Manufacturing clinical trial material (CTM), and the costs for the associated fill/finish and release work, most likely are not the costliest portions of the pharmaceutical process chain. But delays in starting the 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 today on timely CTM manufacture (to keep clinical protocols on time and on budget), many companies are looking for cGMP contract manufacturing organizations (CMOs) that can 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 must 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 a CMO that does not have comprehensive capabilities in-house and readily available will add unnecessary time in the CTM process. The customer must perform a GMP audit of the CMO, plus all of the other companies (formulators, laboratories, labelers, etc.) the CMO uses in the supply chain. This will add significantly to the overall cost and time for the technical transfer of the product.
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.
Some limited-capability CMOs are adding testing and other functions to create a more streamlined process. But this involves more than just installing the equipment and setting up testing methodologies. They may lack the expertise necessary to perform the tests quickly and correctly. In addition, limited-capability CMOs frequently struggle with keeping a laboratory staff occupied due to the lack of work in a certain process. Pharmaceutical testing requires a high degree of knowledge. A full-service CMO with an in-house specialized laboratory performs this work on a routine basis and has accumulated significant experience that will pay off in time and cost.
THE QUICKEST PATH TO SUCCESSFULLY RELEASED CTM
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.
Working with a full-service, experienced CMO is the quickest route to successfully released CTM. To help illustrate this principle, let’s review the CTM process from the first steps through the completion of an early-stage clinical final drug product (FDP).
I. RAW MATERIALS
All raw materials used in GMP manufacturing for clinical material will need QC inspection and QA release. Starting 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 that 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.
II. IN-PROCESS TESTING (DURING THE FORMULATION STEP)
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 cost 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.
III. FINAL DRUG PRODUCT
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 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 having a fully capable laboratory directly tied to your clinical trial manufacturing organization. This allows for a more streamlined process and directly impacts the overall timing of a product release on a tight clinical program schedule. Today’s 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.
About the Author
Alex Mello is Director of Project Management, Manufacturing, for Microtest Laboratories. Mr. Mello’s 15 years of experience span Aseptic Fill/Finish, Microbiology, Method Transfer, Stability of Drug Product, Medical Devices/Combo Devices, and Sterilization Sciences. He holds a graduate degree in Biological Sciences and is a Specialist Microbiologist (NRM). To contact Alex directly, contact 800-631-1680 ext. 121 or firstname.lastname@example.org.
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