
That’s part of the reason why encapsulated drugs remain so popular; they’re inherently patient-friendly because they are easier to swallow than large tablets. Plus, their form and function are both simple and familiar to pharma, most care givers and patients.
Market and patient access add to the objectives. For example, in emerging markets where nasal and pulmonary drug delivery is vital to combat prominent respiratory conditions, capsule-based dry powder inhalants are becoming a popular alternative with developers because of their simplicity, cost effectiveness and ease of use.
JR: The increased demand for small batch manufacturing and experience in handling drugs containing high potency APIs is our specialty.
With expertise from concept to commercialisation, we think strategically about a partner’s product and developing it with commercialisation in mind to save time, reduce costs and expedite time-to-market.
In the last 5 years, we have invested $100 million in our Greenville (NC, US) facility so that we can respond to varying demands from our customers. This facility was built with containment in mind so that we can move product easily through the difference phases to global commercialisation.
With regard to HPAPIs, safety is paramount. Metrics is well-versed in performing risk assessments, manufacturing and handling processes, and dealing with various finished products.
Our strong focus on containment protects operators and mitigates the risk of cross-contamination. We have and continue to consciously build flexibility and resiliency into our processes.
We’re currently building three production suites that are specifically designed for small potent batches. The rooms themselves are potent-capable with single-pass air, misting showers and one-way flow.
Our operators are experienced in dealing with process/technology transfers and choosing specialised equipment that is both right for the job and has the ability to flex and have containment options built around it.
Again, we’re investing in equipment with containment features for potent handling that is designed for higher yields and able to support small batch sizes. The new equipment can automatically test in-process samples to ensure consistency throughout the batch.
Balancing safety and containment with flexibility requires skill and experience. To this end, we can incorporate existing processes as well as use QbD principles to design processes that are robust, safe and repeatable.
We have ensured that our analytical labs are equally flexible, providing multiple techniques in one space and multiskilled scientists who can work collaboratively on any issues, be proactive to potential problems and be consistently agile in their approach for each customer.
Part I of this article can be read here.