52 Perspectives: “Key Success Factors in Contract Manufacturing Small-Molecule Drugs”

2. What are some of the processes you’ve developed that help reduce manufacturing costs?

Now, more than ever, pharmaceutical companies are struggling to do more with less. Even amidst uncertain funding or an emphasis on late stage products, companies need to show progress with their early drug development candidates. Contract manufacturing partners can really make a difference in helping clients work smarter by providing solutions that both accelerate drug development and reduce project costs. For this reason, we focus on providing solutions, not just services. Xcelience offers a number of defined formulation development and manufacturing programs that enable a faster, more cost effective path to proof of concept, in some cases reducing time to first-in-human by 45% relative to traditional formulation development, while at the same time reducing project costs.

Sometimes it’s necessary to scale down rather than up in order to serve our clients best. Earlier this year, we expanded our GMP manufacturing capabilities to include a small-scale batch manufacturing line, and added the same capability under non-GMP or experimental conditions to enable formulation development and clinical supply manufacturing on a smaller scale. By purchasing a low-volume feeder, the Diosna P1-6 High Shear Granulator and the Vector LD CS, Xcelience was able to deliver a manufacturing solution to clients with limited API, saving them time and money, without compromising quality.

3. Where are you investing money in new state-of-the-art equipment and what benefits will you realize from this investment?

Having the right equipment and acceptable capacity are table stakes in the contract manufacturing world, but I will always argue that equipment alone can’t deliver lasting advantage. Xcelience adds innovative equipment where it makes sense to meet customer needs, but we believe it’s our unique combination of expertise, innovative equipment and quality systems harnessed together that provides sustainable competitive advantage.

The investments we choose are strategic. Here’s an example: Xcelience was the first US CRO to implement the patented Xcelodose® 600 precision micro-dosing system which fills API directly to capsules enabling clients to accelerate speed to Phase I studies. Later, we were one of the first CROs to implement the new Xcelodose® 600S series. Today, our Xcelodose® systems are in near constant demand, running full-time and we’ve earned the reputation for being the most experienced service provider of API into capsule services having processed more than 30 APIs and 100 batches. (Xcelodose is a registered trademark of Capsugel BVBA).

In addition to investing in equipment that accelerates drug development, Xcelience also invests in equipment to improve compound knowledge, reduce material costs, and expand client options. Our XRD (x-ray diffraction) instrumentation enables us to provide physicochemical tests at the prenomination and lead optimization stage that maximize the probability of compound success. For analytical services, our investment in UPLC instrumentation helps to reduce project costs by minimizing solvent requirements. Finally, our Micron TF1 Blister Packaging Thermoformer (complete with In Pack) provides another important option to meet the unique challenges of today’s demand for manufacturing and packaging of clinical trial materials in both GMP and experimental settings.

4. Tell us about recent authorizations and certifications by government agencies and how they have affected your business

There is a growing focus on Quality by Design (QBD), which will force a change in how products are designed and developed. The intent is to develop a close integration of the three key elements of any product: API, quantitative formulation and the manufacturing process. In essence, QBD is an approach that can be used for attaining quality through careful evaluation of all attributes that characterize product quality from early development through the product’s lifecycle. QBD involves making decisions based on knowledge and sound science. This will allow for identifying critical process parameters and quality attributes of the product and how they relate to the product’s purity, quality, potency and in vivo performance. This will mean it’s necessary to identify critical process parameters and quality attributes. It will be necessary to collect enough data to define the design space for every critical parameter in the process. This approach must start with the selection of the excipients and never really ends. The goal is to even have continuous improvement once the product becomes commercialized.

5. Tell us about a new pharma customer success story from the past year Early Accelerated Stability Studies

Some drug substances are sensitive to the presence of water vapor or moisture. When a drug substance interacts with moisture, the water is retained by either bulk or surface absorption. Moisture absorption can affect the stability of the drug substance depending on how strongly the water is bounded. This depends on whether the water is in a free or bound state. Moisture can also cause a salt form to break down or disassociate leading to undesirable properties and stability concerns. Selecting the most stable solid form prior to the GMP batch of active pharmaceutical ingredient has the potential to facilitate subsequent drug development. In a recent project, we designed a set of customized accelerated stability conditions so that, within a very short period of time, our client had data, which allowed them to select between two different solid forms to identify the lead candidate with the highest probability of success. This minimal up-front investment could save numerous days lost to issues that might have arisen in downstream process or manufacturing phases by selecting the sub-optimal candidate that possesses stability issues.

Our Strategy: Two different solid forms were subjected to high temperature and high humidity for a pre-determined period of time. Each form was tested by chemical and physical means to determine any change from their initial results.

Xcelience Methods: The two different forms were analyzed by use of X-ray Powder Diffraction (XRPD), High Performance Liquid Chromatography (HPLC) for assay and related substances data, Visual Appearance and Thermal Evaluation. TGA evaluation is quite useful in determining hydrate formation. DSC, coupled with XRPD, may help in determining shifts in melting temperatures due to drug substance and moisture interactions.

The End Result: In a shorter period of time than with a classical or typical stability program, we were able to determine the lead candidate as one that was less hydroscopic and more stable (e.g. less likely to form a polymorph, since material sensitive to change in temperature can cause this). Accelerated stability studies may also be used to determine the best storage conditions.

6. What suggestions would you make to pharma professionals about researching and new development and manufacturing partners?

Drug development is both an arduous and nimble act, with each step requiring an agile, expert, customer-driven contract provider. Everyone talks about partnership, but at Xcelience, we talk about joint ownership. For as long as a project is in our hands, we feel that we are, together with our client, jointly responsible for its success.

Joint ownership means that you and your outsourcing team should feel the same sense of urgency and responsibility. Your CMO should make you feel like its lab is an extension of your own facility through close project communication, dedicated equipment, or FTE programs. Your people should be allowed in their plant, or transfers should be coordinated.

Joint ownership means the CMO understands that you may be working with limited funding, a challenging molecule or an accelerated timeline. So you need the right technology at the right place at the right time, not just some canned solution.

Finally, joint ownership means that your CMO will measure performance in the context of your goals, not its own. It should pick the right people with the right expertise in order to foster a culture of responsiveness and to deliver solutions that speak to all levels of your needs.

About Xcelience

Xcelience is an early development contract research organization focused on formulation development, preformulation services, analytical services, and clinical trial manufacturing. Xcelience was the first CRO in North America to implement 2 Xcelodose Precision Micro-Filling System encapsulators which fill API directly to capsules. Xcelience recently added new preformulation services with an XRD and expanded packaging capabilities to include a Blister Packaging Thermoformer machine.