Getting packaged investigational materials dispensed to the patients taking part in clinical trials, on time and correctly, requires orchestrating myriad activities. This is the third in a series of articles outlining specific quality concerns associated with packaging clinical trial supplies and how to effectively manage those concerns.

Several years ago, when I worked for another company, a worst case scenario played out. Incorrect supplies were shipped to an ongoing clinical trial, and we were in the middle of an investigation to determine the root cause of the error. A member of upper management burst into the room to express disbelief that supplies had been mixed up and sent to the clinical site.

“It’s simple,” he said emphatically. “You grab the supplies, put them in a box, label it and you’re done!” 

If only it were that easy. I have spent my career in supply chain/logistics for the pharmaceutical industry, both on the client and supplier sides of the industry, and this remains a common misconception. The final leg of the process presents endless opportunities for missteps and delays.

Delays of any kind are inacceptable in our business. Delays keep patients from getting treatments that they desperately need. Every step of the drug development pipeline is essential, and clinical packaging and distribution is no less so. The systems and processes exist to create a fool proof, robust supply chain, but all parties must understand what’s involved and analyze and prepare for possible pitfalls. Even the most simple blinded trial can easily go awry if the parties aren’t aware of a government approval process in a distant country, a shipment is mislabeled, or a product is allowed to expire. Introduce third-party blind, double blind and IVS/IWRS (interactive voice and interactive web response) studies and the complexity multiplies exponentially.

Labeling: Not as simple as it seems
Labeling across all of these types of studies requires detailed processes and systems to set up and handle the randomization of supplies and the labels themselves.

For third-party blind studies, in which only a third-party otherwise not involved in the study holds the key to the results, the main part of the label is blinded with a tear-off portion for the pharmacist preparing the drug to be dispensed to the patient. It’s critical to control who at the site will have access to the supplies so as to ensure that only those open to the study have access to the drug prior to dispensing to the patient. 

For double-blind studies, care must be taken to ensure the materials are adequately blinded. The finished product (both active and placebo) need to look identical. Most times, the active and placebo drugs are packaged/labeled at the same location and a blinding check is performed. However, if the active drug is manufactured at one facility and the placebo at another, a blindness check should be performed to ensure that the drug and the placebo are indistinguishable. This could mean taking pictures of the finished product from both manufacturing sites to compare the supplies, or shipping supplies to the same location to perform a physical comparison. Blinded studies that use IVRS/IWRS for randomization purposes can run into issues if duplicate randomization numbers are produced for the same protocol. When programming a double-blinded, IVRS/IWRS study, it’s important to ensure that the system has the ability to determine if a protocol has duplicated randomization numbers. 

Expiry updates across multiple locations
Some think that performing an expiry update to existing clinical supplies is a simple task as the supplies are already labeled and only the retest date on the label needs to be updated due to increased stability of the supplies. On the contrary, expiry updates are one of the more complex labeling jobs. An expiry update usually occurs prior to existing supplies reaching their retest date. Because of this, the goal is to maintain the current distribution of supplies while managing to secure the necessary approvals to re-label a portion of those supplies prior to distribution. Supplies at this point may be based in various locations: the location where the supplies were labeled, multiple country depots and/or at clinical sites. 

Let’s say that Lot XYZ was labeled in the EU. The supplies are currently located at CDMO 1, in two country depots, and ten clinical sites. If all of the supplies need to be updated, at a minimum, an expiry update labeling job is required at the CDMO, both country depots and all ten clinical sites. Additional labeling jobs may be required, depending on whether or not it’s possible to stop the distribution of supplies, and on whether or not the expiry date has already passed. If you need to continue distributing supplies and dispensing to patients, you would first try to flood the sites with enough freshly-labeled supplies to perform the expiry update at the depots all at one time. If the sites do not have enough storage to accommodate the additional supplies, you would have to update a portion of the supplies at the depot while continuing to ship the current supplies to the clinical sites. Once the portion of supplies have been expiry updated and all necessary approvals have been obtained, then your systems would have to be set up to allow the newly expired materials to ship to the clinical sites while the older portion goes through the expiry update process. 

If a company decides to pursue expiry updates, it must also consider what quality system are in place to control the distribution of updated supplies. In many cases, one lot may have supplies with different expiry dates, different QA/QP statuses and different country regulatory approvals. A portion of the supplies may then be released, while another portion needs to be placed in a different status to ensure that the supplies are not distributed until all approvals are obtained. If supplies need to be QP released, this adds additional complexity. QP stands for qualified person, and is a requirement in the EU for all products destined for human use. The most crucial factor in QP release is to ensure the necessary country regulatory approvals are obtained and supplies do not ship to that country in the interim. The company’s quality system must be robust enough to allow one lot to maintain many different attributes, while still maintaining control over the distribution of supplies to multiple locations.

The Mystical QP Release
Recently, I was approached with an unusual scenario for the packaging of clinical material in the UK. The packaging effort would utilize bulk drug that was manufactured in the US and exported to the UK.

“This material was manufactured in the US. We’ll send it to the UK, package it and then export it to Canada. There’s no way we’ll need a QP release,” my client contact said. “Will we?” 

This is a perfect example of how easy it is to take a little knowledge about the clinical supply chain distribution puzzle and extrapolate inaccurately. The scenario was rectified rather quickly. Yes, we did need a QP release; in fact we would need more than one. One would be to export the drug from the UK to Canada, but also we would need QP release for the supplies that would be imported from the US into the UK for the packaging effort. To further complicate things, in order to facilitate the QP to release for the incoming packaging materials, the QP would need to review each batch document stemming all the way back to the bulk material. The need for a QP to perform audits of manufacturing, laboratory and packaging facilities prior to the release of incoming materials can easily become a huge bottleneck to the entire process. 

It’s important to fully understand the extent of the QP network before choosing a CDMO. QP release and any other governmental requirements demand specialized resources and time.  The last thing any of us want is to be forced to explain to a study team that a start date won’t be met due to an oversight in meeting regulatory approvals that should’ve been foreseen. The following checklist has proven invaluable to me during initial study discussions. Although the checklist does not offer a roadmap on how to compile and complete each item, it does tend to engage CMC groups, study managers, and others who many have not been previously involved in a global study:

• Study Protocol
• Statement of BSE-TSE Compliance
• Stability Data (supporting shelf life)
• Clinical Trial Application (CTA)
• CTA Approval for Each Member State
• Quality/Technical Agreement
• Investigational Medical Product Dossier
• Certificate of Conformance/Certificate of Analysis
• Audit Reports (as applicable)
• Batch Records
• Artwork
• Product Photos
• QP Declaration
• API GMP Certificate
• Ethics Approval

Temperature Data: The Role of Cold Chain
The need to monitor in-transit temperature has been an ongoing topic in the industry for decades. There have been volumes written about it and entire companies created to handle the transport of pharmaceuticals. It is truly a niche market. Many of us recall—back in the day—when we would put together insulated boxes and conducted extravagant shipping studies. We would ship material to far off places, only to have the recipient return the parcel to us, where we would then review the data, tweak the configuration, and try it again until both parties were comfortable with the viable shipping configuration for the actual drug. Those were truly the pioneering days. New companies were spawned from these unsophisticated experiments and those companies took us to the next level. Now we have companies that are able to provide shipping solutions for almost any temperature range and duration the industry can throw at them.

The importance of face-to-face contact with global depot facilities
Let’s conduct a global study. Seems pretty straight forward. There are plenty of patients worldwide who are interested in participating in a clinical study. There are multiple depot facilities in almost every country in the world. Then we begin to consider custom clearances, requirements and timelines that are different in almost every country, especially if a study involves a remote country, and the situation becomes considerably more complex. To this you may add a further, fuzzier set of requirements that involve a level of mutual cultural understanding to ensure that everyone is working with the same set of expectations.

Knowing how to properly engage across cultures is the key to managing a global study.  It’s best for the study team to discuss any possible foreseen and unforeseen pitfalls of global depot management early on in the process. Then, I have found in my experience, there is no substitute for face-to-face meetings in each global depot facility, not only to audit it, but to establish a relationship with the key individuals and to get a feel for cultural expectations in the relationship.

Conclusion
I have only touched on some of the complexities of the clinical packaging and distribution processes, but enough, I hope to impart some sense of the amount of preparation and skilled understanding that go into running a smooth clinical trial.  In past years, we compensated for lack of understanding in how to account for and efficiently use clinical drug supplies by over producing material. It was a costly, imprecise and risky method. Spill over technology and the advent of focused clinical service providers have helped the pharmaceutical industry optimize drug supply in a global setting. 

The process and timelines of conducting a clinical study have been tremendously reduced in the last few years, in keeping with the importance of getting new treatments to patients as rapidly as possible. This is, after all, why we do what we do. There is a tremendous sense of pride knowing that collectively, as a team, we can harness our expertise to ensure that patients receive the care they need in the shortest possible timeframe. 

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David Dreifke is manager, global clinical supply chain and logistics at Xcelience.