Packaging may seem like the end of the process in medical device and drug development, but it should be at the front of every product developers mind.
As drug and device manufacturers strive to distinguish products in a competitive field, consideration should be given to optimizing packaging and delivery systems. Partnering with experienced packaging manufacturers early on in the development process to create optimized container and delivery solutions gives manufacturers opportunities to improve patient compliance, realize efficiencies throughout a drug’s lifecycle, maintain quality, protect patient safety, facilitate ease of use/administration, and facilitate manufacturing and regulatory processes.
Growing Need for Differentiation: A Drug-Delivery Example
According to the PwC Pharma 2020 report, the trend toward individual therapies will drive manufacturing and distribution techniques in a new direction. By 2020, fixed dose combinations, imaging for diagnostics, new antibody treatments, biomarkers, tissue engineering, nano carriers, gene-based and stem cell therapies are all expected to reach the market.1
Additionally, over the next decade the pharmaceutical industry will see generics will enter the market as more branded drugs move off patent. As these new drugs enter a crowded marketplace, product differentiation will be key to claiming and sustaining market share.
In pursuit of differentiation, innovative administration devices will be needed to deliver new dosage forms effectively, and to maintain supply to meet the demands of future drug products. Suitable materials will need to be qualified to be in contact with drug products to manufacture, contain, protect, ship, track and effectively deliver these dosage forms.
Improving Patient Compliance
Patient non-compliance can be attributed to a variety of factors. Miscommunication between physicians and patients, confusing instructions, overly complex dosing regimens, forgetfulness, and simply not understanding the benefits and importance of compliance (and the consequences of non-compliance) are just a few of the problems patients encounter when managing long-term conditions.
Adherence can be improved by providing simplified medication packaging, effective medication reminders and enhanced patient education. However, as more biopharmaceutical drugs enter the market – many of which may require special drug container closure and delivery systems for issues such as low temperature storage or high viscosity – improvements in product packaging will be necessary. Drug product manufacturers must move from a product-centric to a patient-centric manufacturing focus. Such a move can positively influence patient compliance, as well as the clinical outcome, and can lead to a higher return on investment.
It can take more than 12 years and a significant financial investment to bring a drug product to market.2 A drug product’s success relies on its efficacy, safety and manufacturing efficiencies along with innovative strategies and patient adherence. To facilitate this success, sophisticatedpackaging and delivery systems are necessary throughout a drug product’s lifecycle.
Planning for appropriate container closure materials that can be sustained during the different stages of the drug product lifecycle should consider several major factors, including:
• Mechanical strength;
• Protection of the drug product;
• Potential for contamination of the drug product;
• Stability of the material;
• Visual appearance;
• Impact of sterilization;
• Compatibility with the drug product and the other packaging components; and
• Supply chain security.
These elements should be evaluated appropriately and proportionally to each lifecycle stage, recognizing opportunities to identify areas for improvement.
In the initial stages of development, vials and closures are typically used. However, with certain drugs, such as oncology drugs, vaccines or anti-infectives, the ultimate strategy may include administration via prefillable syringes or, as a long-term goal, auto-injectors. In these cases it is desirable to have the ability to form the same primary materials into different sizes and shapes suitable for these advanced delivery systems. For instance, high performance cyclic olefin polymers such as the Daikyo Crystal Zenith polymer can be custom molded and may be especially compatible with biopharmaceuticals. Crystal Zenith is a strong, stable material that can be subjected to sub-zero temperatures, is break resistant, can be e-beam sterilized, and has relatively few constituents with less potential to interact with a drug product.
The qualification of drug packaging and delivery materials can be time consuming and expensive, as both chemical and physical attributes need to be assessed for suitability, and the drug product’s compatibility with the packaging materials must be verified over the intended shelf life. Limiting the number of primary materials that will be in contact with the drug product is an economical and timely advantage when chosen early in the development cycle. 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.
Collaboration between drug and packaging manufacturers can enable performance goals to be met efficiently while better managing operating costs. A strong relationship between the pharmaceutical manufacturer and packaging supplier can provide necessary support for day-to-day efforts, including appropriate selection of materials, solving of challenging problems, and assuring continual supply of product.
Milestones established throughout development will allow qualified materials to be adapted to meet demands of next generation delivery systems. For example, the first generation drug product delivery system may be administered intravenously or packaged in a vial that typically requires trained professionals to administer the dose properly. A prefillable syringe system could be fabricated from the applicable qualified materials for the next generation. The application also may be suitable for an auto-injector.
Ensuring Drug Quality and Patient Safety
Efficacy and safety are the foremost considerations in the development of a new drug or biopharmaceutical product. Packaging and delivery systems are critical in ensuring that there are no issues that could negatively impact these characteristics over the drug’s shelf-life and during its administration.
The characteristic of the drug is at the core of this issue; however, if the drug achieves its therapeutic objective, the container closure system and delivery system should enhance the experience without causing any negative impact from a compatibility or stability standpoint.
When identifying and assessing risk to the efficacy of a drug product, the following factors should be considered:
• Storage and shipping environments;
• Integrity of primary and secondary containment;
• Delivery of accurate doses;
• Change in drug product potency and physical characteristics;
• Impact of sterilization on container closure systems;
• Sensitivities to moisture;
• Extractability of organic and inorganic substances from containers; and
• Toxicity of substances that may to leach into the drug product.
Strategic considerations for safety include:
• Contamination caused by harmful substances migrating into the drug product from contact materials;
• Measures to protect against drug counterfeits;
• Trouble-free administration; and
• Protection of the individual administering the dose.
Both the primary package and the delivery system can have an impact on the patient’s well-being and should be factored into the drug product lifecycle plan. For example, the efficacy of a lyophilized drug product may be impacted if an inappropriate closure is chosen. Moisture could migrate through or from the closure and could, over time, cause chemical and/or physical changes to the lyophilized drug cake. Such changes could result in risk to the effectiveness of the medication, and thus the well-being of the patient.
In the case of patient safety, the primary container closure system can be compromised by minor impurities from the system. Minor changes in the drug formulation also could lead to significant impacts in clinical safety. Selection of materials to be compatible with drug products should be qualified for potential leachables.
The compatibility of primary container closure systems is just one packaging consideration. 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. Planning during product development to identify attributes to support drug product safety and efficacy in relation to container closure and delivery systems can provide the means to mitigate risks.
Ease of Use and Administration
The function of a delivery system, whether used by a health care 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.
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 to ensure accurate dosing. 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 healthcare.
A pharmaceutical company can gain a competitive advantage by planning for a self-administration system in the earliest stages of development. Moving the point of administration from the clinical setting to a home care settingwill provide direct and indirect benefits to the patient. Self-injection systems can result in cost savings, so an efficient and effective delivery system will facilitate patient adherence and have tremendous economic value. Initial user requirements should be evaluated for special handling requirements, ease of use, patient and caregiver safety and competitive advantage.
The addition of a reconstitution, transfer or delivery system may also facilitate ease of administration. Watson Pharmaceuticals’ freeze-dried drug Trelstar (triptorelin pamoate for injectable suspension) uses West Pharmaceutical Services, Inc.’s MixJect drug transfer device to provide reconstitution with a diluent prior to injection by syringe.3 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. Patient compliance is the lifeline to preserving product loyalty and is the most valuable asset in maintaining a competitive advantage.
Facilitating Manufacturing and Regulatory Compliance Processes
A pharmaceutical or biotech organization must evaluate options that can allow them to be as efficient and lean as possible. Many industry business models are changing to bring greater focus on understanding the organization’s core expertise and then work with supplier-partners for products and services that fall outside of the pharmaceutical company’s core areas. Quite often there may not be a significant amount of expertise relating to packaging and delivery systems within a pharmaceutical manufacturer. 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 in R&D studies and in 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, it also puts the responsibility for issues such as validation squarely on 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 and differentiate the product.
Regulatory compliance is another route to 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 Current Good Manufacturing Processes (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 Food and Drug Administration. 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.
The formation of partnerships with packaging manufacturers early in the development process can help ease the transition from research to commercialization as the market expands. The trend toward individual therapies has created a manufacturing challenge that together, drug and packaging manufacturers can solve with a patient-centric focus on the lifecycle of the drug. New manufacturing techniques, as well as expertise in the regulatory and compliance environments, can help bring new products to market efficiently and cost-effectively while differentiating the product through unique administration and delivery systems. As these trends continue, patient compliance should rise, benefitting patients and manufacturers alike.
The author would like to acknowledge assistance from West’s Diane Paskiet, associate director, Scientific Affairs.
1 PwC “Pharma 2020 Supplying the Future”
2 Joseph A. DiMasi, Ronald W. Hansen, and Henry G. Grabowski, “The Price of Innovation: New Estimates of Drug Development Costs,” Journal of Health Economics, vol. 22, no. 2 (March 2003), pp. 151-185.
3 Packaging Digest, February 2010: Drug Delivery with Ease and Comfort, Reed Business Information, a division of Reed Elsevier Inc.
Daikyo Crystal Zenith® is a registered trademark of Daikyo Seiko, Ltd.
Trelstar® is a registered trademark of Watson Pharmaceuticals, Inc.
MixJect®is a registered trademark of Medimop Medical Projects, Ltd., a subsidiary of West Pharmaceutical Services, Inc.
Leveraging Packaging and Delivery Systems for a Competitive Advantage
Early partnership with packaging providers creates optimized solutions—a drug-delivery example.
By Fran DeGrazio
Published November 8, 2011
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