Stability Optimization

Navigating the maze of container/closure systems

By Kelly Lin and Andrea Wagner

Stability optimization of a drug product is commonly only considered during the drug development phase. The decision to package a product in a vial or a syringe is typically made in the early phases of drug development and testing and is based on allowing for ultimate flexibility for the clinical site. The stability of the drug product with the container is tested throughout the drug development life cycle but, again, is typically only performed on a container that allows the ultimate flexibility in dosing and administration at the clinical site.

Once the drug potency and administration dosage have been decided upon, typically in the final stages of drug development (Phase III trials), then the question of what would be ideal commercial packaging is taken into consideration. Unfortunately, at this point it is too late to switch to the optimal container, whether it be a syringe or a vial, plastic or silicon free, due to the lack of stability on the “ideal” container choice.

Additionally, some products like proteins and peptides, the foundation of many biopharmaceutical products, have unique properties that make them highly sensitive to their packaging. Some proteins adsorb to container surfaces, causing the drug to lose potency. Others are sensitive to the silicon oil used to lubricate the syringe and stopper, resulting in protein degradation.1 These problems, while not insurmountable, can be catastrophic to a drug company if discovered on the eve of a new product launch.

To determine the best “fit” for their product, drug companies need stability data collected over a span of several years prior to a commercial launch. Decisions made early in the development process can leave a drug company locked into its original container choice, which may not be the best container for the product, or can lead to significant delays in bringing a product to market.

Container stability optimization helps drug manufacturers navigate the maze of choices and challenges associated with final product packaging. Using stability data collected from a range of containers, beginning as early as Phase II in the development cycle, stability optimization gives drug companies flexibility in their choice of containers as well as the information they need to find the best fit for their product.

Containers

Vials have long been the industry standard for parenteral product packaging. This is due in large part to the dosing flexibility that they give the clinician during clinical studies which can vary significantly depending on the efficacy of the drug. This is why drug development companies perform clinical trials. Vials also have known stability in terms of leachables and extractables from glass and present fewer variables in clinical development that the developing company needs to be concerned about if they are to use an alternative container, such as a plastic container or a syringe. Vials also offer the ability to present a product in a liquid or lyophilized state, as well as an option for amber tinting to protect light-sensitive products.

Additionally, products in a vial come in contact with fewer surfaces. A vial container/closure system includes the vial itself, as well as an elastomeric stopper which is held in place by a metal crimp. As a result, there are fewer variables to be considered in terms of leachables and extractables making their way into the product from component surfaces.

Despite these advantages, vials are more difficult to use and require more product overfill. In order to access a product inside a vial, an administrator must use a syringe to draw the product out. This requires that a vial be overfilled, sometimes by as much as 25%, to ensure that the administrator withdraws the entire dose. Overfilling increases the likelihood of dosing errors as well as wastes valuable bulk substance. Additionally, a product that has been lyophilized in a vial must first be reconstituted before being administered, adding another step to the process.

Prefilled syringes are a fast-growing alternative to vials for many parenteral products. According to one recent estimate, the market for prefilled systems has grown by more than 20% in the last three years and will likely see a sustained growth rate of between 10 and 15%.2

The increased popularity of prefilled syringes can be attributed to the advantages they offer relative to vials, including decreased overfill requirements, greater ease-of-use, improved dosing accuracy and enhanced product differentiation. Additionally, prefilled syringes offer more filling options. In traditional operations, prefilled syringes are filled using online filling followed by stopper (piston) placement. The major disadvantage to this method is the large air bubble that is left in the syringe, at least 2.5 mm in size. To address this, vacuum stopper boxes have been used to remove most of the air. This is accomplished by online filling followed by offline vacuum stoppering. More recently, syringe-filling equipment has been modified to allow for online vacuum filling followed by online vacuum stoppering. A relatively new method has also been introduced in the last few years which uses online vacuum filling and online vacuum stoppering together with proprietary technology to eliminate the bubble inside a syringe.

Factors that may affect the drug product stability in a prefilled syringe are:

• interface of the product with the metal in a needle (if the syringe is a staked needle);
• contact between the drug product and the silicon in the syringe barrel (most syringes are coated with silicon to ensure piston movement down the barrel of the syringe);
• interface of a bubble with the product. This is present in vials as well but syringes offer bubble-free presentations that could enhance stability.

Materials

Borosilicate glass has long been the industry standard for parenteral products in both vials and prefilled syringes. It is easy to sterilize and offers better visibility as well as enhanced barrier properties. It also has low reactivity and its nature and content are better defined and understood. For companies moving their product from a vial to a prefilled syringe, this is especially important, since they know what to expect and how to compensate for any shortcomings.

Glass, however, contains small amounts of alkali ions, which can cause a pH shift in some sensitive products.3 It can also harbor residual traces of tungsten, a byproduct of the glass-forming process, which can cause protein aggregation in some biopharmaceuticals.4 Proteins and peptides can also adsorb to glass which can potentially lead to a decrease in the potency of the drug.5 Furthermore, glass is breakable and requires added care when filling and handling.

Plastic has been an alternative to glass in vials and prefilled syringes since the early 1990’s. The earliest plastics, however, were made of polypropylene which did not offer the clarity of glass or many of its barrier properties and ease of sterilization. Polypropylene plastics also presented more challenges with regard to extractables and leachables than glass due to lack of historic data.

Manufacturers have begun to develop new plastics, such as cyclic olefin copolymers, that are able to hold their own against glass. These plastics offer, high heat resistance, and a low level of extractables and leachables and are less permeable to water.6 They are also more transparent, lightweight and shatter resistant, enhancing visibility and facilitating filling operations as well as ease of use.

Surface Treatments

In addition to making enhancements to the component materials of a container/closure system, syringe manufacturers are finding ways to mitigate the effects of silicon on sensitive biopharmaceuticals. Silicon, which is used in both glass and plastic syringes, can cause issues with product stability. Some syringe manufacturers have started baking the silicon onto the syringe.7 Others have developed barrier films to aid in lubricating the components while protecting the drug product from contaminants that could potentially be leached from the elastomeric stopper. West Pharmaceuticals, for example, has introduced FluroTec, a fluropolymer barrier film used on syringe components to facilitate the administration of the product and to guard against extractables and leachables. This syringe system provides a silicon-free container, which is a significant advantage for silicon sensitive products.

Container Stability Optimization

Container stability optimization assists drug companies in optimizing their choice of container/closure systems. The key to this is the ability to place a drug product in several containers/closure systems simultaneously as early as Phase II trials. This allows a drug manufacturer to accumulate the information necessary to determine which system is best suited to the product.

It is likely that most drug manufacturers cannot undertake container stability optimization in-house, given the range of filling capabilities required.

Following is a list of some of the criteria to be considered when choosing a CMO to assist with container stability optimization:

1. The ability to fill several containers from a single lot. This will help to reduce wasted product.
2. The capacity to fill into vials, prefilled syringes and other customer containers, which will help maximize the number of options.
3. Knowledge of materials used in the syringe as well as any surface treatments, to limit the potential for extractables and leachables.
4. The option for traditional filling of prefilled syringes, as well as other more advanced methods, including bubble-free filling.

A good program should also be able to provide batch records for each filled lot, as well as generate a stability protocol for every container type tested. Throughout the program, a drug company should expect to receive reports on the progress of their testing as well as a final report detailing all pertinent data and analysis.

The range of options for container/closure systems — as well as the unique challenges of many new drugs and the high costs of drug development — demand that drug companies consider their final product packaging as early as possible. Without early evaluation of the multitude of container choices, the range of options may be significantly diminished due to a lack of appropriate stability data. As a result, a company may find itself on the eve of a commercial launch with a suboptimal container or face long delays in bringing the product to market.

Problems with final product packaging can be dealt with if identified early. Container stability optimization gives drug companies flexibility in their choice of final product packaging by providing them with critical stability data. When a drug manufacturer is not able to undertake container stability optimization in-house, it is important that it identifies a CMO that is able to meet the criteria for container stability optimization as outlined above. This will ensure that they receive the information they need, when they need it most, to make the best possible choice for their product.

References

1. Lahendro, Bernie, “The next generation of prefillable syringes: specialized plastics lead the way,” OndrugDelivery, September, 2007, p. 7.

2. Furness, Guy. “Prefilled Syringes: Where do we have to go,” OndrugDelivery, September 2007, p. 4.

3. Polin, Jenevieve Blair, “Injecting Excitement into Parenteral Drug Packaging,” Pharmaceutical Manufacturing and Packaging News, April 2005, p. 72.

4. Lahendro, p. 7.

5. DeGrazio, Frances L. “Parenteral Packaging Concerns for Biotech Drug Products,” Drug Delivery Technology, May 2006, p. 44.

6. Harrison, Brianne and Maribel Rios, “Big Shot: Developments in Prefilled Syringes,” Pharmaceutical Technology, March 2007.

7. Lahendro, p.7.

Andrea Wagner is vice president of business development at Hyaluron Contract Manufacturing (HCM). Kelly Lin is the Editorial Specialist at Hyaluron Contract Manufacturing (HCM). They may be reached at 781-270-7900 x114.