Blister Packaging Trends In Clinical Trial Material Supply

Robert Misher, Blis-Tech/Oread Inc.

In the U.S., about 80% of pharmaceutical blister packaging is used for physician samples, with the balance being unit dose blister package formats for institutional use. This use of blister packaging in the U.S. is in direct contrast to how blister packaging is utilized for prescription drug products in Europe. After World War II, the continent had to rebuild its industries, and frequently went with the latest technologies. Blister packaging of drug products replaced bottles during this rebuilding phase. Today, the majority of prescription drug products are blister packaged for retail in Europe while the majority of retail prescription drugs in the U.S. are supplied in bulk bottles.

Bulk bottling of retail pharmaceuticals predominates in the U.S. to this day, primarily due to its lower unit cost. However, this package format presents many disadvantages, for example patient compliance, product protection, visibility, dispensing, and tamper evidence.

Pharmaceutical non-compliance in the U.S. is a major healthcare issue. As many as 90% of prescribed medications are taken improperly, with less than 70% of all medications actually consumed. In the U.S., non-compliance costs the healthcare economy approximately $100 billion per year. Non-compliance is also a critical issue during clinical trials, although reliable figures do not exist for associated costs.

For several reasons, clinical trial drug supplies (solid oral doses) have historically been packaged in bottles rather than in blisters. First, of blister packaging costs more per unit dose than bottle packaging, primarily due to the small packaging runs needed to produce product for several hundred patients. Second, the time in which to complete the entire process was longer in duration with blister packaging due to the acquisition of blister tooling and the associated film and foil supplies. The majority of blister tooling for commercial equipment can average from six to sixteen weeks to complete and qualify. This additional project time was a significant disadvantage due to the short lead times associated with supplying clinical trial materials for patient evaluation. Third, most companies have a large investment in bottle filling equipment and few have blister packaging equipment for clinical trial supplies.

Despite these problems, blister packaging of solid oral doses for clinical trials offers many advantages over the standard form of bottle packaging:

• Drug compliance, facilitated by blister packaging, is mandatory to achieve reliable study results.
• Clinical trial dosing regimens can be quite complex, sometimes requiring several combinations of drug products to be taken at the same time.

Clinical studies are conducted to evaluate various dose levels, patient dose titration, product combinations, performance against a comparator and/or a placebo dosage form. Due to the clinical trial process, the drug products used must look identical to prevent any patient preference or bias of the product. If the products can not be made to look identical, then a "double dummy" format would be designed. This involves the use of two identical dosage forms that must be taken together at each dosing time. These trials, if packaged in bottles, require a patient to take several identical looking dosage forms from numerous bottles several times per day. To be effective, these products must be taken in the correct sequence and at the indicated intervals. Blister packaging allows these products to be individually packaged in the correct combination and in the prescribed dosing regimen.

For example, if a study design required a patient to take a placebo tablet and a 10 mg capsule in the morning and a 5 mg tablet and a 10 mg capsule in the evening, a bottle package format would require the dispensing of four bottles to the patient. One for the placebo tablet (a), one for the 10 mg capsule AM (b), one for the 5 mg tablet (c), and one for the 10 mg capsule PM (d). The patient would have to properly dispense the morning dose from the two bottles (a and b) and then dispense the evening dose from the two bottles (c and d). Depending on the time of day the dosing occurred, the patient might be required to travel with these four bottles.

Study designers are concerned that the subject may remove the product from the bottles and transport the dosage forms in a "loose" fashion, increasing the chances that the incorrect product would be taken at the specific time period. By blister packaging the dosage forms at the specific time intervals, placing the blister in a heat seal card printed with the dosing schedule and utilizing various colors or shading for interval differentiation, the patient can easily dispense the product(s) to be taken for that specific day and time. Blister packaging thereby enhances patient compliance to yield more reliable study data.

In addition, the blister format is easier to transport than the multiple bottle scenario. In many cases, daily medication cards are utilized if the products are to be dispensed numerous times per day and require a "mobile" package design.

In the blister package format, the patient also has the ability to keep track visually of the daily medication requirements as the product is in a daily and specific dosing regimen (calendar pack) configuration. A bottle package, by comparison, does not allow the patient to determine whether the daily dose was taken. Blister packaging provides additional methods to assist the patient to keep accurate tracking of the dosing regimen. Areas can be printed on the blister card for each day of the week for the patient to enter the date and maybe even the time the drug was taken. This provides the patient with the information required to keep track of the daily medication requirements and to identify if a specific time period was accidentally missed. It also affords the clinical monitor the ability to review the blister card, upon return, to identify any dosing discrepancies and to monitor the compliance rate.

Product visibility also allows the efficient reconciliation of the drug product from the patient supplies by the study monitor. During a clinical trial, patients are required to return the dispensed product package during their routine site visits. With bottles, the monitor is required to "dump" the product and perform a count and then return the product to the original bottle. The visibility of the product in the blister eliminates this time consuming process. The sponsoring company often repeats this reconciliation process once the supplies are returned from the site. The savings offered by the blister would be obtained twice in this scenario.

Competing package forms cannot offer the same level of product protection as blister packages, which is especially important during the clinical drug development process. Extensive stability data may not be available during the clinical packaging and therefore more protective packaging may be required until additional stability data is available. One blister package component system can support multiple study designs, thereby requiring minimal stability support. However, changing the fill volume of a bottle package, per study, may require the support of additional stability studies.

A wide variety of blister film and foil materials are available to choose from for pharmaceutical clinical packaging. Forming film choices include but are not limited to PVC, polypropylene, several coating grades of PVC/PVDC, and PVC/Aclar. A wide range of foils can be used to provide push through and/or peel/push product dispensing. More recently, cold form aluminum blister formats are being used to provide maximum product protection. This package format uses a formable foil to create the blister cavity and a foil lidding to seal the package.

The blister package, in addition to material choice, also provides the unit of use protection the bottle does not. Each time a patient dispenses from a bottle, contamination of the product may occur. Since most patients tend to store medications in the bathroom, the product is subjected to the heat and humidity of this room environment. The blister packaged product is individually sealed and is not directly exposed to these conditions until the patient dispenses that particular dose. Of far more concern to the clinical team is the potential of foreign product being introduced into this particular bottle by the study patient or other members of the family.

The blister package is inherently tamper evident. Due to the individual unit of use packaging, a blister configuration offers continued tamper evidence even after a dosage form has been dispensed as the remaining dosage forms are still individually sealed. Any break in the individual seal cannot be repaired or re-sealed, thus identifying a tampering of the package integrity. On a bottle, once the tamper evident seal is broken, no further tamper evident features are available and tampering of the bottle cannot be determined.

As can be seen from the evidence, a blister package is a far superior package configuration for investigational drug products. Over the last several years, blister packaging of clinical trial materials has been on the rise. Several reasons for this increase in the use of the blister packages begin with the ability to successfully outsource the packaging of the clinical drug product. By outsourcing the clinical blister packaging, many of the initial reasons for not utilizing a blister package configuration can be overcome. The sponsoring company does not have to make the investment in the machinery to produce the blister package format. In many cases, companies do not have enough clinical blister package volume to justify either the purchase of a blister machine or the hiring of a mechanic to support the blister line. This low volume also makes it difficult to use in-house production blister equipment, as the cost of equipment changeover would be restrictive.

In addition, the contractor's machinery needs to be extremely flexible to address the numerous configurations that are required to meet the frequently changing clinical study designs of the large number of companies they service. Ease of product changeover is critical, due to the small volumes of product produced for clinical trials. If changeover time is lengthy, the associated costs are allocated only over several thousand units, versus hundreds of thousands of units for commercial packaging. This inherent flexibility allows the normal short time frames for product delivery to be achieved.

Custom built, proprietary equipment utilized at Blis-Tech (Fairfield, NJ), a division of Oread (Lawrence, KS), is specially designed with the flexibility to handle any clinical package format and has the capability to form any of the thermoformable materials into a blister format. The Blis-Tech machinery permits the filling of multiple drug products onto a single blister sheet rather than the standard method of packaging color-coded, individual drug product strips. The use of drug product strips requires: the handling of the unlabeled inventory of identical looking but different drug product strips, the ability of operators to see colors accurately for product loading, and multiple operations to complete the blister packaging of the supplies. The single sheet filling method minimizes the variables that are involved in the packaging operation and thus reduce the error potential of drug placement.

In addition, by producing a single blister sheet that is then sealed in a blister card, the patient does not detect the outlines of the multiple strips sealed in the blister card. This single product outline improves the study blind. Due to the machinery's flexibility it also seals the lidding foil and the blister card. The simplicity of the machine permits the tooling costs to be a fraction of what the typical blister tooling costs are and, with tooling acquisition taking less than three weeks. With machine versatility, low tooling cost, and ease of product changeover the blister package becomes cost competitive with bottle packaging.

It is not surprising, given the overwhelming benefits presented for blister packaging and with the current ability to outsource the clinical packaging function, that the blister approach has gained worldwide popularity in support of clinical trial programs, including the U.S.

Further Reading

1. D.L. Bloom, "High -Tech Drug Packaging Can Boost Patient Compliance," Managed Care Magazine, June 1997.
2. "Plastics in Healthcare Packaging," Business Communications Company Inc., February 1997.
3. "Pharmaceutical Packaging in Blister Form," Manufacturing Chemist, November 1994.

Robert Misher, Vice President of Clinical Packaging at Blis-Tech, a division of Oread (Lawrence, KS), holds a BS degree in chemistry from Widener University and an MBA in finance from Drexel University. He has worked in Package Development supporting clinical trial packaging operations for Wyeth-Ayerst and Boehringer Ingelheim.

For more information: Robert Misher, Blis-Tech, 80 Little Falls Rd., Fairfield, NJ 07004. Tel: 973-575-5958. Fax: 973-575-6166.