Fran DeGrazio, West Pharmaceutical Services

Today’s pharmaceutical industry is challenged with an array of issues to achieve the goal of developing and delivering safe and efficacious drug products. Ultimately pharmaceutical companies want to bring products to patients that help them manage or cure their disease or prevent an illness from occurring. The reality is that the industry must achieve these technical goals while effectively executing a profitable business model. 

A delivery system can provide economic value to both manufacturer and patient. Cost savings can be realized when drug product administration moves from the clinical setting, either a doctor’s office or hospital, to a home care setting. Ultimately, self injection can remove a considerable cost so an efficient and effective delivery system has tremendous economic value. 

For example, a drug product may be initially administered intravenously or packaged in a vial or syringe that requires trained professionals to properly administer the dose. In an auto-injector, the dose is pre-measured. The system requires little or no training to use and can be used in the home setting, which alleviates travel and office visit costs for the patient. As these savings are realized, the trend toward self-injection will continue to rise across the globe. 

	The foremost considerations in the development of a new drug or biopharmaceutical product are its ability to be efficacious and safe. Packaging and delivery systems are critical in assuring that there are no issues that could negatively impact these characteristics over the drug’s shelf-life and its administration. 

Historically, the package and delivery system has, at times, been relegated to an afterthought. In the recent past, however, the importance of these critical systems has taken a more substantial role in the industry’s view, especially in the case of industry-leading pharmaceutical and biotech organizations. 

If we view the area of injectable drug packaging (containment) and injectable drug delivery systems (administration) as two segments of a continuum, there are six primary tactics that should be evaluated to deliver on the strategies: 

	Of course, the characteristic of the drug is at the core of this issue. However, if the drug achieves its therapeutic objective, the container closure system cannot have any negative impact from a compatibility or stability standpoint. Will the drug be stored or shipped under cold conditions? Will the drug be provided in a prefillable syringe system which acts as both its primary container and its delivery system? Are there sensitivities to certain potential extractables? Considerations for both organic and inorganic extractables and their migration form as soluble, semi-volatile and volatile should be evaluated. 

All of these issues have implications not only on the drug itself but also on the container closure system that is chosen as the primary package. The container closure or delivery system could have a deleterious effect or it could provide a beneficial effect for the drug product over its shelf-life. For instance, certain types of container closure systems may help extend the shelf-life of a sensitive biopharmaceutical product by minimizing and controlling extractables that could lead to leachables in the drug product. An example of the potential impact is given in the following case study as presented by Ingrid Markovic, Ph.D. of the CDER division of the FDA.

A therapeutic protein product was changed from a lyophilized to liquid presentation. Due to this change a divalent metal cation migrated from the rubber stopper into the drug product vehicle. The released metal cation activated a process-related impurity causing N-terminal degradation of the final product. In the end, the leaching of the metal cations was mitigated by implementing a modification of the elastomeric closure by adding a fluoroelastomer film. [1] 

Another example of the potential impact is an elastomeric closure system on a lyophilized product. If an inappropriate closure is chosen, moisture could migrate through the closure or from the closure itself. Over time, this may cause chemical and/or physical changes to the lyophilized drug cake, resulting in a risk to the effectiveness and well-being of the patient. (Fig. 1). These are relatively simple examples of the impact a primary package could have on drug efficacy. 

FIG. 1. LYOPHILIZED PRODUCT IS SUBJECT TO CAKING FROM MOISTURE INTRUSION IF IMPROPERLY PACKAGED. credit: West

	Safety is an issue of utmost importance, and there is a range of aspects to consider. Of course, the drug itself is the primary driver for this attribute, but the container closure/delivery systems have some bearing on the patient’s well-being. Factors related to contamination of the drug product, counterfeit defense, trouble-free administration and protection of the caregiver are all strategic considerations relating to safety. As with efficacy, both the primary package and the delivery system can have an impact that needs to be considered and evaluated. In the case of the primary container closure system, seemingly minor impurities from the container closure system and/or minor changes in the drug formulation could lead to significant impacts in clinical safety. One example is the reported case of leachables acting as adjuvants triggering immune response. [1] 

Secondary packaging, such as aluminum seals with plastic buttons, is commonly used to minimize tampering. The surfaces can be used for printing or other technologies that can help convey warnings and cautionary statements. (See Fig. 2). 

In the case of delivery systems, safety is extremely important as there are immediate implications to the patient. One of the most significant aspects is the relationship of needle safety to both the caregiver and the patient. The use of passive safety needle systems is a way to address this issue while reinforcing product differentiation. 

	In respect to the primary package, it is critical to think through not only requirements for long-term storage but also how the product will be used in the field. For instance, in a vial/stopper/seal format, how will the drug be accessed? Does it need to be reconstituted or transferred prior to delivery? Problems in the field are typically related to not understanding these types of issues in practical usage. 

Certainly there are many critical considerations that relate to the functionality of delivery systems. A device must function as it is intended. Delivered volume needs to be consistent. When working with a device supplier, it is essential to understand if they have applied techniques such as a Human Factors Analysis (HFA) to anticipate the ways a device or delivery system can be misused in the field—especially with systems intended for self administration or home health care. 

Delivery systems can be designed around specific therapeutic categories. New materials like cyclic olefin polymers offer flexibility in molding, which in turn can enable improved product features. For example, those suffering from rheumatoid arthritis may have dexterity issues that can be mitigated by producing an easy-to-use system that has a single, large, push-button activation. Those suffering from diabetes, where feeling may be lost in hands, may require audible or visual cues that the injection is complete. As the market moves more toward self-injection, the ability to differentiate a product based on a delivery system’s features will accelerate consumer acceptance. 

The function of a delivery system, whether used by a healthcare professional in a clinical setting or by an individual in a home setting, is extremely important and is a critical complement to the efficacy and compliance of a drug product. 

There are cases where the addition of a reconstitution, transfer or delivery system has allowed for growth of a drug in a relatively stagnant or super competitive marketplace by facilitating administration. An example of this is Watson Pharmaceuticals’ freeze-dried drug Trelstar® (triptorelin pamoate for injectable suspension). To market Trelstar in the US, Watson formed a partnership with West Pharmaceutical Services, Inc., in an effort to provide a safe and convenient delivery device. West’s MixJect® drug transfer device provides reconstitution with a diluent prior to injection by syringe.[2] The entire process makes administration and disposal significantly easier and safer for patients and caregivers. Watson has found the response from patients and physicians to be very positive. (Fig. 3) 

FIG. 3. WATSON PHARMACEUTICALS' TRELSTAR INJECTABLE FEATURES A RECONSTITUTION STEP PRIOR TO ADMINISTRATION. credit: West

	In respect to the strategy of productivity, a pharmaceutical or biotech organization must evaluate options that can allow them to be as efficient and lean as possible. Currently many industry business models are changing to bring a much greater focus on understanding the core expertise of an organization and work with supplier-partners to utilize products and services which fall outside of the pharmaceutical company’s core areas of expertise. Quite often there may not be a significant amount of expertise relating to packaging and delivery systems within an organization. In addition, with the limitations of resources in general, it may be much more effective from a strategic standpoint to work closely with partners to adopt packaging and delivery systems that will minimize the expertise and manpower needed both in R&D studies and in actual commercialization.

	An example of convenience from a packaging component standpoint is the consideration of what component preparation and packaging is used. For instance, ready-to-sterilize or ready-to-use options, already formatted for barrier isolators, are convenient ways to minimize labor and capital expenditure in component preparation. 

In respect to delivery systems the use of sterile, ready-to-use devices is quite common. Not only does this facilitate usage but puts the responsibility for issues such as validation squarely on the shoulders of the system supplier. In addition, such devices are convenient for the end user. Options such as kitting, combining the drug and delivery system together, can aid in end-user convenience, while also delivering on the aspect of differentiation. 

	Compliance is a must and it is a valuable asset in maintaining a competitive advantage. By building a relationship with a supplier to push the compliance of a container closure/device system upstream, a pharmaceutical company can minimize its exposure and expense to package a drug product. It is critical that the supplier has a full understanding of the cGMP and quality systems requirements associated with packaging components, medical device components and medical device production requirements. With respect to components, Drug Master Files (DMFs) are typically used and are the responsibility of the supplier to submit and coordinate with the FDA. If these are not adequately built or updated, this can impact the pharmaceutical company’s drug application—thereby losing valuable time in the approval process. In the case of medical devices or similar delivery systems, a 510(k) notification is submitted by the device manufacturer, who is clearly responsible for the cGMP and quality aspects of the delivery device. In both cases there is a critical partnership to be developed between the pharmaceutical /biotechnology industry and its suppliers for the purpose of achieving both technical and strategic objectives. 

	A drug product cannot be evaluated separately from its container closure system, from both regulatory and commercial acceptance perspectives. In many cases, this means the coming together of the drug package and its delivery system. In some cases, the system may encompass a vial/stopper/seal system and a vial adapter, which assures consistency in drug removal, or it could be as involved as a prefilled syringe in an auto-injector. 

In any case, there are multiple criteria that need to be evaluated to ensure that a drug product makes it through development and regulatory approval expeditiously. It is critical that the entire process be scalable and commercialized in an efficient, compliant way that can be reproduced with a minimum of variability, while being flexible enough to incorporate and support changes over time because of purposeful product lifecycle management. 

Collaboration can enable performance goals to be met efficiently while better managing operating costs. A strong pharmaceutical manufacturer-packaging/delivery system supplier relationship can be achieved by communicating defined expectations through open and honest dialogue. A true partnership will provide the necessary support for day-to-day efforts and for solving challenging problems, assuring continual supply of product. PC

	1. American Pharmaceutical Review, June 2009: Risk Management Strategies for Safety Qualification of Extractable and Leachable Substances in Therapeutic Biologic Protein Products, by Ingrid Markovic, Ph.D.

	2. Packaging Digest, February 2010: Drug Delivery with Ease and Comfort, Reed Business Information, a division of Reed Elsevier Inc.

	Trelstar® is a registered trademark of Watson Pharmaceuticals, Inc.

	MixJect® is a registered trademark of Medimop Medical Projects Ltd.

	Flip-Off® is a registered trademark of West Pharmaceutical Services, Inc., in the United States and other jurisdictions. 

Frances L. DeGrazio is Vice President, Marketing and Strategic Business Development at West Pharmaceutical Services, Inc. 

Articles

Often mistakenly considered an afterthought, today’s packaging and delivery systems can powerfully affect the safety, efficacy and commercial success of injectables