Clinical trials are extremely complex activities requiring the synchronization of many disparate functions and processes. For any pharmaceutical manufacturer, the first goal in any clinical study is optimizing clinical trial supplies, so that packaged investigational materials are dispensed to patients enrolled in a clinical trial, on time and correctly.

A number of highly specialized activities are required to coordinate, package and distribute the supplies to clinical sites so that they can be dispensed to patients in a timely and controlled manner.  These activities include, but are not limited to, project management, randomization generation, clinical packaging, labeling, blinding, supply chain logistics, distribution, return drug accountability and destruction.

As a growing number of pharmaceutical and biopharmaceutical companies outsource more of the services required for clinical trial supplies, the process can become even more challenging. As companies adopt streamlined business models and focus on their key strengths, they will not have the inhouse capacity for most or all of the highly specialized functions required for clinical trial supplies.

It’s critical that virtual companies, or companies outsourcing any portion of the process, have a clear understanding of their resource gaps, and that they partner with the most qualified organizations to ensure clinical study success. This article will be the first in a series designed to provide virtual companies, or any pharmaceutical sponsor outsourcing clinical work, with a better understanding of what’s needed to optimize clinical trial supplies.

Several disciplines are intrinsic to the Clinical Trial Supplies process and life cycle. Regulatory affairs professionals, biostatisticians, clinical operations staff, IT experts, Quality Assurance personnel, pharmaceutics, analytical and stability experts all help determine the full picture of your clinical trial.

Project Coordination
Project coordination function is the glue that connects all of the activities required for a successful clinical supplies project. A Project Coordinator with excellent communication skills and attention to detail, will be needed to handle the planning, consultation, coordination and communication tasks required.

Typically, the project coordinator will run meetings with the sponsor on a scheduled basis to review the progress of the project timelines. During these calls, he or she will provide the advice needed to make informed and sensible decisions. 

As the old saying goes, “You don’t know what you don’t know.” A good clinical supply solutions group will steer you through the process by prompting a basic list of questions that ultimately will create a clear image of what your requirements are. 

Some of these questions seem so straightforward and obvious that, taken in isolation, can be taken for granted or even overlooked.
However, they need to be looked at in the context of the overall project, and clarified at the start of any clinical project, since they will be the key to understanding the specific needs of the clinical trial involved.

There are many levels of perspective in these lines of enquiry, starting at the very highest overview and basics for trial. Examples of questions at this level could be:

• How complex or how simple is the clinical trial?
• What is the scope of work? 
• Are there key deliverables? 
• Who is responsible for what and when? 
• What are the key attributes included in the timeline? 
• When is the study to start? 
• When are the clinical supplies required? 
• What is the dosage form? 
• Has the Material Safety Data Sheet been evaluated?
• Is this a global study? 
• What type of study is this…an open study, a double blind study, a randomized study, a crossover study, a titration study, a dose ranging study? 
• What phase trial is this…Phase I, Phase II, Phase III, Phase IV?

The clinical trial protocol and the supply chain logistic requirements must be analyzed.  The project coordinator will discuss initial findings with the sponsor, and refine an understanding of the work required, to tailor a solution that meets the needs of the clinical trial and ultimately, the patient. 

Pulling Things Together
The project coordinator has helped with the interpretation of the trial requisites and you have a basic understanding of what needs to happen.

What is needed now is a team of experts to pull it all together.  Here, again, the project coordinator will be critical in pulling together all the different specialists required. He or she will secure the correct packaging components from potentially multiple vendors, relay label text and production of proofs, generate the randomization schedule, synchronize the delivery of bulk drug or comparator and confirm the process for uploading data to an IXR (Interactive X-Response) system. 

Once the protocol has been interpreted, the label proofs approved, the randomization is in place, the components are approved, the drug is received, the batch records are written and approved for use, the equipment is available, the green light is given and the packaging is underway!

Dealing with Complexity: International Projects
Now the project is underway. Flash forward, you have perfect, current good manufacturing process (cGMP)-certified clinical trial supplies. Now, all you have to do is supply 150 sites across 16 countries. Oh yes, you forgot that your product is temperature sensitive and needs cold chain refrigerated shipping (2oC to 8oC).  You may also be asking: what is a QP?

Working with you and your project coordinator, a good Clinical Supply Solutions provider will assist you through the logistical confusion of multi-country, multi-site dispatch planning.  Often, field experts will speak directly with you and confirm key project requirements, which will allow them to build up a specific program tailored to meet the needs of your product and your
recipient clinical sites. They will typically ask such questions as: 

• What are the product storage and handling conditions? 
• How many clinical sites are there?
• Where are the investigator sites located…countries? 
• Are depots required? 
• Is stability data available?
• What type of clinical labeling is required? 
• Where will the randomization come from? 
• Is an interactive Web Response System (IWRS) required? 
• Are your materials going to Europe?

Shipping to Europe requires a separate Qualified Person (QP) release. A Qualified Person is a trained and licensed quality specialist who is associated with and named on a company license that will be granted by the applicable EU regulatory health authority for that country.

The project coordinator will act as a liaison between the QP and the sponsor. He or she will be charged with collecting the essential documents needed to allow for the review of batch records and the cross reference to the specifications laid out in the Investigational Medicinal Product Dossier (IMPD) that has been submitted (and approved) by the applicable regulatory authority for each EU country hosting the clinical trial. 

What is Primary Clinical Packaging?
Primary packaging materials or container closure systems are those items that come in direct contact with the investigational drug product. An example would be a HDPE (High-density polyethylene) bottle and cap which, when filled with tablets or capsules, creates a container closure system.  This closure system stores and protects the contents from environmental derivatives such as moisture or light. 

A primary packaging activity is, therefore, one in which the drug product is placed inside its immediate container and closed from the environment. Some examples are, tablets in plastic bottles with caps, filled tubes containing a cream (also with a cap), filled pouches holding powder and heat sealed along the edges, blister strips made of a polyvinyl chloride (PVC) and foil combination, or even an aluminum/aluminum complex.

What is Secondary Clinical Packaging?
Secondary packaging is the next layer out from the primary packaging component, and is often referred to as a “kit” or “pack.”  These terms are associated with the base primary units being collected and presented in a form applicable to how the material will be dispensed at the clinic. An example would be a one-month patient kit which contains four weekly blister cards. 

What Role Do Clinical Labels Play?
Clinical labels play an extremely important role in the control of Clinical Trial Supplies and in patient compliance, providing proper instructions to help them take the medication correctly.

It is important to use the right font size so that patients can read these instructions easily.  It is also critical to use terminology that patients can easily understand. Require storage conditions for the medication can be placed on the label to ensure that the medicine remains safe and efficacious.

Key numbers or codes on the labels, which can include protocol numbers, patient numbers, med ID numbers, visit numbers, and bottle sequence numbers, should be printed on the label so that they are legible. These codes can be used by personnel in clinical packaging operations, clinical supplies distribution, depots, to aid in the handling and dispensing at the clinical site, and lastly, during drug accountability functions. 

Sponsor company information, regulatory information, quantities, content, expiration/retest dates and other information may also be on the labels. Specific label content requirements may be found in various regulatory authority documents and guidelines. 
A variety of label types with a myriad of features such as size, shape, color or configuration may be used on clinical supplies, depending on whether the package is a primary container, secondary container, or a container that may be sent to various international countries. 

If the trial is blinded, requirements must be kept in mind. Clinical labels can be designed with multiple tear-off panels for different clinical requirements. 

If a record of dispensing needs to be kept with patient records, a two-part label can be used on the patient kit. At the time of dispensing, the tear-off section of the label can be separated from the main section of the label and placed in the patient record. 
Clinical booklet labels can be used for international trials where each page of the booklet label contains the label requirements/language for a specific country. An index page helps the patient find their specific page while the cover page contains variable information. 

Clinical Trial Packaging Vs Commercial Packaging 
Simply put, there are two key differences between commercial packaging and clinical trial packaging. Typically, commercial packaging consists of identical and repeated packaging runs that are performed over and over again many times for however long the product market demands it. 

There are different regulatory requirements for the information that must be presented in or on the commercial pack, but essentially the driver behind the packaging will be the result of market research and the cost maintenance of the physical packaging components. The granting of a commercial authorization or license to produce a product is reliant on the consistent, qualified and validated processes and equipment that are required to repeatedly and exactly reproduce the product to the same standard each and every time that it is produced.

This in no way should imply that a different level of standard is applied to clinical trial packaging.  It is simply that the ultimate purpose for the product is different. 

Although large and repeated production runs may be required for the clinical trial supplies, the runs will only continue for as long as the trial is active. Their end use can often be more complicated. For instance, in multi-product titration packs, daily, weekly, or monthly packs, different treatment arms, cross-overs, all of which must be considered at the start of the project when the project coordinator initiates the planning stages of the clinical trial supply. 

The result of this specialized end product means that many clinical trial packaging and labeling operations are highly technical. Large amounts of time are devoted to planning and formulating the packaging process and converting this into a set of written instructions (the batch record) that are followed to the letter and provide all the necessary information to produce the finished item.

Often clinical trial supplies are individually unique in that they will be identified by specific numbers assigned to the trial, these are referred to as subject or patient numbers or even med IDs which are printed on the outside of the package. It’s mainly for this reason that most clinical trial packaging is performed manually or with the assistance of some form of ancillary semi-automation. 

Blinded Studies
A huge difference between clinical trial supplies and commercial packaged product is the principal of study blinding, the practice of disguising the true identity of component drug product in the finished clinical trial supply.  This anonymity of treatment (blinding) is designed to reduce bias in the observation and clinical actions during the course of the trial, which may be influenced by the knowledge of whether an active or placebo product has been dispensed to a patient. Since unintentional influence may have an adverse impact in the statistical evaluation of study results, blinding is taken extremely seriously. Every effort must be taken during the trial to protect the true identity of the assigned treatment groups. 

The concept of blinding requires that all distinguishing features of the investigational material be removed or duplicated across all treatments so that every element is identical; this can require that the material used in the study look, taste, smell and feel the same. For example, if the clinical trial supplies consisted of blinded bottles containing active capsules and bottles containing placebo capsules, all of the components and capsules need to look identical. This would include the labels on each bottle, the bottles, the bottle caps, and the active and placebo capsules.  There can be no text, no batch/lot number, or item code on the labels that can differentiate the bottles or their contents.

The most commonly used equipment reflects the type of dosage form. The machinery that is used to package tablets, capsules and to label vials and aerosol canisters is most common. However, the arsenal of specialized clinical supply equipment could include machinery for form/fill/seal blisters, blister card heat sealing, various vision systems to detect empty blister cavities in blister strips or label placement on bottles, bottle filling lines to accurately dispense product into bottles with specific quantities of tablets or capsules, and the use of UV-activated ink only visible under alternative light sources.

Specialty capabilities include those solutions for less common but still important clinical trial supply needs. Examples include nitrogen flooding capability for blisters and/or bottles where the drug product is extremely sensitive to oxygen, pouch filling equipment, the handling, packaging and labeling of ultra-cold materials, the packaging of various controlled substances or very high potent compounds. Robots can be programmed to perform a variety of tasks that can improve the efficiency and accuracy of various packaging processes.