There is an ever-increasing world of routes of administration for new drugs, but these new options mean that our packaging decisions have grown more important. One must continually review the spectrum of options for drug delivery containers, with a goal towards increased compliance and accuracy of delivery. When developing a drug product or even re-facing an existing product, the packaging surrounding the drug product is critical. When it comes to parenterals, there has been an explosion in packaging formats developed over the past 10 years. The typical formats of vial and injection by syringes has expanded to include dual chamber devices, cartridges and electronically-enabled devices that deliver drugs in vitro through direct and continuous injection. So how do we assess which packages best fit new parenteral products?

Historically
Ampules were the container of choice for most parenterals over 100 years ago. The use of ampules provided a simple glass container with no requirement for silicon coating or treating. No rubber stoppers or elastomers were utilized to enclose the drug. This type of packaging became undesirable due to the requirement to “break” the glass and then draw the drug into a syringe to inject. The opportunity for breakage, coupled with the danger of being cut during administration, made this packaging option less attractive as vials and syringes became more widely used. Additionally, ampules require heat and open flames to seal; this type of packaging could be prohibitive to organic-based compounds.

The use of vials is common but provides challenges to the user as well. It is closed with an elastomeric closure, typically made of elastomers that may or may not be coated with Teflon, then sealed with an aluminum crimp to secure the stopper in place. The use of a vial requires the user to manipulate the container, draw the product into a syringe and inject this for delivery. The ease of use is less than desirable especially in self-administration, where the patient may have a disease condition limiting her dexterity. Additionally, the accuracy of dosing can vary. This is the fundamental disadvantage to the use of vials as a primary packaging for parenterals. Vials do offer flexibility in the dosage and is the primary advantage in clinical use, prior to the dosage being dialed in for the patient. With long-term use of products, such as with insulin, this can present compliance issues. Despite ample capacity for filling the devices, the overfill required by vials — typically 20 to 25% — can be extremely costly and can pose a disposal problem if the drug is toxic or controlled.

Table 1: Chart of Parenteral Packaging Choices

Concerns	Glass Vial	Plastic Vials	Glass Syringe	Plastic Syringe	Dual Chamber Syringe Class	Dual Chamber Syringe Plastic	Ampules	Cartridge Glass	Cartridge Plastic	Custom Glass	Custom Plastic
Stable Products	X	X	X	X			X	X	X	X	X
Unstable Products	X				X					X
Increased Stability Concerns		X		X	X	X		X	X	X	X
Multiple Dosing	X	X						X	X	X	X
Glass Particulate Concerns	X		X		X		X	X		X
At Home Use			X	X	X	X				X	X
Stopper Use	X	X	X	X	X	X		X	X	?	?
Metal Exposure			?	?						?	?
Leachables	X	X	X	X	X	X	X	X	X	X	X
Extractables	X	X	X	X	X	X	X	X	X	X	X
Gas Permeation		X		X		X			X		X
Cost of Container					X	X				X	X
Availability of CMO					X	X				X	X
Time to Produce					X	X				X	X

The table above lists a variety of considerations for choosing a primary parenteral package. The fact to keep in mind is that the package is part of the drug product. Or as some say, “It is the drug product as well”. Once the parenteral is surrounded by the packaging, it cannot be separated and must be treated as one and the same. The container and its interaction with the drug must be evaluated for leachables and extractables. Therefore, the more complex the packaging matrix, the greater the possibility of the drug changing due to its interface with the container.

The syringe and vial both have basically the same structure. When using a syringe for packaging, a key concern is the ability of the stopper to move during transport. This can be addressed by locking the stopper in place or removing the air in the syringe. Syringes have the following advantages:

• Low to no holdup volume
• Exact delivery every time
• Higher compliance
• Ease of use

Syringes are also being utilized in pen systems that allow the user to easily carry them and inject them without the manipulation of needles or depressing a plunger. There are a number of items that need to be considered when choosing a container.

			At $100/ml	At $50/ml	At $25/ml
Injected Volume	Overfill Volume	Units sold  per year		Cost of Overfill
0.5	0.5	100,000.00	$ 5,000,000	$ 2,500,000	$ 1,250,000
0.5	0.5	500,000.00	$ 25,000,000	$ 12,500,000	$ 6,250,000
0.5	0.5	1,000,000.00	$ 50,000,000	$ 25,000,000	$ 12,500,000
0.5	0.5	2,000,000.00	$ 100,000,000	$ 50,000,000	$ 25,000,000
0.5	0.5	20,000,000.00	$ 1,000,000,000	$ 500,000,000	$ 250,000,000

Dosage Considerations

• Large or small
• Varied — development vs. commercial
• How to get flexibility with many competing factors?

In Phase II you are looking to determine dosing, so flexibility is important — vials are typically the option of choice. When considering vials, you must assess the following:

• Lower stability
• Dosage/administration repeatability
• Drug handling at site

For syringes and cartridges, you have to consider the following:

• Higher stability
• Flexibility in dosing limited or requiring operator calculation
• Reduced hold-up and less site handling
• Multiple dosing — like a vial — in the case of a cartridge

In the start of the clinical testing, drug containers are not the most pressing issues to contend with. Drug developers typically are concerned with the drugs’ performance. Selecting a container that offers the most flexibility is usually the path chosen. I would recommend, though, that you give some thought to the drug container at this phase. Commercial utility is critical to ultimate success in the marketplace. If you choose a container that is simply flexible but not practical in the commercial setting, you can end up losing market share or have a product that you cannot sell in its current container. So why not switch it? As we are all aware, this would require stability testing, which takes years to conduct. Meanwhile, other products with similar indications will capture the market share of your perfected treatment, principally because of the packaging. Here are some considerations to be aware of when choosing your parenteral drug’s container:

• Aggregation – silicon coating, air in container, metal contact
• Heat – no ampules
• Moisture – plastics a concern
• Cold – glass may be the best choice
• Metal – staked needle or contact with vial seal
• Oxygen – need low permeability container, such as glass or heavy plastic
• Light – amber container or secondary packaging
• Silicon oil – special containers that are silicon free

Cost Analysis for Hold-Up
Not enough consideration is given to hold-up volumes. These exist in both vials and syringes but are much greater in vials. Flexibility is the key in early stages; if syringe or cartridge stability is not performed, you may not be able to switch in time. This can result in millions of dollars of lost drug product, especially with the more expensive biologic drugs currently being developed. The chart below illustrates this cost for consideration.

As the table above shows, especially for low volumes where hold up can be as high as 100%, that you could be throwing away $100MM dollars if drug product costs are $100/ml in a year. This has been considered a low dollar value and some drug product can cost as much as $1000/ml. This points out the need for upfront consideration of container type.

The choice of a parenteral container is one that should not be made as an afterthought. Flexibility can be expanded by testing a variety of different containers early in development, to allow for their use in the commercial venue. There are many delivery devices, such as pens, and electronic-enabled devices that use syringes, vials, and cartridges to increase compliance.

There are also different types of materials to choose from, such as glass, plastic, and glass-coated plastics. These choices continue to look at systems that completely eliminate silicon, air, glass particulates, etc. Many companies are working to help to provide end users with options that allow for the greatest flexibility and improved patient compliance. When compliance is higher the drug has the best chance of treating the illness.

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Andrea Wagner, Ph.D. is founding partner at UpSell Strategy, a consultancy with the mission of increasing clients’ sales through metric-driven management and mentoring of sales forces. She can be reached at awagner@upsellstrategy.com.