By Dr. Sue Miles, Head of Clinical Trials at Brecon Pharmaceuticals Ltd., Brecon Pharmaceuticals Ltd
SubscribeThe issues surrounding the labelling of pharmaceutical products have generated considerable coverage in the press over the last few months.
This upsurge in interest has been sparked by two imminent changes in labelling legislation. The first comes from the FDA and relates to licensed products, while the second change is driven by the European Union (EU) and focuses on investigational products. Dr Sue Miles, Head of Clinical Trials Services at Brecon Pharmaceuticals Ltd, considers the implications these changes will have on the assembly and packaging of pharmaceutical products.
FDA final ruling
On 25 February this year, the FDA issued its final ruling on the requirement to include barcodes on the packaging of human drug products and biological products.
The background to the ruling is the desire to reduce the number of adverse events and transfusion errors that occur. The FDA estimates that this new ruling will prevent over 500,000 such errors over a period of 20 years, with an associated cost saving of $93 billion in the same period.
In some hospitals that are already using barcoding systems, medication error rates have been reduced by as much as 85% and one hospital in the US has administered 5.7 million doses of medication to date without a single error. On the downside, according to the FDA’s own figures, the financial impact of this ruling on the pharmaceutical industry is expected to be $28 million in the first two years. Despite this there has been widespread support for this approach to improving patient safety from healthcare professionals, hospitals and trade and professional associations alike.
The barcoding in question is the encoding of each product’s identity on the labelling of thousands of human drugs and biological products. Following the new ruling the minimum information to be included is the National Drug Code, but companies can also optionally choose to include features such as lot numbers and expiry dates. The required barcode format is linear, which is the same format as is currently used on millions of packaged consumer goods.
Drugs that receive approval on or after 26 April 2004 will need to be compliant with this ruling within 60 days. In addition, currently approved drugs will need to be compliant within 2 years of the April 2004 deadline, allowing for current stocks to be exhausted. Finally, if a drug has an expiration date that exceeds two years and the drug was not subject to the barcode requirement at the time that it was marketed, it will be allowed to remain on the market without a barcode. There are a number of classes of drugs that are excluded from this ruling, however, and these are listed in Figure 1.
Drug classes exempt from the FDA’s ruling on barcoding |
Physician samples All OTC products (except those dispensed in a hospital pursuant to an order) Allergenic extracts Intrauterine devices that are regulated as drugs Medical gases Radiopharmaceuticals Low density polyethylene form fill and seal containers Prescription drugs shipped directly to patients Compounded drugs Investigative drugs |
Figure 1.
EU Directive 2001/20/EC
Following the implementation of this Directive in May 2004, new regulations will apply to the way in which clinical trials involving human subjects are carried out within the European Community. The overall objective of the Directive is to introduce the application of GxPs to clinical trials, but the labelling of clinical trials supplies is also affected and this article will focus on the Directive’s impact on this specific issue.
The new labelling requirements for investigational products are summarised in Figure 2. There is a statement in the documentation, however, to the effect that some information may be omitted if its absence can be justified e.g. by the use of a centralised electronic randomisation system. To add to the complexity of the new requirements, the particulars should be printed in the official language(s) of the country in which the product is to be used and, in most cases, the particulars should appear on both the immediate container and on the outer packaging.
Information required on Investigational Medicinal Product labels |
1. The name, address and telephone number of the sponsor, CRO or investigator. 2. The pharmaceutical dosage form, route of administration, quantity of dosage units and, in open trials, the name/identifier and strength/potency. 3. The batch and/or code number. 4. The trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere. 5. The trial subject identification number or treatment number and, where relevant, the visit number. 6. The name of investigator (if not included at 1 or 4). 7. The directions for use (but the label can reference a leaflet or other document). 8. “For clinical trial use only” or similar wording. 9. The storage conditions. 10. The period of use (use-by date, expiry date or re-test date as applicable), in a month/year format that avoids ambiguity. 11. “Keep out of reach of children” except when the product is for use in trials where the product is not taken home by subjects. |
Figure 2.
What impact do these new regulations have for the contract packaging industry and a sponsor’s choice of partner?
The impact of the FDA’s ruling on the barcoding of licensed drugs for the contract packaging industry is minimal as packaging is designed and printed uniquely for each product. The impact on the industry of the EU Directive is more widespread and could lead to the requirement to implement new systems and technologies.
The first essential requirement is to establish a clear understanding of the exact implications of the new labelling standards, with careful reference to the country-specific differences. In addition, due to the Directive’s drive towards GxPs, the methodology for producing labels and the QA/QC processes that control this methodology are increasingly important and liable to the attentions of auditors.
Running off labels using a laser printer in a general office is no longer acceptable if the finished product is destined for an EU country. Specific aspects of the label production process affected by the requirement to adhere to GxP principles include:
Approval: Customers expect to see three levels of internal approval for all new label masters in addition to their own ‘external’ approval. Labels should not be released for printing until all four approvals have been obtained.
Segregation: Auditors will expect to see that draft and approved labels are properly segregated (both physical labels and electronic copies) and that there are procedures in place to ensure those non-approved labels cannot be printed. In addition, procedures must be in place to ensure that the print line is clear before the next print run is initiated.
Version control: Label masters should be controlled in a similar way to other critical documents such as protocols and Standard Operating Procedures.
‘WYSIWYG’: In the eyes of auditors, label printing systems should abide by the ‘what you see is what you get’ principles.
Equally important is the availability of flexible label printing systems that are able to meet the technical challenges of meeting the new requirements.
A particular example of this is the requirement to have labels printed in multiple languages. This may be overcome by the use of multi-language booklets, but these are not suitable for the labelling of all products. Thus, the industry is faced with producing country-specific labels and, in the case of labels destined for Switzerland for example, they will have to contain all the text in French, German and Italian. This requirement creates its own challenges in the design of labels and the sheer volume of text that is necessary, which in turn, leads to the need to be able to print in various fonts and font sizes and on labels of flexible size, shape and material, and to be able to attach labels to products in different ways.
The inclusion of variable information on labels such as patient IDs, site IDs and batch numbers, leads to a more complex label set-up and many label printing systems are limited in the number of variable fields that they can handle on one label. This limitation may lead to the requirement for considerably more label masters for each trial, with the associated increase in cost and in checking and approval procedures.
Modern label printing systems include the ability to apply ‘masks’ to these variable fields to ensure that the correct information is entered in the correct format. In addition, variables can be taken from a pre-defined database, or can be prompted at the time of printing. In this latter case, the application of field masks becomes almost essential if the variable to be entered is of a fixed length.
Also many sponsors now also ask for information such as the Patient ID to be printed on labels in barcode format. Currently, some label printing systems are unable to print these variable barcodes.
In order to meet the requirement to produce patient-specific packs, label-printing systems are being pushed to handle more and more sophisticated randomisation and study design scenarios. Modern systems should be able to handle multiple formats such as parallel or cross-over design studies with ‘scrambled’, block or stratified randomisation methodologies.
Finally, with the requirement to include expiry or re-test dates on labels, there is an increasing necessity to update the information contained on the packaging during the course of a clinical trial. The Directive states that ‘this operation should be performed at an appropriately authorised manufacturing site’ and ‘in accordance with GMP principles, specific and standard operating procedures and under contract, if applicable, and should be checked by a second person. This additional labelling should be properly documented in both the trial documentation and in the batch records.’
The implications of these new labelling requirements for non-EU sponsors can be best illustrated by the following case study.
An American sponsor company was planning a trial outside the EU and then, relatively late in the planning stage, a decision was made to include the UK and Switzerland. The labels had already been designed to meet US standards and a. The sponsor was unaware that these labels would not be acceptable in the EU, but subsequent discussions highlighted a number of deficiencies. In addition, the late inclusion of sites in Switzerland necessitated the design of a separate 3-language label.
The ‘footprint’ of this 3-language label was limited by the shape and size of the packaging to the same or smaller than the original. Thus, in order to print more than 3 times as much text onto a label with the same sized footprint, either the font size had to be dramatically reduced (this was subsequently found to render the text illegible), or a custom-designed butterfly label was required. This latter solution stretched the label design software and also led to the requirement for study-specific label stock and cutters. Eventually, however, the label shown in Figure 4 was designed, approved and printed in time for the start of the study.
As this case study highlights, the implications of the new labelling requirements may not as yet be fully assessed by many sponsors outside the EU. Although relatively straightforward, the new requirements do vary from country to country and it will be important for sponsors to ensure that their service providers are fully compliant and can provide the appropriate advice.
Undoubtedly the introduction of the new legislation over the coming months will represent an important period of transition for the industry, but if the new regulations achieve their objectives then they will represent a major step forward in the improvement in patient safety.
Dr Sue Miles, is head of Clinical Trials at Brecon Pharmaceuticals Ltd. Sue has an MA from Cambridge and a PhD from Edinburgh and gained valuable industry experience working in preclinical research in the pharmaceutical sector. Before joining Brecon Sue was CEO at Quantum Research Ltd for 6 years.
The author can be contacted on: suemiles@breconpharm.com