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 over encapsulation processes

Blinding, as found in the roles and guidance for pharmaceutical manufacturers and distributors Annex 13 is a procedure in which one or more parties to the trial are kept unaware of the treatment assignment. As it relates to an investigational medicinal product, blinding shall mean the deliberate disguising of the product in accordance with the instructions of the sponsor

Without maintaining a proper blind, patients who know what treatment they are receiving might harbor favorable expectations or increased apprehension, thus skewing the study data

Over encapsulation is a process by which one or more products are assembled into a hard gelatin shell, which may or may not be filled with an inactive bulk agent or excipient

The ability to maintain blindness throughout the complete clinical trial processes must not only focus on the visual aspects of the product but also take into consideration the other human senses. Taste and smell are by far the two most difficult senses to blind against

Many years ago, I learned of a study in which the client's product had a strong odor. In order to mask the smell, the client inserted a single table into a canister desiccant for use during assembly of bottles. The bottled product inherited the pungent smell, thus maintaining proper blindness

Unfortunately, not all products have a blinding solution

Within clinical trials, over encapsulated material will undergo further processing. Based on the client's protocol, this will often be assembly into foil blister packs or bottling operations

Just as with many companies across the globe experiencing economical struggles, the pharmaceutical industry is feeling the pressures to be more effective, efficient and leaner. Whether it be the rising cost of R&D, the astronomical funding required to bring a new product to market, the potential need to purchase specific equipment and tooling for use during your clinical packaging, employing healthcare costs, large pharma to small bio tech companies are being forced into outsourcing work

Are the chosen materials suitable for the target patient? To elaborate, is the size capsule suitable for children, seniors

Manufacturing and packaging of clinical supplies only continues to increase in complexity. Over encapsulation, bottling, blistering and/or labeling each possesses its own set of challenges. It is not simply a case of variation of batch size, multiple setups with the required process checks, but variation in capsule size, flow of excipient used and the shape or dimensions of the input product that pose further challenges

Complexity of dosages may require specific unique solutions. Certain strengths in the comparative product may not be available, requiring insertion of multiple units of the same or differing product

Purchasing of a global comparator should focus on how readily available the product is--additionally, what quantities will be required as the clinical trial progresses

Are expiry dates lengthy enough to allow for packaging, testing, material release and patient enrollment

The selection of backfill should pose no impact to the over encapsulated product and should allow for efficient processing

We will further evaluate both the comparator and backfill selection in upcoming slides

Over encapsulation is the most widely accepted blinding technique. Why? Capsule shell suppliers offer a vast array of opaque colors that can be used to obscure input components

Your final assembled unit is visually identical from one product to the next, thus reducing influence from the trial participants, investigators, assessors

The over encapsulation process allows for one or more products to be placed into a capsule shell. This aids in configurating [sp] dosage that may or may not be available in the market

Processes and testing must show that product quality has not been altered and requires justification of expiry date as each component, the input unit, shell and backfill each retire expiry date

The analytical segment of this presentation will assist in guidance to correct expiry dating

Patient compliance requires maintaining a blind that resists tampering and clearly reflects when tampering has occurred

Rapid unblinding to identify the product in case of an emergency

More often, the comparator selection will seek to take on a market leader. Let us not think that this selection does not pose its own challenges

As discussed previously, consider the lead time for the delivery and expiration dates of your comparator product. Can the comparator be used across global markets

Once consumed, will the capsule shell and added backfill break down in suitable timing to allow release of the product? Is the physical shape and size of the product able to fit into suitably sized capsule shells

This again relates back to your target patient. For example, a stroke victim may have difficulties swallowing a large capsule

Is the comparator product too brittle to effectively use automated processes as this could jeopardize timelines and costing

Suppliers can produce consistent stocks of hard gelatin capsules where the range of diameters and length allow many products to be over encapsulated. It is important to ensure the color of the capsules chosen completely obscures the input material

Confirm that the comparator or the IMP [sp] fits within the capsule shell without distorting the shape. This may require splitting of the input units

Is the shell a universally accepted color? This is vitally important as some regions may not allow certain colored capsule shells to enter their borders

Provide thorough research to understand and consider what the acceptable daily intake is for both the capsules and the colorings

Within the DB series line of capsules, it offers a smaller size, which helps to improve compliance, completely overlapping of the capsule top to the capsule bottom

Once closed, the locking mechanism makes the unit difficult to open without damaging the exterior shell

Numerous sizes are available and offers a globally approved color selection, allows for high speed production capabilities

Blend and/or excipients are primarily used to prevent rattling, fill capsule void and manufacture of placebo to match capsules containing excipient only

What excipient should be used? It is important that this be inactive, often is the same excipient that is used during the formulation of the active product or the comparator product

Off the shelf products that are available include powder, pellets, sugar spheres. Blends may also be utilized. This may be a lactose with a magnesium stearate

Excipient chosen may impact upon machinery type used. Dependent on the quantity of material to be over encapsulated, shape of the product and the number of input components, there are a series of processes that may be used, including manual, semi-automated or automated processes

Manual encapsulation operations are most suited for smaller size batch runs including over encapsulation of one or more units, placebo to match capsules containing a placebo tablet or a backfill only and can accommodate uniquely shaped tablets that do not lend themselves to the automated fill process

Although manual processes allow for a quicker setup, the manufacture of capsules is a time consuming process with challenges of obtaining consistent weights across all units

Semi automated encapsulation becomes most relevant when manufacturing small to large size batch runs that include assembly of placebo to match capsules or insertion of one or more active solid dosages into capsules that may or may not contain backfill

Limited capabilities exist to automate the unit insertion depending on size and shape of the unit

Semi-automated processes allow for an increased rate of capsule assembly by use of automated fill processes or tooling assist [sp] processes. This process is also best suited when the input unit needs to be broken in half to properly fit within the capsule shell body

Average capsule weights become more consistent by use of semi-automated and fully automated equipment

Fully automated encapsulation is recommended when manufacturing medium to very large size protocols that include assembly of placebo to match capsules or insertion of an active solid dosage into capsules that may or may not contain backfill

The automated equipment allows for the most efficient rate in capsule assembly as rates may increase to nearly 42,000 capsules per hour

Certain automated equipment may allow for the insertion of multiple units of the same product into each capsule body

Average capsule weights become increasingly consistent through the addition of a controlled dose of excipient to each capsule instead of simply flood volume filling

Following the completion of over encapsulation processes, check weighing should be performed to confirm uniformity of weight and to detect any potential miscompiled capsules. Additionally, when having utilized a backfill, capsules should pass through a deduster to remove any powders from the outer capsule shell

A final check should be to pass all units through metal detection equipment. Thank you