Mr. Brian Hilton: Welcome. My name is Brian Hilton, Production Manager with Almac Clinical Services. Within this segment, we will evaluate the blinding considerations during the bottling, blistering and walleting processes

Bottling is likely the simplest, most efficient method to assist in maintaining blind during the patient dosing

As many variations and bottling components exist between suppliers, it is recommended to source efficient quantities of each component from not only the same supplier but also the same batch for each campaign of your clinical trial

Within your study, consider if bottles of various dosages will be compiled side by side within a patient kit to ensure blindness can be maintained beyond the bottling processes

Visual variations in the way products are bottled, capped, sealed or labeled may break the study blind. A 60 CC bottle may be tall and thin or short and stocky. Consider the destination in which your supplies will be distributed. A thicker bottle density will withstand higher pressures during air transits

Differences in text on the cap and/or seal liner can be a quick visual identifier of differing products

Although adding components in any aspect of the clinical packaging process provides further challenges to maintaining blind, each come with their advantages. The addition of a cotton rayon polyester filler can significantly reduce the risk of product breakage during transit

These fillers may be cut into various lengths, depending on the bottle size versus product fill level. However, it is also important to consider factors such as patient population or product stability when selecting a suitable filler

For moisture sensitive products, a canister or sachet desiccant is very effective in removing moisture in the head space of the bottle present at the time of packaging. While every gram of silicone or clay only absorbs one-third of its weight, the appropriately sized desiccant minimizes the risk to absorbing moisture from the product

Although blistering provides additional challenges to maintaining blind, is more complex in nature and arguably less efficient, blister packaging has its benefits

The general principle of blister packaging is to hermetically seal each tablet or capsule into its own cavity. Two basic types of pharmaceutical blisterings exist

Thermoform material utilizes a clear plastic providing transparency to the product within each cavity. Cold form material utilizes a foil as the essential component of both webs

Cavities are formed by cold stretching the foil and provides no transparency to the product once sealed

As a whole, blister packaging is believed to be better than conventional packaging as it maintains product integrity as well as protection, tamper evident as each dose is extracted one at a time, and reduces the risk of accidental misuse by the patient

Sourcing a new comparator product already contained with a blister pack may require deblistering and reassembly into new blister packs as differences in materials used may be difficult to mimic

Subsequently, different blistering equipment may or may not provide identical blister packs. A small sampling of the many different blistering materials and configurations are highlighted on the following slide

Although less efficient, manual blistering allows for the assembly of multiple products to be arranged in any configuration with any preformed base tray

Whether handling multiple, identical or non-identical products, clinical packaging vendors should have detailed procedures in place to minimize the risk of product crossover and/or contamination

Automated blistering can offer significant advantages through any assembly of blister packs. Depending on each package's equipment library, automated equipment has the capabilities to offer single or mixed product fills into multiple blister pack configurations

Various equipment options also allow for the addition of a print mat, which is an imprinted code applied to each blister pack for product identification and is only visible up until time of wallet assembly, pinhole detection and fully integrated vision systems

Manual feeding online requires the placement of the input unit directly into the open cavity

During mix filling, individual and locked product toppers are required during the mix product packaging

Numerous options exist for blister packaging of multiple products of varying size and shape to be assembled into a single blister pack

Maintaining product compliance, especially when mix foiling, is achieved through various verification systems. Pre-programmed vision systems are trained with the size, shape and color of the product and will detect an accidental miscompiled blister pack

Product may be issued in small sub-lots and reconciled more often at tighter reconciliation limits

Check weighing of all blister packs, both Thermoform and Cold Form, is utilized to assist in detecting an open cavity

X-ray verification in assembled cold form blister packs may detect a miscompiled blister pack without the need to conduct a full product recovery

Although simplified, walleting still poses challenges to maintaining blind during the assembly process. To maintain blind during assembly of wallets, careful consideration should be given to apply tracer markets, embossings or print on the blister pack versus its orientation into the wallet stock

Confirm that the print will not be visible at patients dose their medication through the push through lidding

To minimize risk of assembly of incorrect wallets, physical barriers should segregate operations utilizing more than one identical product. Additionally, sub-lots and more stringent reconciliation limits are recommended

As indicated in the below photos, variation of wallet stock, color and visibility of print codes each provides a risk to maintain blind

Manual walleting allows for many different input units to be assembled into a larger wallet stock that would not fit on automated equipment. Although allowing for any configuration, speed of operations are dictated by personnel

Semi-automated processes allow for increased efficiencies as the speed of operations is dictated by the equipment. As personnel man product fill stations along the equipment, the number of input units may be limited

Masking may be utilized to assist in correct product placement as well as visual verification prior to sealing of the wallet

Fully automated walleting equipment provides the most efficiency into wallet assembly. However, it comes at a tire [sp] tooling cost and significantly longer equipment changeover times. Automatic loading of blister packs into two piece wallets eliminates operator manipulation

Visual systems detect the presence of each blister and confirms correct orientation. Thank you