The world’s biologics market is growing fast. It is expected that the market will reach $250 billion in 2024, nearly doubling from where it is today. The numbers of parenteral biologics filled in lyophilized vials are also growing rapidly, largely as a result of the complexity of biologics as well as issues that pertain to stability of liquid formulations. In parallel, costs associated with new drug development have also continued to grow, nearly doubling within the last decade. Never before has the investment in diluents been more critical.

Most common diluent programs: Vials versus syringes
Vials and syringes comprise the two most common forms of diluent programs. Because kits with diluent vials are more complex, comprised of two vials, two syringes and three needles, the full process up until injection can take as long as 25 minutes. Additionally, there is a risk of incorrect dosing and needle stick injuries to the health care professional and patient alike.  An injection kit using a diluent syringe instead of a diluent vial involves two syringes and one vial with the lyophilized drug, and only one needle for the injection. This kit improves compliance and lowers the risk of potential dosing errors or contamination. Fewer steps with only one needle for the injection also means there is a reduced risk of injury from needle sticks and an increased comfort for patients and health care professionals. Prefilled diluent syringes can also enable opportunities for product differentiation in the market.

Prefilled syringes offer drug manufacturers options when considering the diluent necessary to reconstitute a lyophilized parenteral drug, opting for either a customized diluent program or an already established diluent program. Before proceeding with any decision, however, it is necessary to answer some important questions, including:

• How much time do I have until product launch?
• Do I want to invest in my own diluent program?
• Do I have a packaging material preference?
• In which countries will the product be launched?
• Which extractable volume is needed to reconstitute my drug?
• Is my drug product silicone oil sensitive?

It is also important to consider the attributes of each diluent program and how they fit within overall development. These include:

• Timeline to be ready for commercial fill—product development including packaging material, filling, stability, process qualification and launch planning
• Regulatory—CTD for drug application
• Packaging material—customized and standardized options
• Equipment for compounding, filling, and terminal sterilization (investment or available)

Because the development work has already been completed in an established diluent program, the stability data and regulatory documents are ready to be submitted, allowing for a shorter lead-time for commercial fill and launch planning. While a customized program provides high flexibility in choosing the right packaging materials, a well-designed program could offer high-quality packaging materials that are standardized.

Diluent programs: Factors to consider for success
For companies choosing an appropriate diluent program, the choice of packaging material is a critical success factor. Thus, high quality packaging materials are important, especially when working with water as a diluent. Low quality packaging materials can lead to pH shift and a higher content of leachables, which can result in risks to the active product following reconstitution. Conversely, high quality packaging components support diluent stability.

Syringes with sterile water for injection (sWFI), for example, are not buffered and are, therefore, aggressive to the packaging materials. sWFI syringes with high quality packaging materials for reconstitution of lyophilized products offer a number of advantages that can reduce the risk of interactions and support long-term stability of a product. Choosing a glass barrel that is specially treated with ammonium sulfate minimizes the reactivity between water and the glass barrel, enabling a stable pH value. A tip cap, which is made of the same material as the rubber stopper reduces the level of packaging material variations coming into contact with the diluent and, therefore, minimizes the risks of interaction. Additionally, because Teflon provides a tight barrier between the stopper and the diluent, there is a reduction in extractables and leachables when choosing a stopper with a high quality Teflon coating.

When working with a diluent there are a number of important considerations that must be taken into account. These include knowing where the product should be launched, and which pharmacopoeias must be addressed e.g. USP, Japanese or the European pharmacopoeia. Once this has been established, a check of the possibility to harmonize different pharmacopoeia requirements to reduce costs and get synergy effects is recommended. This approach gives a contract manufacturing organization (CMO) the flexibility to test only once, and according to the most complex and stringent pharmacopoeia, wherever this is possible.

In addition, knowing where to launch the product determines the storage conditions to be included in the stability program. Cold storage is always at 2-8°C. If the requirement is storage at room temperature, it is necessary to know where the product will be launched. To cover room temperature in the U.S., Europe and Japan stability data must be evaluated at 25°C. In warmer countries such as Mexico, the stability must be evaluated at 30°C.

For diluents, two different situations have to be considered for determining the storage conditions. First, before the diluent is packed with the drug product it may be stored at room temperature and corresponding stability data need to be available. Secondly, after the diluent is packaged with the drug product, cold storage may be necessary due to the lyophilized product and the stability data for storing the diluent at 2-8°C must be evaluated as well.

Consider ‘bracketing’ for improved flexibility
When developing a diluent, take into account the many advantages a well-designed bracketing concept allows, for example, flexibility of storage conditions and filling volumes. The following project example will help explain this concept.

In this example, the bracketing concept for the diluent was a filling volume of 0.50 ml to 3.0 ml, meaning any filling volume between 0.50 ml and 3.0 ml would be possible. What then is the best way to get good stability data? Both extremes of the filling volume (0.50 ml and 3.0 ml) need to be included in the qualification and stability program. The most critical filling volume is the low volume of 0.50 ml as it has the worst case ratio of filling volume to product contact surface area. Thus, it is recommended to test a third filling volume as a backup strategy, for example 1.0 ml; a filling volume the CDMO had previously good experience with. If problems with the stability of 0.50 ml were experienced, it would still be possible to fill between 1.0 ml and 3.0 ml. However, if there was no backup strategy it may well be that only 3.0 ml would be possible, leaving no flexibility with other filling volumes.

The same is true with storage temperature. For cold storage of a product, stability data at 2-8°C is required.  Room temperature in many countries is 25°C. As previously stated, in warmer countries it is 30°C. Therefore, it is recommended to evaluate the stability data at 30°C, and to keep additional samples at 25°C. If there are stability problems at 30°C, you can go back to 25°C as a fall back option. To secure the room temperature storage in U.S., EU and Japan, stability data at 25°C is sufficient.

A long shelf life is crucial for a diluent. In this particular example, the shelf life of the diluent is 5 years. This means that the stability of diluent syringes with 0.50 ml, 1.0 ml, and 3.0 ml was tested in different storage conditions for five years.

As demonstrated, a bracketing concept allows for flexibility in filling volumes and storage conditions, and a long shelf life supports the flexibility for packaging the diluent with the active product without limiting the shelf life of the final package.

A case study
In order to demonstrate how an established diluent program and bracketing concept can support the life cycle management of a product, consider the following case study involving the development of additional customized filling volumes.

In this example, a customer had made the decision not to invest in its own diluent program since the established program of a CDMO was available and suitable for their lyo- product. Two filling volumes were launched (0.8 ml and 1.3 ml), both of which were covered by the bracketing concept. In the life cycle management of the product, a pediatric dose of the product was developed, necessitating the need to establish a third and fourth (0.3 ml and 0.4 ml) filling volume outside the bracketing concept.

Because the customer was using an established diluent program, it was possible to extend the bracketing concept to incorporate the new filling volumes and select the same packaging combination as the other two diluents. Thus, it was only necessary to do qualification batches and pump studies for the ‘worst case’ lower new filling volume i.e. 0.3 ml. The filling volume of 0.4 ml was automatically qualified by this approach. As a result, the customer received an extended bracketing concept and had higher flexibility in developing further filling volumes for launches, saving valuable time in development work and profiting from a faster time-to-market.

Because diluent programs for specialized lyophilized drug products can vary significantly, it is important to choose a high quality diluent to preserve the efficacy of the drug product. Whatever your choice, do not let your diluent be the weakest link in your drug product. 

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Daniela Guttmann holds an MBA in International Business Development from the ESB Business School Reutlingen, Germany. She started her career path in the pharmaceutical industry in 2003 contributing to different areas of the business in Latin America and Europe. Daniela joined Vetter in 2011. Currently she works as a product and service manager, responsible for the secondary packaging, serialization and sterile water for injection services.

Dr. Karin Kottig studied food chemistry and earned a Doctor of Philosophy (Ph.D.) in pharmaceutical chemistry at the University of Münster in 2000. Karin began her career at Vetter Pharma-Fertigung GmbH & Co. KG in 2000 as manager, chemical analysis quality control and was named manager, contract service analytics in 2006. In this position, Karin heads up a team of 13 professionals and is responsible for Vetter-wide stability studies and contract service analytics including stability studies for development as well as commercial products.