FDA defines “unit of use” packaging as “A method of packaging drug product into a single container which contains more than one dosage unit, usually sufficient quantity of medication for one normal course of therapy.” The link for this reference is http://www.fda.gov/downloads/ICECI/ComplianceManuals/ComplianceProgramManual/ucm125411.pdf.

All drug products may fit into this classification, though maintenance drugs may not always fit this definition.

Based on the senior-friendly caveat, the design uses child-resistant foil that is typically a paper-backed foil that provides for peeling back the paper to expose the foil and allow the tablet or capsule to be pressed out. The challenge is always to find a way to get the paper-peeling process started without significant effort. This is not necessarily a size issue, but rather a design issue.

When the forming tool is manufactured, the unsealed area where the paper is to be peeled should be recessed just slightly (0.010-0.012 in.). This will create a “bubble” on the underside of the blister card. Additionally, the sealing tools should be recessed to ensure that the foil is not sealed to the blister at this location. When the perforated blister is separated, the target area for starting the peel process is easily accessible by the senior patient.

The physical properties of the majority of packaging components change with age and storage conditions. Even in controlled temperature and humidity conditions, the exposure to UV rays can degrade plastics, discolor corrugate, and yellow varnishes. It is important to work with your component suppliers during the specification development phase to understand the usable life of materials and the defined storage conditions to ensure that life span. For instance, fiber board used in carton manufacturing can lose some of the memory resulting in reduced machineability when processed through an automate cartoner, making them more difficult to open. Thermoforming films can become brittle over and with UV exposure, resulting in difficulty during processing (these must be stored in the defined conditions, which should be provided by the vendor). Any time your component includes an oil-based derivative, the storage time and storage conditions must be a consideration in usable life.

 Storage time and usability should be the responsibility of your vendor to determine and guarantee. There are vendors who will retest materials at the end of their prescribed time frame to determine if the life can be extended; normally this is a one-time retest with limited guarantee based on continued controlled storage conditions.

 This issue speaks to the need to control inventories such that useable life does not have to be a primary consideration. However, when not practical or price leveraging is important, storage conditions must be understood. It’s not a great deal if you buy a large quantity cheap but ultimately throw away half because of aging.

Answer:

It might be best to answer the last question first: “What does your organization follow?” We follow cGMP guidelines. We run all pharmaceutical orders as individual structures and copies.

Here are the rest of the answers, broken out:

Question: At what level is implementation of W.I.P. segregation expected in the pharma industry?

Answer:  Keep all orders segregated by individual structures and copy.  The best way to handle this is to enter every order individually.  W.I.P. management throughout the operation can be handled several ways; the most common practice is wrapping and labeling pallets and placing them in separated rows on the manufacturing floor.

Question: My concern is not to over-engineer this process while meeting the needs of our customers. So questions are as follows.  Is it a common practice to cage W.I.P. material?

Answer: By running every structure and every copy individually, you’re set up for success, not for over-engineering the process.  Segregation in cages is not necessary for basic copy separation protocol.

Question: Do people in this industry use individual cages for separate orders produced?

Answer: That is one option. Another option is simply wrapping each pallet through Work in Process.

Question: Or is it more of a common practice to segregate job orders on clearly marked pallets, and control them within one secured cage area?

Answer: Storing pallets in a secured caged area is not necessary.  As long as the pallets have been wrapped and clearly marked, you don’t have to have them in a caged area.

When first dealing with CFB, or cold-formed blister, it is imperative you work with an experienced contract packager and with an experienced tooling supplier. Cold forming a blister entails forming the cavity without heat by using reinforced aluminum foil to provide for the stretching of the foil during the forming process. Cold forming is the ultimate blister barrier for light, moisture, and gas. The moisture-vapor transmission rate is zero. Because forming the blister is a process in which the foil is shaped and stretched to the required size, this process requires that the cavity be oversized.

There are some additional process requirements associated with cold forming:

·        The product must utilize a dedicated feeder. A dedicated feeder such as a SimTap or Aylward model would accomplish this for one tablet/capsule per cavity.

·        The sealing temperatures tend to be higher for a thermoformer due to the overall thickness of the materials being sealed together.

·        The thermoformer must have pinhole detection to ensure that fissures do not form in the foil during the forming process.

·        The blister card must have an adequate seal area around the outside of the card (minimum 4 mm) to ensure that the barrier properties at the seal are good. The only paths for moisture in this package are the seal area and any fissures in the cavities themselves.

The typical structure for lidding used for cold forming is the same as with PVC. The PE layer is adjacent to the product, and the lacquer is to the outside to provide for printing onto the foil. The typical structure of the formable foil will be PVC (product side)/Alu/OPA. The OPA helps strength the formable foil. The 0.04-mm foil does not provide sufficient structure for forming a cold-formed blister.

The alternative to cold forming is pouching if your desire is to use 0.04-mm foil. This process was used in the past successfully, but it offers little protection for the product if it is sensitive to handling, e.g., if it is a soft tablet.

Waste control is the responsibility of the contract packager (converter) as long as it has the product under its control. Waste is handled one of two ways: it is either returned to the customer, or it is destroyed by the contract packager. Tracking the waste subsequent to the batch record close out by net weight is sufficient. The net weight of the container is required to perform the destruction or return the waste to the customer.

You should also already know the tablet quantity in waste, since that number was used during the reconciliation of the tablet or capsule upon the completion of packaging. The tablet quantity is typically calculated by dividing the net weight of the waste product by the average tablet/capsule weight (either determined by the contract packager or provided by the customer). The customer has the batch documentation to show the number of tablets or capsules in waste.

When the contract packager assumes responsibility for the destruction, the net waste weight is provided to the customer for the verification of destruction. If a third party is performing the destruction, certification is required to be received by contract packager with a copy provided to the customer.

Here are some things that have to be looked at, with the assumption that this is a heat seal and not glue, that the heat seal material is some kind of plastic (ie.: polyethylene or PVC), and also assuming that the paper is curling at the edges:

• Does the paper cover the entire surface - is it sealed to the entire surface?
• Has the seal strength been measured on an Instron or similar equipment?
• It is likely that the coefficient of expansion of the material is allowing the rigid surface to expand during storage, causing the material to release in orderto relieve the stress at the seal.
• The interface between the coated paper and rigid surface must be understood.
• The bonding material used to seal the material would need to have similar properties (coefficient of expansion), though this may not help.

Some follow-up information would be helpful to provide a more detailed answer. For example,

• Heat seal material?
• Is this a chemical seal activated by heat or moisture?
• Is this strictly an adhesive - how is it activated?
• What size rigid material? Flat? Solid? Or does it have cavities that are being covered?

The answer lies in the paperboard/carton package design itself rather than the blister. The package needs to be designed in a book-style fold-over carton so that there is an actual spine, if you will, to prevent foil-to-foil denting or damage.  Instead of using a wallet-style fold, which allows the two sides to touch, you would create two folds on either side of the spine’s center, say a half-inch on either side for example, so the package closes like a book. Create the same kind of folded spine on the opposite side and then it can be tucked back into the package.

Let me know how I can be of further assistance, and thanks again!

It is the ultimate responsibility of the NDA/ANDA holder as they own the product. The owner of the NDA/ANDA will decide which components and materials will be selected to package their product. To demonstrate equivalency of materials when a change is desired,  stability testing will always be an acceptable method for demonstrating equivalency. However, this is not always cost or time effective when equivalency can be demonstrated through science. It is very advantageous for the drug manufacturer, contract packager, and material provider to leverage their resources to build the case for equivalency. In many cases, data such as the MVTR (moisture-vapor transmission rate) provided by the material provider may be used. At other times, the contract packager may provide additional data from engineering studies, such as placing “moisture dots” within the sealed primary package to confirm moisture protection. Data from these tests can be compared with the existing specification, allowing the contractor and customer to agree the two are equivalent prior to the customer filing with FDA via an annual report or another necessary filing.

This question would be best answered by a pharma company. The reason: from a packaging point of view, it would be difficult to speculate on any particular drug’s effectiveness and clinical usage. That said, here is the packaging side’s perspective:

When it comes to compliance packaging playing a role in establishing regimen effectiveness, the pharma companies would determine dosage and if necessary, titration needs. Then it would work with the pharma packager to develop the best means of assisting patient compliance and safety as well as assisting physicians’ control over and monitoring of patient dosing regimen. Assistance can come in the form of a daily annotated peel-and-push foiled package, an F=1 blister package, or any number of other structural design elements. It would again then fall to the drug company to use appropriate protocols and to establish benchmarks and effectiveness metrics to capture, build, and analyze unbiased, comparative data. Innovative packaging can then augment the pharma companies’ ability to be successful as they foster patient compliance.