Manufacturing clinical trial material (CTM) — along with the associated fill/finish and release work — is usually not the costliest portion of the pharmaceutical process chain. But delays in starting a clinical trial can make the most dogged project managers wince in pain. As they approve a change order for the delay, they know a gap has been created in the project’s timeline and budget.

With the intense focus on timely CTM manufacture to keep clinical protocols on time and on budget, many pharma companies turn to cGMP contract manufacturing organizations (CMOs) to perform all of the required processes needed to release their material for clinical trial use. These processes include excipient and API release for GMP manufacture, formulation, in-process testing, environmental monitoring, filter integrity testing, and final release testing. CMOs with the most capability and flexibility can produce CTM much quicker than those that subcontract the work to an approved GMP testing house. Their expertise and expansive services portfolio allow the product to be released faster to the clinic, minimizing any impact on the timeline and cost of the specified clinical protocols.

Selecting the wrong CMO with which to partner may result in time-consuming and costly ramifications to CTM production and release.

A CMO that does not have comprehensive capabilities in-house and readily available can add unnecessary time in the manufacturing and release process. In these cases, manufacturers must perform a GMP audit of the CMO, plus all of the other companies (formulators, laboratories, labelers, etc.) the CMO uses in its supply chain. This will add significantly to the overall cost and time for the technical transfer of the product.

A limited-capability CMO that has added testing and other functions to create a more streamlined process may have the equipment and testing methodologies in-place, but pharmaceutical testing requires a high degree of knowledge. Does the lab have the expertise necessary to perform the tests quickly and correctly? Some CMOs may struggle with keeping a laboratory staff occupied due to the lack of work in certain projects.

 Conversely, a CMO that has all of the required capabilities in-house will enable more rapid response time and greater project control. For example, obtaining in-process testing results may require 24 hours if performed by an outside lab. But these tests can be completed in the same day if processed by the CMO’s lab. In addition, if there are time or temperature constraints on the formulation process, then faster turnaround for the in-process testing becomes a necessity, since the material cannot go through a waiting period.

In addition, a full-service CMO with an in-house specialized laboratory performing such work on a routine basis likely has accumulated significant experience that will pay off in time and cost. Moreover, CTM is difficult to schedule since it revolves around the clinical program’s start time and is tied to its success. A CMO that meets the production schedule can minimize potential restart activities.

Due Diligence in CMO Selection
When selecting a CMO partner for CTM production and testing, apply due diligence to the process by focusing the effort on a review of the CTM process itself — from the first steps through the completion of an early-stage clinical final drug product (FDP). The chart below illustrates some of the criteria:

Raw Materials
All raw materials used in GMP manufacturing for clinical material will need QC inspection and QA release. This starts with the container closure system; the glass, stoppers, and crimp caps need to be inspected for defects and for dimensional state. These activities are performed by a trained QC analyst who should be found at CMOs with qualified in-house QC laboratories. Excipients used in the manufacture of clinical material will need to be minimally assessed for identity. Typically, FTIR is utilized unless there is a USP/EP test for identity in the monograph. A CMO’s fully operational analytical department has the flexibility to test for all different types of assays, including wet chemistry. With a standing GMP laboratory on site, there is a major gain in time since the samples do not need to be sent to a third-party lab for analysis. When samples are shipped off site, many things can occur that slow down the release process. Samples can get compromised during shipment (lost shipments, sample exposure/contamination, etc.) or at the external testing facility, and lab turnaround times may not fit the production schedule. The bottom line: when samples must leave the CMO, there is a loss of control that frequently results in delays and inefficiencies.

In-Process Testing (during formulation)
For in-process testing of any formulation, it is critical to have assay capability at the CMO. In-process testing can range from simple procedures, such as pH or osmolality, to complex, such as HPLC or GC. In-process testing at the clinical stage does not require a full validation program, but the assay must be qualified. Obviously, one does not want to fill/finish a formulated FDP when the formulation is not correct. This will result in too much time, effort, and money being spent.

Having the testing capabilities in-house provides attractive benefits. The assays can be tested quickly and results reported rapidly so as to not hold up formulation and fill/finish activities. The samples are kept on-site, are available for immediate testing, and there are no issues with integrity. Additionally, if there is an assay problem (out of specification or assay failure), it can be addressed immediately and steps can be taken to determine root causes in real time. Typically, while in-process testing is underway, the formulation is being mixed and awaiting test results in order to move forward with the filling process. This represents a critical “go/no-go” step in the process. In fact, there may be several of these steps, depending on the formulation.

Final Drug Product (FDP)
The FDP testing = release of the FDP = distribution to the clinic. Therefore, the testing needs to be performed in an expeditious and fully compliant manner. A fully capable CMO has the ability to test and release the FDP under GMP conditions. By having the laboratory on-site, these tests can be run immediately after fill/finish is completed. The test data can be reviewed and the Certification of analysis (CoA) can be issued within a very short time. This capability allows for quicker release of the FDP and faster shipments to the clinical sites in order to meet the needs of the client. Additionally, it allows for the client to perform only one audit for both manufacturing and testing, which is a benefit from both a cost and time savings perspective. FDP tests for clinical trial materials must be qualified or validated to provide the confidence the assays are robust.
 
There are major value-added components of partnering with a CMO with fully capable in-house laboratory resources and expertise directly tied to a clinical trial manufacturing organization. Doing so allows for a more streamlined process and directly impacts the overall timing of a product release on a tight clinical program schedule. Pharmaceutical firms operate in a highly competitive market. For companies and their investors, being first to clinic represents a valuable first step moving products forward in the pipeline and onward to final revenue generation. Employing due diligence to ensure the selection of the right CMO partner is a critical element in that achievement.

---

Alex Mello is director of Project Management, Manufacturing, for Microtest Laboratories, a provider of testing services and contract manufacturing for medical devices, pharmaceuticals, and biotechnology. He can be reached at amello@microtestlabs.com.