A Quality Approach to Components

- Mike Schaefers
Vice President - Global Product
Management and Marketing Operations
West Pharmaceutical Services, Inc.

With a steady rise in injectable biologic drugs coming onto the market, there is growing need for safe and effective packaging that addresses the specialized characteristics of these novel therapies. This article discusses increasing demand for quality in drug packaging and the benefits of instuting a Quality by Design (QbD) approach to the design and development of packaging components

Driven by concerns for patient safety, regulatory agencies across the globe are asking pharmaceutical companies to build quality into their products from the start to ensure consistent quality throughout a drug products lifecycle. Increasing regulatory scrutiny and quality standards are placing added demands on drug manufacturers and their suppliers. Quality is particularly at the forefront with the influx of new biologic and biosimilar drugs.

Over the past several years, there has been a steady rise in new biologic drugs coming onto the market. This trend is likely to continue in the future , with the QuintilesIMS Institute predicting that biologic treatments for autoimmune diseases, including treatments for rheumatoid arthritis , psoriasis, ulcerative colitis, Crohns disease and a range of related disorders will continue to see increasing usage across geographies and will reach USD 75-90 billion in spending by 2021. In addition, biosimilars will be available for several of the leading autoimmune products by 2021, potentially allowing wider use of these medicines.1

With increasing numbers of injectable biologic and biosimilar drugs becoming available for use by healthcare providers and patients around the world there is growing need for safe and effective pharmaceutical packaging that addresses the specialized characteristics of these novel therapies.

The Complex Needs of Biologics

Biologics and biosimilars offer many patients new hope in the management of their chronic conditions. However, despite the promise for patients, maintaining the safety and efficacy of these cutting-edge therapies can present unique challenges around packaging , containmentand delivery for pharmaceutical manufacturers.

To begin, many biologic drugs are sensitive, creating potential for interaction with containers and packaging components. Areas of concern include potential delamination of glass vials, interaction with silicone oil and tungsten from glass syringes, and extractables and leachables from elastomeric closures. All of these issues may compromise a drugs quality and potentially put patients at risk. Additionally, some biopharmaceuticals require storage at extremely cold temperatures. Such nuances inherent to these advanced therapies are leading drug manufacturers and their packaging and delivery system providers to think differently about containment and delivery to better ensure drug efficacy and patient safety throughout a drug products lifecycle.

To that end, pharmaceutical manufacturers are now making packaging and delivery systems an integral component of drug development and research, as opposed to an afterthought to address right before bringing a therapy to market.

Increased Regulatory Focus on Quality

With many sensitive biologics coming on the market as combination products, the compatibility of packaging components with injectable drugs and their delivery systems is being closely scrutinized. In order for a treatment to be effective it is important to ensure that the drugs delivery system is easy to use, reliable and effective. As part of an integrated delivery system, packaging components play an important role in drug quality, patient safety and device performance. They, therefore, must be given careful consideration as part of the drug development process.

For example, the US Food and Drug Administration (FDA) defines a combination product as , "A product comprised of any combination of a drug and device; a device and biological product; a biological product and a drug, or a drug, a device and biological product." 2 Manufacturers of combination products in the US must abide by two FDA regulations for good manufacturing practice:

• cGMP Finished Pharmaceuticals part 21 CFR 210-211
• QSR Regulation for Devices 21 CFR 820

Some of the primary areas covered by CFR 820, and which differ from CFR 210- 211, include management responsibility, purchasing controls , corrective and preventive action and design controls. As part of the industrialization of syringe plungers using the QbD approach, aspects of CFR 820 must be incorporated into the manufacturing process.

These regulatory requirements are challenging drug makers to look for consistent, reliable, high-quality packaging components that meet the standards of good manufacturing process as well as the high expectations of end users.

Quality by Design for Drug Packaging Components

To address these challenges, the adoption of Quality by Design (QbD) concepts in the design and manufacturing of packaging components is gathering momentum within the industry . QbD delivers an improved, data -driven output, providing manufacturers with superior product and process understanding that minimizes risk, emphasizes patient-critical quality requirements and enhances drug product effectiveness.

The scientific , risk - mitigation based QbD approach is fast be coming an essential strategy for bringing high - quality therapeutics to market quickly and efficiently. By building QbD principles into design and development from the very beginning, manufacturers can decrease variability in the manufacturing process and the end product. High-quality components designed using QbD process e scan enhance the performance of drug delivery systems and protect sensitive drug products with exceptional cleanliness and barrier properties, while helping to ensure patient safety and drug product efficacy.

Combination products such as prefilled syringes, auto-injectors and other selfinjection systems are rapidly gaining momentum among drug manufacturers. According to the "Drug Delivery Products" report from industry market research firm The Freed onia Group3 , demand for parenteral drug delivery products is projected to rise more than 10 per cent annually to USD 86.5 billion in 2019, with prefillable syringes accounting for the largest and fastest growth among parenteral devices.

Market trends toward home - use and patient self-administration of drugs used to treat chronic conditions have made prefillable syringe systems - and selfinjection systems that utilize prefillable syringes - ideal choices for many singledose drugs. For drug manufacturers, prefilled syringe systems for biologics, vaccines and other injectable drugs offer convenient, fixed-dose options that are easily adaptable to automated injection devices. Additionally, prefillable syringe and self-injection systems may be able to reduce therapy and injection costs, as well as significantly reduce overfill when compared to single-dose vials. Prefillable syringe systems may also optimize the number of doses from the existing drug supply, while offering delivery options that can help to differentiate drug products in an increasingly crowded market.

For patients, prefillable syringe systems offer ease of use and enhanced convenience for those who require frequent dosing and, when combined with an auto-injector system, can provide a more portable drug delivery system. Use of a prefilled syringe system also has the potential to minimize microbial contamination and reduce medication dosing errors.

By considering the impact that prefillable syringe systems and their components can have on a particular drug product early in the drug development process - and employing QbD strategies to overcome development challenges - drug manufacturers can minimize the risk to quality and position the product to meet the needs of the ongoing drug product lifecycle .

Instituting a QbD Approach for Components

The QbD approach promotes a holistic understanding of the drug product, its integrated delivery system and the manufacturing process. Employing a QbD strategy starts with product development. When designing and developing a product using QbD principles, manufacturers must define desired product performance goals and identify Critical Quality Attributes(CQAs). The product and process can then be designed to meet those attributes, potentially improving understanding of how material attributes and process parameters impact CQAs and enabling manufacturers to mitigate variability. As a result of this knowledge, a company can continually monitor and update its manufacturing process to ensure consistent product quality.

One class of products in particular that is essential to understand and assess during the QbD process is prefillable syringe plungers. Plungers (also called pistons and stoppers) are critical elements because they serve as the primary seal for container/closure integrity, help maintain the purity of drugs during shelf life, and function to transfer contents of the barrel and deliver drugs to the patient. Plungers are typically made from butyl rubber and can be coated with a fluoropolymer film that can increase lubricity and serve as a barrier between the drug and the elastomer, reducing the potential for extractactables and leachables.

As industry demands for higher-quality components have evolved, there is growing need for plungers developed using QbD processes. The design and manufacturing of high-quality plungers should follow a development lifecycle program that uses a Quality Target Product Profile (QTPP) to establish CQAs for control of breakloose and glide forces. The QTPP can serve as a guideline throughout the development process - which should include risk - based design inputs , Finite Element Analysis (FEA) modeling, data generation on multiple concepts and final product performance verification with barrels from multiple suppliers - to ensure that targeted specification values for breakloose and glide force are met.

By applyinga holistic, QbD approach to the design and development of plungers and other prefillable syringe components, packaging manufacturers can gain a thorough understanding of both the product and the process. This, in turn, enables multiple benefits for manufacturers and end users:

Improved Functionality - High-quality plungers can enhance the functionality of prefillable syringes and self-injection systems. Using QbD principles can help to optimize break loose and glide forces - aspects that are very important when syringes are used in combination with an injection system. By optimizing a delivery system's functional and dimensional performance, it is possible to improve the consistency of injections and the rate of injection times.

• Patient Confidence - A self-injection system needs to function consistently and reliably in order for patients to have confidence that it will work. QbDdesigned components allow for largersize delivery systems and greater dosing volumes which may enable home administration , encourage device use and more accurate dosing, all of which can help boost a patient's confidence in their use of a selfinjection system.

• Efficient Manufacturing - Employing a QbD approach in the manufacturing process can significantly reduce plunger variation from part to part. This can help facilitate more efficient manufacturing processes and support a reliable supply of drug products.

Use of QbD principles ensures that components are developed using sciencebased and data-driven decisions, and that they meet critical specification for defects, visible and sub-visible particulate and extractables consistently. The knowledge gained throughout the QbD process can be used on an ongoing basis to maintain continuous improvement by the manufacturer.

Partnering for Quality

Drug packaging components play a vital, but often overlooked, role in drug safety and efficacy. Growing use of biologics and the trend toward self-administration means manufacturers need to select components that have a high level of reliability, consistency and compatibility with sophisticated drug products and delivery systems over the course of their lifecycle. Components are a critical part of integrated combination products and are essential to ensuring delivery systems are safe, intuitive and easy to use, but it can be difficult to know which component is the best quality fit for a particular drug product.

Problems with primary containment materials can result in delayed regulatory approvals , packaging variability and shortages of needed drug product on the market. All three problems can significantly damage a company's bottom line as well as its reputation. But higher quality can come with higher investment, so the challenge for drug containment manufacturers becomes achieving the balance between managing the costs of provide higher-quality products while staying mindful of the customer's total cost and profitability.

Fortunately, there are new component offerings on the market designed to address the need for high-quality packaging solutions. These include prefillable syringe plungers designed using QbD principles to provide high reliability for breakloose and glide force, dimensional accuracy and consistency, sub-visible and visible particulate control, and low parts per million (ppm) defect attributes.

When selecting components for primary packaging , it is important that drug manufacturers also look for products that have barrier film technology, are vision verified and that are "ready to use."Careful consideration should be given to components that are designed and manufactured according to QbD principles and have optimal levels of dimensional and functional performance. These features can help minimize risk further down the line toward commercialization.

To maximize a drug product's safety and efficacy, pharmaceutical companies and their drug packaging and delivery partners should build new quality principles into the entire manufacturing process, from design and development to commercialization and administration. Selecting a packaging partner with expertise in QbD early in the development process can help drug makers choose a high-quality component for use in prefillable syringe systems that will meet demands for high quality, improved total cost, and increased safety and security for the drug product.

By working with a packaging partner that employs a QbD philosophy, pharmaceutical manufacturers can employ high-quality packaging components that can help lower their total cost of ownership through reduced compliance risk, filling rejection rate and process costs. Full return on investment can be realized once a drug product is commercialized and has gained patient loyalty through ease of use , therapeutic benefit and high confidence in the delivery device. Perhaps most importantly though, components created through a QbD approach offer features that are designed to ensure the highest levels of reliability, which ultimately helps the pharmaceutical industry to achieve its most critical goal: providing the safest and most effective drug products for their patients.

Conclusion

From early stage development, through manufacturing, to patient use, modern biologics and biosimilars require innovative solutions for containment and delivery. In addition , regulatory agencies and pharmaceutical companies have increased quality expectations in an effort to enhance patient safety.
As the next generation of drugs become available, the limitations of past approaches to containment and delivery are more pronounced, and greater scrutiny should be paid to the interaction between the drug product and its container closure system. Additionally, stability during shelf life, particulate burden and the ease of delivery to patients are important factors to consider.

In order to ensure that biologic drug products are used to their full potential, biologics and biosimilars manufacturers along with their containment and delivery system partners need to collaborate early in the drug development process to gain a thorough understanding of the needs of both the patient and the drug product.

With this close collaboration, novel primary containment materials and innovative delivery systems can come together to drive product differentiation, patient compliance and caregiver safety for the cutting-edge therapies of the future.

References

1. Quintiles IMS Institute. Otlook for Global Medicines through 2021: Balancing Cost and Value. December 2016.
2. U.S Food and Drug Administration. Combination Products. Acessed February 2016.
3. The Freedonia Group. Drug Delivery Products. December 2015.