The Evolution of the ‘One-Stop Shop’ in Clinical Supplies Sourcing

By Paul Skultety, Alex McClung, Ted Koontz and Damian Gant, Xcelience, a division of Capsugel Dosage Form Solutions | May 5, 2016

What does a one-stop shop really mean and is it always best for the client?

In today’s pharmaceutical market, innovation and speed-to-clinic are more critical than ever. Small companies and specialty pharma players are increasingly relied upon to deliver these important requirements within the industry. One area attracting increased focus is these companies’ outsourcing capabilities, including drug design, development and clinical supply sourcing. 

Many of these contract development and manufacturing organization (CDMO) companies are promoting themselves as a “one-stop shop,” but what does this really mean and is it always best for the client? Sure, pharmaceutical companies would like to deal with one CDMO who can address any problem statement optimally and service them from point A to point B. However, there is a wide range of product design capabilities amongst CDMO players, and an even larger range of process design capabilities, which can be critical in scaling a product concept and bringing it to market. And to optimize a product concept, a CDMO must have a range of enabling technologies to address specific problem statements, vs. stretching a single technology’s boundaries. Specialized handling capabilities are also often required, such as the case with high containment isolation. 

These factors must all be taken into consideration when evaluating one-stop shop and speed to clinic claims. 

Clinical supply sourcing is such a broad capability and involves many moving parts. So how should a client choose between potential partners? What sets each CDMO apart as a clinical solutions provider?

1. Design and Preformulation and Formulation Development
While many CDMOs have strong manufacturing roots, a smaller number have historical development, and before that, design capabilities. Effective design has dependencies on both project approach—including the ability to fully define the problem statement(s), and tailor a solution based on meeting the target product profile (TPP) and commercial objectives—as well a technology range to facilitate that approach.

Successful pre-formulation and formulation development hinges on several key factors, including efficient feasibility assessments, technology breadth for formulation optimization, and phase-appropriate equipment to accommodate early stage development work through to manufacturing the first clinical supply. 

In the early stages of the development cycle of an API, feasibility screening is critical and the supply of API can be very precious. Ideally, a comprehensive pre-formulation evaluation is completed on the API prior to the initiation of the formulation development work. This work-up includes characterizations, such as polymorph studies, pH solubility profiles, moisture absorption/desorption profiles, particle shape and particle size distribution. All of the information gathered at this stage will be helpful in the later stages of the development process.

Access to a range of technologies for addressing key formulation challenges is critical for formulation design optimization and scale-up. If a CDMO is not well versed with the range of technologies available for meeting a target product profile and addressing a given set of formulation challenges, a sub-optimal formulation may result which can cause further delays. If a service provider’s experience is primarily in using a ‘hammer’ to address a particular challenge such as low solubility, then all problems will appear as ‘nails’ potentially to the detriment of the client’s compound. 

Developing fit for purpose formulations is an important need in early stage evaluations, with formulation optimization and scale-up done after successful demonstration of feasibility. Small-scale equipment is available to do feasibility work. For some processes, proprietary lab-scale processing equipment has been developed and fabricated to accommodate early feasibility work, such as pharmaceutical spray dryers, wet milling equipment and jet mills. This equipment has proven valuable for successful feasibility assessments with minimal bulk API usage—as little as 200mg.

An additional key tool is the use of Capsugel’s Xcelodose Precision Powder Micro-Dosing System to manufacture clinical supplies for early clinical studies. There are two main approaches for developing Phase I clinical supplies for oral solids: the traditional approach and the use of Xcelodose Systems. The traditional approach requires development of a formulated tablet or capsule and necessitates a significant amount of API and time for the development of a stable formulation. There is limited ability to make adjustments if there is a change in the required dosage strength(s). The more complicated the formulation, the more time and quantity of API is necessary to complete the work. An alternative is to use the Xcelodose Systems to fill the API directly into capsule shells without the use of any additional excipients. This approach allows for more flexibility in the number of strengths that can be manufactured, using a minimal amount of API. The strength(s) to be manufactured can be changed late in the development cycle, closer to the time of clinical supply manufacture, without serious consequences. Using Xcelodose Systems also limits stability concerns, and can cut months off of the time it takes to prepare for a Phase I study. If the Phase I study is successful, then a more traditional formulation can be formulated to be ready to start Phase II clinical trials. 

2. cGMP Manufacturing
In the clinical supplies arena of cGMP manufacturing, there are many suitable platforms that can be used in the development process of an oral dosage form. The need for specialized delivery among dosage forms is now the norm. Compressed tablets are still the primary dosage form of choice but they come in many forms. Single layer tablets are developed for immediate release as well as modified (delayed or sustained) release profiles. The modified release tablet can be a matrix blend of polymer and excipients or coated in order to achieve the desired release profile. On occasion, the combination of a matrix blend and coating are required. The blend formulation can be achieved by direct blending, high or low shear granulation, dry granulation (roller compaction or slugging) and fluid bed granulation. Bi-layer tablets are also a popular choice for modified release tablets in which one layer constitutes the immediate release portion, and the second layer provides a modified release dose. The use of bi-layer tablets is also an appropriate choice for combination products in which the active ingredients may be incompatible. Other tablet forms, such as orally disintegrating tablets (ODTs) and osmotic tablets may be suitable delivery platforms depending on the therapeutic need.

An alternative to compressed tablets is multiparticulate (MP) dosage forms. The use of MP technologies can be extremely useful in targeted delivery and release rates within the body. Coated spherules can be achieved by layering the drug substance and coatings onto a substrate pellet. Various coatings are then applied to ensure release in certain targeted areas of the body. An alternative to coated spherules is sphere production by means of extrusion and spheronization (ES). ES allows the formulation of dense pellets that contain a significant portion of drug substance as part of the matrix. The big advantage of ES is the increase in drug load per pellet as compared to coated spherules. This reduces the overall pellet fill weight and ultimately the size of the capsule, which is desirable for patient compliance. Another multi-particulate technology is lipid multiparticulates (LMP). This involves dissolution of the drug substance in a lipid matrix, which is then transformed into pellets through a melt-spray-congeal process. LMP is especially beneficial for improvement in bioavailability and offers high drug loading. LMP spheres can also be coated for additional release control. MP and LMP coating is achieved through the use of bottom-spray (Wurster) insert contained within a fluid bed processor.

All MP platforms can be encapsulated into a standard two-piece capsule or filled into a sprinkle capsule for pediatric and older adult applications where dysphagia may be an issue. It is also possible to fill multiple pellets within a single capsule to achieve the desired dosing. Other capsule-filling options include powder, pellets/powder, tablet/powder and micro-dosing of powder. Another unique approach is liquid fill into a hard two-piece capsule. For more challenging molecules, it is possible to dissolve or suspend the API within a simple lipid-based matrix and fill this mixture into a two-piece capsule. The capsule can also be filled using a hot-melt formulation, which solidifies at room temperature. Once the capsules are filled and closed, they are sealed using liquid encapsulation micro-spray (LEMS) or banding process. The liquid-filled two-piece capsule is beneficial for improving drug bioavailability.

3. Quality
From a quality perspective, there are three areas related to clinical supplies sourcing where CDMOs differentiate themselves.

The “little c”: The little-c in cGMP represents the notion that the industry and regulators will never be satisfied with the “current” state of business. Pharma quality is always trying to keep up with or drive the next incremental improvement.  The sharp operators will try to advance the little-c to create competitive advantage, and there exists a dynamic tension between industry and government as to who is going to define the new standard.  Serialization and DSCSA is a great example of the little-c, and how industry and regulators are advancing these standards. 

Rich and diverse regulatory landscape: The complex regulatory environment drives the industry to default to the highest standard, not the minimal or least burdensome approach. The reality of the CDMO business is it must operate at a global level to remain competitive, and harmonize policies, procedures and practices to comply with multiple regulatory standards. Where those standards overlap, leading CDMOs are taking the most conservative standard and creating policy to meet that standard. Where standards do not overlap, these CDMOs are creating new policies to comply with those unique requirements associated with a single market. 

Control of outsourced processes: As CDMOs become more specialized and more technically competent in certain areas, often the outsourced projects are already outsourced. Higher risk outsourcing includes contract labs and subcontracted manufacturing/packaging/distribution operations. Ensuring these are under control requires both a high-touch, look-often philosophy. Convincing clients and regulators that outsourced processes are under control necessitates extensive and frequent documentation and a demonstrated willingness by the CDMO to walk away from a supplier that can’t manage its expectations.

4. Packaging and Labeling
Specialty companies like Capsugel bring a similar range of capabilities to clinical supplies sourcing. Xcelience deliberately chose the term clinical supplies solutions over service because it firmly believes that its team of clinical packaging professionals brings much more than just a service to a project. Clinical supply is more than simply putting a sticker on a bottle. It requires a wide range of skills to make the most efficient and compliant patient supplies.

The solutions provided are based upon interpretation of the protocol and the construction of a comprehensive project plan that incorporates elements such as label design, text translations, component selection and carton/insert/wallet arrangements, in addition to essential platforms such as the randomization, temperature conditions, and sensitivity to light. To help support temperature-sensitive products, secondary packaging under refrigerated conditions (2°C-8°C) is available to minimize time outside of this condition. 

A large feature of this ability is moving bulk product, literally hot-off-the-press, from the manufacturing room directly to the packaging group under a conditional release. This conditional status allows the movement of material forward, but also prevents it from inappropriate issuance or dispatch. This feature drastically reduces overall timelines because there is no time lag between bulk product manufacture and packaging of finished goods. The packaging can be completed and the product approved for release to meet even the most aggressive timelines. 

In choosing a CDMO for clinical supply sourcing, pharmaceutical companies should evaluate the strength of their potential partner’s capabilities across each of the design, development and manufacturing phases. Partners with deep experience and know-how specific to design and development, as much as manufacturing, should be preferred. Further, partners with a depth of technology capabilities to address certain problem statements—including solubility issues, site delivery and pediatric dosage forms for oral solid delivery—and the ability to commercially manufacture those technologies, will likely help lead to the best possible product outcome. The “one-stop shop” is a worthy partner, but only if the CDMO truly lives up to that name. 

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