Clinical Trial Supplies - Planning the Perfect Packaging
By Dr Sue Miles, Director, Clinical Trials Services, Brecon Pharmaceuticals Ltd

Dr Sue Miles is the Director of Clinical Trials Services at Brecon Pharmaceuticals Ltd, a leading outsource services provider to the pharmaceutical industry.

Sue is a graduate from Cambridge University with a PhD from the Faculty of Medicine at Edinburgh University. She was previously Chief Executive of Quantum Research UK, which provides electrocardiography, respiratory and blood pressure monitoring support for the clinical trials industry.




The scope of a clinical trial can be vast, with some complex studies enrolling thousands of patients in several countries around the world. Naturally, in practice, the patients are the priority for the sponsor and the packaging process generally has to fit in with pre-set targets and time scales. However, the design of a clinical trials pack can be fundamental the success or failure of the trial. This article provides an overview of the issues that should be considered when designing the perfect packaging solution for clinical trial supplies.

Fundamental Design Issues

Product integrity
The basic requirement of packaging for any drug product is that it maintains the integrity of its contents. However, the physical and chemical characteristics of a drug will often limit the primary packaging options, and the existing stability data of one type of packaging as opposed to another, will often dictate the final decision.

Patient compliance
Another important aspect to consider when planning the perfect packaging is patient compliance and how easy it will be for patients to remember to take their medication when required. This is particularly important if the patients are self-medicating at home and the dosing regime is complicated. For instance, if the dosing regime is as that shown in Figure 1, simply supplying patients with drugs A-C in bottles may not be a satisfactory solution.

In such cases, the development of a study-specific wallet design may be more appropriate which will be covered later in the article. Another key consideration is whether or not patients will need to carry their medication with them during the day. If this is the case, clearly the smaller the packaging the better. However, if the patient population is elderly, then very small packaging may be difficult for them to manage. It is therefore vital to clearly assess the patient population’s life style and dexterity within the early stages of the packaging design process.

Obviously, if the medication is to be administered to patients in a hospital or clinic environment, this issue has far less influence on the overall packaging design.

Protocol design
The design of the protocol will also have a significant effect on the design of the packaging. In addition to the dosing regime, the presence or absence of a run-in period and the length of the study in total will have an impact.

If the drugs are handed out to patients at each study visit then the pack design must ensure that there are sufficient quantities of supplies to last between visits (including any necessary overage). If the visit schedule is uneven (i.e. visits are sometimes weeks apart and sometimes months) or if the dosing regime changes throughout the course of the study, then there will be a requirement to introduce visit-specific packs.

A further major consideration is whether or not the study is to be blinded and, if so, what positive or negative controls are to be used. Blinding methods and their implications are discussed in more detail later.

Storage and distribution
Storage and distribution has an important impact on the design of the packaging. A mistake that is often made is to neglect the consideration of the storage and distribution requirements for the clinical trial supplies until near the start of the study. Specific issues include temperature and humidity limits, distribution routes and the amount of storage space available at individual study sites. If supplies are to be held at local depots in each country, the size and format of the storage space may dictate the maximum size and shape of each pack.

Reconciliation
At the end of the study, every tablet, vial, or pot of ointment will need to be reconciled and it may be that some designs of packaging make this process easier. Although, a minor point, it is one that is often overlooked at the design stage.

Once the overall design of the study has been considered, there are a number of additional issues that require resolution.

PACKAGING COMPONENTS

The primary consideration when deciding on the packaging components is the physical and chemical characteristics of the product(s). If there are temperature and/or humidity constraints, specialised packaging materials may be required.

Bottles
Bottles come in many shapes and sizes and are manufactured in a range of materials. Most sizes are available in most materials, but the specific characteristics of the product under development will often dictate the choice. For example, some bottles have very small necks and may not be suitable for large tablets. Alternatively, in the case of bottles for liquid-fill, some materials may interact with the product and effect its stability. Due to the increasing requirement for child-resistant packaging, child-resistant lids on bottles are becoming ever more popular, but it should be noted that these lids fit only a limited number of neck sizes.

Vials
Typically, vials would only be used in trials where the medication is to be administered in a hospital or clinic environment. As vials need to be filled under sterile conditions, any study-specific packaging design will normally only consist of labels and patient packs.

Tubes/pots
Creams and ointments will normally be supplied in tubes or pots and, as with vials, the only requirement for the design of packaging for a clinical trial will be labels and patient packs.

Blisters
Thermoform and cold-form blistering is becoming increasingly popular in clinical trials. Patient compliance can be improved by the walleting of blister strips (see below), but blister packing can be a more expensive operation than bottling due to the likely requirement for specific tooling.

Wallets
Walleting of blister strips provide many advantages as they provide plenty of space for instructions which, in the case of complicated dosing regimes, can markedly improve patient compliance. For example, a wallet design such as the schematic shown in Figure 2, will ensure far higher compliance than the earlier suggestion of sending the patients home with three separate bottles of tablets. There is however, a drawback to this approach, as the wallets are likely to have to be custom-made with a resultant time and cost implication.

Cartons
Boxes can be purchased in a variety of shapes and sizes and it is important to choose cartons and shippers appropriate to the size of the packed materials. Boxes with divisions will enable study supplies to be held in visit-number order, and are well worth considering, especially if different types of packs are to be issued at each visit.

LABEL DESIGN

Following the implementation of the EU Clinical Trial Directive (2001/20/EC), there are new labelling requirements for clinical trial supplies destined for use within the EU, and these are summarised in Figure 3. To add to the complexity of the new requirements, the details should be printed in the official language(s) of the country in which the supplies are to be used and, in most cases, the same particulars should appear on both the primary and secondary packaging.

Labels can contain up to three types of information: general identification and instructions (see above), dispensing records and code break information.

Dispensing records typically take the form of a second part to the label that can be removed and attached to the CRF. When designing this type of label, it is important to consider the amount of space that will be available on these documents.

Code breaks can take a number of forms. The most common is a code break envelope, where the details are printed on a third sheet that is only accessible once the envelope has been opened (such as the envelopes often used for wages). Code breaks can also take the form of barcodes or scratch-off panels on the labels that are applied to the actual drug supplies.

The production of labels for use in clinical trials must be carried out under GMP conditions. Each label needs to be checked and approved before use and a 100% reconciliation of the labels is required at the end of the packaging process.

BLINDING METHODS

If a study is to be blinded, the choice of blinding technique may have a fundamental effect on the design of the clinical trial packaging as the amount of medication to be taken and its final size and shape may be altered as a result of this process.

Matching products
Initially, the simplest solution to the problem of blinding would appear to be to produce comparator or placebo medication that looks, tastes and smells identical to the study drug. However, there are many complications with this seemingly simple solution.

If an active comparator is remanufactured to match the study drug, issues such as the amount of active ingredient, the excipients used and the amount of compression (for tablets) will effect the bioavailability and stability of the product. Therefore, data from a study in which the comparator was ‘re-formulated’ will not be valid for a comparison with the commercially available product.

The manufacture of matching placebos is also more complicated that it first appears. The best source of matching placebo product is the manufacturer of the study drug, particularly in the case of tablets. Any other manufacturer will need to invest time and money in providing tablet-press tooling. There may be issues with capacity, however, which could effect the study’s time lines.

Double-dummy
As it is often difficult to manufacture matching products, another approach is to use a double-dummy design where the medication looks different, but each patient takes one of each – one being the active and the other the placebo. This can work well, but does double the amount of medication to be supplied to each patient, thus having a profound effect on the design of the packaging.

Over-encapsulation
The over-encapsulation of tablets or capsules can be an easy and affordable solution. In this case, placebo and active product that look very different, can be inserted into matching capsules, making the finished product look identical. If small tablets are to be used, it is normal to ‘back-fill’ the capsules to ensure that the finished goods do not rattle.

Unfortunately, over-encapsulation does not provide the perfect solution either. It will only work with tablets, capsules or powders, and the size of the original product may exclude this option as capsule shells are only available in a limited number of sizes.

In summary, the influences on the design of packaging for clinical trial supplies are many and diverse. Their relative importance will vary greatly dependent on the specifics of the study in question and therefore each clinical trial requires an individual tailored approach. It is therefore important that all the factors are given serious consideration as early as possible in the packaging design process, which will ultimately help to find a perfect packaging solution for a successful clinical trial.

.Figure 1 – Theoretical dosing regime of the type that could cause patient compliance issues if the study drugs are supplied in bottles.



Figure 2 – Schematic of the design of a weekly wallet which would improve compliance with the dosing regime shown in Figure 1.



Figure 3 – Following the implementation of the EU Clinical Trial Directive (2001/20/EC) in May, this information is now required on clinical trial supplies which are destined for use in countries within the EU.



PMPS - September 2004

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