Formulations of low-dose drugs require a careful balance of several factors to ensure that each dose has an acceptable blend and content uniformity. Determining the right methods and equipment specifications to pair with the selected material requires expertise across multiple areas of the development process.

When at this critical step in the drug development process, companies are faced with the question of whether to complete these activities in-house with purpose-built facilities that can be capital intensive, or to outsource the work to a contract developing and manufacturing organization (CDMO). Further complicating the choice is the wide selection of CDMO providers in the market, making it important that a customer fully understands their needs and seeks a supplier that is able to meet those requirements.

In this article, two cases are reviewed where customers had an immediate need for lower dose capsules in the clinic, which posed several challenges in blend formulation with very tight timelines for delivery, and needed to ensure greater uniformity of a pharmaceutical product. Optimized equipment and targeted modifications were applied to the formulations to solve the clients’ needs, and the analytical team aligned to deliver qualified methods to support release testing of batches of the new formulation. Working with a CDMO that has strong formulation expertise, and the best interests of the customer and end patients in mind, can bring added value in cases such as this.

 

Pharmaceutical formulation is the process where the active pharmaceutical ingredient (API) and different chemical substances are mixed to create an end-user drug product. The amount of active drug in the product varies depending on the format and expected end users of the product. Formulation studies are carried out for new drug products to verify the activity of a drug and what combination of chemical substances is needed to reach the appropriate format and dosage. The dosage should not only have a uniform amount, it should also have uniform appearance.

 

Low-dose drugs can pose challenges during filling due to physical limitations of the equipment being used and the ability to achieve blend homogeneity. When doses are low, transfer accuracy can be compromised and lead to a higher reject rate. Here, the challenge was to add components to the formulation that would not alter the potency or safety profile of the drug substance, while improving the flowability of the product during capsule filling. The use of automated equipment to maximize throughput capabilities offers flexibility in transferring specific doses to capsules, but there are some limitations.

 

An existing method for the neat powder in capsule was used as a starting point, but recovery using that method was not adequate. The team theorized that the sample diluent was not breaking up the blend sufficiently. One of the excipients, methyl crystalline cellulose (MCC), may have accounted for this by creating a complex with the API that filtered out during sample preparation. A key deliverable for the client was the development of a validated method for maintaining content uniformity using a new diluent to disrupt the complex formation. By selecting a new diluent during method development and using a ‘flood fill’ encapsulation method to accommodate the increased bulk of the formulated material, accurate content uniformity testing was achieved for the drug substance.

 

It takes expert knowledge of the chemical process in order to trace a physical limitation during manufacturing back to its chemical origin. Here, the limitations of the ProFiller ‘flood fill encapsulator’ during the filling operations were addressed by adding the glidant silicon dioxide to improve the flowability of the drug substance. This allowed the equipment to produce reliable low-dose capsules to meet the clinical demand.

 

Uniformity is a critical attribute in drug product formulation because it will ultimately impact the clinical effect on the patient by affecting drug dissolution, absorption and bioavailability. Achieving uniformity in formulation development not only has an impact on the product, it helps manufacturers to satisfy regulatory requirements and reduce lost revenue caused by insufficient or rejected product.

 

To verify that the critical attributes of uniformity have been achieved, thorough testing of formulations is critical. This helps to determine the uniformity after blending and after encapsulation with the goal of assessing the potency of the material. It also serves to demonstrate to regulatory authorities that the process is controlled to ensure the same amount of drug substance in each dosage.

 

Rather than relying on a single form of analysis, several methods were applied to ensure quality, including Karl Fisher (KF) water content and related substances methods. These methods can be redeveloped as needed according to the unique attributes of the drug substance. For example, after adding the excipients to the formulation in this case study, the water content increased dramatically. The existing KF method for the neat powder had to be modified for a different level of standard and melting temperature in order to yield valid results for the new blend formulation.

 

Chromatography was used to measure content and blend uniformity across several samples, and to quantify potency when performing the assay method. When the team detected excipient interference using the original method, they adjusted the wavelength to isolate the API.

 

In this case, the experts also developed a dissolution method for the material from scratch. Samples of the acidic media were pulled across various time points to assess the timing of drug product release while the dosage form disintegrates in the dissolution batch. Dissolution methods can be especially powerful because they mimic the drug activity in vivo.

 

All four of these methods were developed in parallel to dramatically compress the timeline and speed up time to market for the customers. With validated methods available, batch release testing was able to take place as product came off the manufacturing line, and the team was able to deliver the low-dose capsule formulation on time and on budget.

 

Every drug producer must evaluate the value of carrying out operations internally versus outsourcing to an experienced supplier. For formulation of small molecule drugs, the right CDMO can have a deep impact on the success of a drug manufacturers process, so choosing the right supplier is critical. A proper CDMO will apply expert knowledge of the root causes to address both chemical and physical challenges that customers come against during product development, and in key final phases, like formulation.

 

Beyond expertise, there are other advantages to working with a CDMO, including a drastic decrease in capital investment, elimination of transfer and scale barriers, and access to the newest technologies and methods. Where an individual company may not be able to take advantage of the latest equipment and advances, a CDMO has a vested interest in staying ahead of the curve to ensure that their capacity continues to book.

 

Not only is the choice of a supplier critical, but an often-overlooked element is the stage when outsourcing is engaged, which is more impactful than it may first seem. In today’s market, interest is starting to be expressed in supplier support from earlier and earlier in the process, which reflects the continued drive for quality by design in the industry. Smart design from the start matters, and it has become common to see companies engage CDMOs for process development in discovery phase, as well as for meeting milestones, including regulatory filing and scale-up efforts and specific needs in the clinic. This earlier engagement ultimately improves the drug product formulation process.

 

Additionally, regulatory compliance has become a more important CDMO offering because discovery-based companies often do not maintain their own regulatory affairs departments. And it remains challenging to get into early stage manufacturing without enormous commitments in personnel, training and recruitment. Consequently, regulatory affairs are an expense that these firms do not necessarily fund in-house any longer.

 

Cambrex leverages top analytical and formulation expertise with customer support to overcome challenges and meet or exceed aggressive timelines and regulatory considerations. Leadership is focused on business decisions that advance the level of support available to customers from discovery to commercial development. A global network of facilities with optimized technologies and flexible capacity helps to secure the supply chain and offer the reliability customers need for the life of a drug product.