Time, quality and budget form the decision matrix
Another example of a timing risk stems from product development scientists designing formulations quickly and delaying any further product development until a later date, without correspondingly moving out the clinical start dates. Depending on the development program, the downside to such an approach lies in the risk of proceeding further along the development program without fully understanding the product. For example, a company looking at a combination product for a 505(b)2 submission performs a clinical trial using the two active materials in their current, separate dosage formats. Anticipating favorable results, the company decides that within a year from receiving the results, it would proceed with a next-staged trial with a single dosage format that contains both APIs. However, being risk averse, the decision to commence formulation and development activities is delayed until definitive positive results are obtained. This leaves the company fewer than 12 months to complete the CMC requirements for the drug product.
In a perfect world where all tools and personnel are completely at one’s disposal, experimentation can be performed in numerous parallel fashions and results are perfect and errors never occur, such a project could be accomplished. Yet reality (Murphy’s Law, to some) relates a different story. Companies begin to push their CMOs. Strongly forged relationships between the two begin to suffer, experiments do not always work exactly as planned and mistakes happen. In a rush to supply product, concessions begin to be made. A “Hail Mary” attitude may begin to creep into the scenario, and experiments that worked once are used as the basis for proceeding ahead full force.
It is a common misconception that following current Good Manufacturing Practice (cGMP) will cause unnecessary delays in the supply of clinical materials. Increased paperwork and adherence to stricter guidelines during manufacturing, packaging and testing are sometimes seen as impediments in accelerating the delivery of product for a clinical trial, particularly for Phase I clinical materials.
These CMC activities, performed in a cGMP environment, do not in and of themselves ensure that the product will pass for use in a human trial. What such environments do provide, however, are assurances that each element executed has an internal system of checks and balances which would prevent failing product to be released and used in a clinical trial. By definition, a CMO that is cGMP compliant should be in a position to ensure that at minimum
- their personnel have appropriate educational and experiential backgrounds
- equipment is installed, operational and fully maintained
- complete traceability and proper storage of ingredients, packaging components and products
- production, process, packaging, labeling and laboratory controls are present
- documentation (from formulation, through production and testing) is complete and has appropriately dated verification steps.
The extent and integrity of a CMO’s quality system should be determined through an audit performed by a company or its representative. Weak systems can significantly delay getting finished product to the clinic on time. For example, a product manufactured in equipment that has not been properly maintained which could impact the results obtained during laboratory testing. If a product is formed in an improperly installed blender that has not been maintained properly and, upon testing, aberrant blend uniformity (BU) results are obtained — is there confidence that the failing BU results are due to the manufacturing process, the formulation, the equipment, or all of these? In such a case, it may be difficult to assess; time would be lost in waiting for the blender to be re-installed and re-qualified, and for experiments to be repeated so that the impact of that particular variable could be determined.
Increased documentation also allows for an easier compilation of a development history that can be traced and understood. Having strongly documented, cGMP-compliant, supportive CMC documentation only leads to greater assurances of control — something that is viewed favorably by a Regulatory Agency. Knowing up front where the strengths and weaknesses of a CMO’s quality system lie will assist in selecting the best contractor for the company.
Clinical trials comprise a substantial cost of the overall drug development program, from hundreds of thousands of dollars for Phase I studies through tens of millions of dollars for later-phase trials. Companies, for the most part, have an acute understanding and a willingness to spend such monies. However, when it comes to the execution of CMC-related activities, many companies begin to select activities that they feel will give them the bare minimum of information required for a clinical trial application. Such decisions are often made with the desire to defer any work that has substantial costs associated with it to a time when a partnership can be formed or additional funds can be procured from investors (generally after a successful clinical trial).
Investors or potential partners of today are more sophisticated than ever before. With the increasing number of issues surrounding blockbuster products over the past decade, deeper levels of confidence in both the CMC and the clinical trial results are required. Activities delayed due to cost, and therefore not available for scrutiny by investors, may delay a potential investment or partnership.
As with the factors of “time” and “quality,” money-based decisions have a direct bearing on what can be achieved. Prudent financial officers and controllers will try to balance their budgets, although they may not fully comprehend the ramifications of certain activities. How many times have development scientists needed to explain the rationale behind making a batch to meet equipment capacity, rather than the 1,000 tablets that are required for the clinical trial?
Furthermore, finance departments may be hesitant to release funds for work that could arguably be postponed until later, again impacting the CMC activities that need to be accomplished.
Given the direct impact that CMC has on the overall clinical trial, it is imperative that companies begin to develop and integrate their CMC strategies as early in the development process as possible. To develop the best and most acceptable path is to gain an understanding and appreciation within the organization as to what it is willing to accept. The implications of such decisions — as seen through the interaction of time, quality and budget — can mitigate any risk a company needs to manage during a clinical project.
If ‘quality’ is the uncompromising factor for a company, there needs to be an understanding that the time to execute CMC tasks may take longer and that performing such activities in a cGMP environment may cost more. If ‘time’ is key, then the company itself may need to be willing to accept, certain quality responsibilities and their consequences from the CMO. The company may also need to pay additional funds to the CMO to accelerate their development process for additional staffing requirements and overtime. Finally, if ‘budget’ is the primary driver, then the organization may need to accept that CMC information for its applications and submissions may take longer to obtain. A CMO that is providing their services at a reduced cost may not have the integrity in its quality systems that would allow for confidence in Regulatory compliance.