Correct packaging and labelling of investigational medicinal products are essential for guaranteeing regulatory compliance, minimising error-related costs and, most importantly, ensuring the safety of participants. Percy Ledger looks at the challenges involved, as well as how technology can improve the process.
An old man watches as a sickly porcupine forages in the fields of Tanzania, nibbling the roots of a poisonous plant. Over the next few days, the man sees the creature regain its health and return to its energetic activities. Emboldened and intrigued, he tests the plant on himself and others in his community, noting that, when used in correct dosages, it acts as a powerful treatment for dysentery.
This is the story told to the New York Times by scientist Michael Huffman about how the grandfather of his friend and fellow researcher Mohamedi Seifu Kalunde, a Tanzanian from the Tongwe people near the Mahale Mountains National Park, conducted what was essentially a rudimentary clinical trial. Indeed, some scientists believe humans acquired aspects of their medical knowledge by watching animals react to various plants not normally part of their diets.
While observational studies of what constituted good medicine served humanity well in certain parts of the world, these days, we are lucky enough to be able to rely on well-managed clinical trials with accurately labelled and packaged investigational medicinal products (IMPs).
Proper labelling and packaging is a heavily regulated practice given the serious ramifications of errors in administering IMPs. Whether the drug is an active pharmaceutical substance to be tested or a placebo to act as a control, packaging and labelling can help those administering the IMP to keep participants safe and maintain traceability throughout the trial. It is important that the placebo and active substance appear to be the same for the obvious reason of keeping the trial blind or double-blind.
How this is done depends on whether the drug or placebo’s packaging and labelling can be manipulated before administering to participants. If this is not possible, secondary packaging and labelling can be used to conceal the differences between the two IMPs.
The requirements involved in packaging and labelling trial drugs are often complex and can be liable to errors that are difficult to detect, especially when compared with already marketed products. Label reconciliation, line clearance and in-process control checks by trained staff should be intensified to avoid mislabelling IMPs.
Packaging must guarantee safe transit and storage of IMPs as well as ensure that opening or tampering of the IMPs is easily detectable.
Annex 13, Volume 4 of ‘The Rules Governing Medicinal Products in the EU: Good Manufacturing Practices’ clearly dictates what is required when labelling and packaging IMPs in EU trials. Referencing Directive 2003/94/EC, the annex exhorts those labelling IMPs to include essential information such as the “name, address and telephone number of the sponsor, contract research organisation or investigator (the main contact for information on the product, clinical trial and emergency unblinding)”.
In case of emergency
In a comprehensive paper from 2006 titled ‘Labelling Requirements for Investigational Medicinal Products in Multinational Clinical Trials: Bureaucratic Cost Driver or Added Value?’, Dr Astrid Weyermann wrote that this information is vital. Providing the subject with contact details is especially important in the case of emergency unblinding. Being able to access information about the IMP will help with any emergency treatment that the participant may require.
Other mandatory labelling information, according to Annex 13, includes pharmaceutical dosage form, route of administration, quantity of dosage units and, in the case of open trials, the name/ identifier and strength/potency, as well as the batch or code number and a trial reference code. The last is important because, as Weyermann wrote, “the trial reference code is unique for a trial of a certain sponsor but not necessarily for all CTs of all sponsors. Involuntarily, another sponsor may choose the same code, which then may lead to confusion if the name of the sponsor is not labelled because this code is not subject to an approval procedure like the trade name check. Therefore, both particulars, the sponsor and the trial code, are essential to identify without ambiguity the CT and (indirectly) the IMP.”
The annex also calls for inclusion of the trial subject identification or treatment number and the visit number, which are necessary in blinded trials with more than one treatment, according to Weyermann. The number ensures that the IMP and the subject treated with it can be identified and appropriately traced.
For Weyermann, a “pragmatic approach” is to include the name of the investigator and directions for use, “especially for unusual administration schemes requiring some guidance”. Correct dosage and administration are fundamentals for successful clinical trials. Weyermann suggests that having this information on labels is added value, as directions for use are usually also given to subjects orally and in separate written instructions.
Including warnings such as “for clinical trial use only” and “keep out of reach of children”, assuming the IMPs will be taken by participants at their homes, is essential, as is information about proper storage conditions and period of use, which can include a use-by, expiry or retest date to aid in returning IMPs.
“When the IMP is returned, broader stability data might be available but, if this is not the case, the safety of subjects might be impaired. Nevertheless, it is also recognised that the labelling of the period of use is associated with additional workload with respect to relabelling of the extended shelf life,” wrote Weyermann.
US trials need to meet the labelling and packaging requirements set out in the Code of Federal Regulations. Catrina Leak, senior clinical pharmacy specialist at Human Genome Sciences, said at the Clinical Trial Supply East Coast Conference in Philadelphia that US trials use cautions on labels similar to requirements set out in the EU’s Annex 13.
These include information such as “Caution: New Drug Limited by Federal (or United States) law to investigational use” as well as the name and place of business of manufacturer, packer or distributor, the quantity of contents, proprietary and established name of the drug, and the lot or control number.
Lost in translation
In Leak’s conference presentation, she said that in trials across multiple countries, it is important to choose a CRO that is able to assist in all the regions in which the trial is taking place. A good CRO will need to be able to translate labels into each required language and send a translation certificate to the trial sponsors.
This requirement of multinational clinical trials places tough demands on labelling practice. With trials conducted in different countries at the same time, it is often the case that labels need to be printed in as many as 40 different languages and versions with unique batch documentation. To help cope with the demand, booklet or multipage labels have grown more ubiquitous, as have uniquely designed labels to accommodate the different shapes and sizes of IMPs.
There are a few options available for labelling IMPs to deal with this demand. Using one label for all countries, wrote Weyermann, limits errors such as mismatching languages of labels in immediate and outer packaging, failing to balance the number of labels with the number of IMP packages or sending incorrect shipments from one country to another during the trial. However, if there is an error in the information for one country on the label itself, all countries will need to change the label, which is a costly and time-consuming undertaking.
Another option is that each country receives its own label, reducing the impact of the aforementioned error. However, this option requires the highest number of labels used, resulting in increased workload.
This is a good example of where technology can be used to assist in labelling requirements. Leak mentioned comprehensive, regularly updated electronic databases with preapproved translated label phrases in a variety of languages to use across multiple clinical studies.
The International Society for Pharmaceutical Engineering (ISPE) is a global non-profit association working on standardising labels. It notes that labels need to be able to accommodate the varying shapes and material requirements of IMPs. Wraparound labels, for example, are effective for labelling syringes and vials, and can be resealed after opening.
Regardless of the labels used, it is important for them to be able to withstand the conditions of clinical trials, including transportation of IMPs along cold chains, as well as use in hospitals, clinics and even participants’ homes. Often, IMPs will start from frozen and be heated before the trial begins. It is essential that label manufacturers have tested adhesiveness and readability through these drastic environmental fluctuations. ISPE advises using hardy synthetic materials to meet these demands. Additionally, they need to be user-friendly to facilitate participants’ ease-of-use during the trial.
Beyond providing necessary and essential information, labels and packaging must also be able to fulfil much more. There is a multifunctionality that needs to be exploited by adding vital data such as first opening, product originality and even participants’ compliance with the trial.
This is why technology has the power to add real value to IMP labelling and packaging. Using radio-frequency identification (RFID), near-field communication (NFC) and printed electronics to equip IMPs with smart labels will help track vital data. Monitoring when a product’s seal was broken or whether the correct dosage was administered at the right time are some of the delivered benefits. This technology can even act as a powerful aid in reminding participants to consume the IMPs through scheduled alarms linked to their smartphones or other mobile devices.
There are cases where clinical trials require amendments either just before commencement or during the study. New data might mean IMPs are affected. Perhaps dosage can be increased or expiry dates can be extended. To overcome these changing requirements, just-in-time (JIT) production delivers much-needed flexibility for labelling and packaging. As Leak presented, JIT production allows labelling at the point of distribution, reduces cost and time required in multiple packaging runs, adheres to GMP processes, extends expiry dates and allows the most accurate cautions. It can also help in cases of limited supply where IMPs need to be pooled in a study.
Fortunately, those in need of medication no longer need to study a porcupine’s eating habits to discover treatment options for human ailments. The rigour of formal clinical trials replaces this guesswork, yet, they are not without risk. Studies have to meet stringent control conditions whereby IMPs are administered correctly. Choosing the right information to print on the hardiest labels is essential to ensuring safety of participants and the integrity of clinical trials.