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Clinical Dosage Form Development or an Early Approach to Achieve Peak Sales Step #1

Pharmaceutical Development continues to present many fundamental challenges when dealing with promising drug lead opportunities. This is a factor across all therapeutic areas from Central Nervous System (CNS) to oncology. In an effort to design new molecular entities which are increasingly effective while minimizing unwanted side effects we at times create drug compounds which are poorly soluble or are unstable and difficult to handle during manufacture. While these issues are primarily physicochemical in nature we further complicate the situation by not applying proven techniques during the early phase development of the clinical dosage form to be used in our development program. The thinking here being that we need to minimize early investment while conducting these early studies with the expectation to correct these interim clinical dosage form shortcomings as we approach late phase and commercialization.  This is a flawed approach and ultimately leads to product and process failures during subsequent late phase efforts. How a firm manages the initial steps during development and compound identification may maximize commercial success or set a course for a series of missed opportunities. Success is not necessarily the first to market but rather the first product to achieve peak sales and market dominance. In this series of blogs we plan to touch upon several aspects which will aid formulators, process engineers and project leaders to consider during early phase development leading to late phase and commercialization.

Clinical Dosage Form Development or an Early Approach to Achieve Peak Sales Step #2

We have begun our discussion around the early phase of compound identification and subsequent selection of a clinical dosage form.  This step of compound selection has many variants so we should consider this dimension for a moment. In a fully integrated firm the compounds are transferred to product development from the discovery group through chemical development. The other conduit is through compound purchase from partners or in some cases a firm which specializes in molecular development such as an NCE “boutique”. In any case the chemical development scientists are faced with their own challenges none the least of which is crafting a process which produces a compound with minimal by products as well as one which is econmical to synthesize. During the chemical process development phase a key decision point is reached. That aspect involves the salt selection as well as the base stable form of the compound to avoid potential problems due to polymorphic shifts in the drug substance. A balance of stability as well as by products requires careful consideration as to the salt form selected. The choice of the most economical or easier synthesis is not all ways the best selection and may result in problems during clinical dosage form development. It is not unusual to be asked to formulate a dosage form when presented with a “tar like” drug substance. While there are options one may pursue here the downside is a less the optimal dosage form and delays in bringing the drug candidate into a commercially viable posture.
Given this potential genesis for our drug candidate the formulator must be a part of the compound selection process and minimally the salt selection. All too often we are not part of this decision process and are faced with a difficult task. Having been faced with this several times I can say that we do have alternatives. If the intent is simply to prove effectiveness in humans we can take the time proven route of powder in a bottle or more commonly known as PIB. In its essence this is the most basic clinical dosage form wherein we simply load the drug substance into appropriately selected containers and supply separately a suspending agent and diluent. The clinical study center personnel suspend the drug at the time of administration to the volunteers / patients. Unfortunately we have a less than optimal dosage form but it is here that the formulator has a chance to learn about the drug substance. This enlightenment takes the form of getting insight into the physicochemical properties, micromeritics of the material since after all it needs to be somewhat flowable, stability, as well as the surface activity in suspension. Never miss an opportunity to gain dosage form manufacturing knowledge as this will pay benefits during later phases. We will continue to discuss clinical dosage form evolution from this aspect.

Clinical Dosage Form Development or an Early Approach to Achieve Peak Sales Step #3

We have been speaking about clinical dosage forms. The last form which we discussed was the time honored albeit less than optimal PIB or powder in a bottle. If we have followed good development practices in an effort to develop a knowledge store as noted by the precepts of QbD we have also gained some insight into the physicochemical properties of the drug substance. The fact is this minimalist dosage form approach works for small studies to gain proof of principle. At times, however, the study design may be large or the drug substance properties leave us little alternative. Let’s add into this discussion that we expect the dose to be reasonably large (750-1000mg). Keep in mind that in addition to the drug substance excipients will be required and will increase the loading by 30-60%. The logical next step is to consider how we may manufacture this clinical material and deliver the dose using the simplest dosage form and shortest development time to fulfill a larger clinical program. The formulator and the process engineer have several technical options. We can stay with the PIB, consider a powder filled sachet, or a hard gelatin capsule. The industry has an array of technologies to address these options. The best path to this selection is to speak with equipment vendors or CMOs who can move us down the development path. The fastest trip up the learning curve in this case is Interphex where you may not only learn about the techniques needed but also procure equipment and contract support. If we step back and consider a sachet that has material of construction that assures compatibility and stability (shelf life) and has the capability to be manufactured with a pre-measured diluent reservoir as a final dosage form our next generation PIB is now a unique and a patient friendly potentially marketable dosage form. This would fulfill the need for filling a large dose as well as for problematic drug substances. The hard gelatin capsule option offers us even more options for filling, shell composition, weight control, containment, modified drug delivery, fixed combinations (2 or more drug substances). We will take a look at these as well as the technology to get there as a clinical / marketable dosage form.

Clinical Dosage Form Development or an Early Approach to Achieve Peak Sales Step #4

If you look across many of the prescription products on the market today you will see an array of oral solid oral dosage forms with a high percentage of these dosage forms being tablets and capsules. In many cases it is reasonable to wager that the hard gelatin capsules offered by pharmaceutical firms most likely began life as a clinical dosage form. When you consider the requirements for a clinical form such as blinding, manufacture of a matching placebo, blinding of comparator agents, packaging options and ease of use for the patient the hard gelatin capsule provides a practical and technically sound pathway in our development program. Let’s consider the advantages of this technology starting with the hard gelatin capsule shell itself. They are manufactured in a wide of range of sizes to accommodate drug substance blends of various bulk densities. This allows us a reasonable degree of latitude in our formulation work for even a high dose compound along with the required excipient material.  In the manufacture of clinical supplies for blinded studies involving a comparator agent the array of capsule shell sizes and design offer a clear advantage when manufacturing these materials by over-encapsulation. These advantages   combined with the technical support provided by the capsule shell manufacturers along with their detailed understanding of the array of filling equipment available provide a great resource for the formulator.   When the formulator is faced with a poorly bioavailable drug substance or one that requires contained systems for handling in the early phase of development the understanding gained during the preparation of the clinical form will provide a sound path to commercialization. It is these aspects which we will discuss in further detail. It is intuitive that a forum where you may interact as well as source the components needed to formulate the early clinical material and required hardware while keeping the market entry in scope is to visit INTERPHEX.