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.

CONCLUSION

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
amello@microtestlabs.com.

 

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