A capability of increasing importance across the pharmaceutical and biopharmaceutical industries is the ability to share information in an effort to build awareness and better manage the complexities of drug product development. Because regulatory agencies are charged with ensuring safe and effective delivery of drug products to patients, they have continued to provide guidance on the subject of knowledge management (KM) to reinforce its importance within the industry as a whole.

The advent of biologic based drug products has brought a different set of technical challenges to the industry, versus historic small-molecule, chemically derived drug products. There has been significant growth in biologic drug product approvals over the years. Also notable is the fact that biologics is a broad category; protein approvals are most common, followed by cell and gene approvals. The complexity of these new and developing technologies is one of the factors substantiating the need for new ways of sharing information and doing business.

One of the first places to start to understand the regulatory drivers for better management of knowledge is the International Council for Harmonization (ICH) guidance entitled Q10Pharmaceutical Quality System, which was published in April 2009. ICH Q10 demonstrates industry and regulatory support of an effective quality system and facilitates innovation and continual improvement. More recent guidance documents, such as the draft of ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (to be finalized late-2019), build on earlier guidances to reinforce and provide further clarity for the industry.

QbD’s role in knowledge sharing
Quality by design (QbD) is defined by ICH Q8 as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.”^1,2 It is encouraged as an industry best practice in the development of drug products. Quality risk management includes the design and organization of documentation in support of drug products, assembled in a way that is easy to understand and leverage.

Within ICH Q10, there is a section specifically focused on KM as an enabler of quality systems.  Product and process knowledge needs to be developed from the earliest stages through commercialization, ongoing lifecycle management, and continuous improvement. Every organization should have the ability to build and manage this information as it develops in order to facilitate learnings and minimize both duplication of effort and technical risks. Broadly, KM can be broken into five categories of tools: ones to acquire, store, analyze, disseminate, and support a comprehensive program.

To implement QbD in an effective way, it must be executed from a holistic perspective, utilizing information from an assembly of disparate sources and then leveraging them to assess the criticality of various attributes.1,2 Once the quality target product profile (QTPP) and critical quality attributes (CQAs) are defined, the application of risk management to prioritize the approach to understanding and building the product’s design space and its ultimate control strategy is needed. For documenting and building these relationships, the need for KM is obvious.

Bringing together the world of QbD with the ever-growing world of biologics leads to even more complexity. This is because almost all biologic drug products are delivered by injection, due to their molecular size and sensitivity to degradation in the digestive tract. In an effort to facilitate clinician and patient ease, the industry has moved toward the use of drug/delivery combination products, such as a syringe in an auto-injector or a large-volume wearable system.

The term combination product, per the FDA, includes³:

1. “A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
2. Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
3. A drug, device, or biological product packaged separately that, according to its investigational plan or proposed labeling, is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product, the labeling of the approved product would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose);
4. Any investigational drug, device, or biological product packaged separately that, according to its proposed labeling, is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.”

The complexity of combination products
The advent of these new, more complex drug/delivery systems reinforces the ongoing need to ensure information is being built, retained, and shared not only during development, but throughout the lifecycle of the product. Combination products bring together the worlds of drug products and medical devices from a regulatory and compliance perspective. This means managing both QbD and design controls (DC). The market application holder is responsible for product and process understanding of not only their drug product but the delivery system that is used in their ultimate combination product. Thus, building more collaborative ways of exchanging information within a pharmaceutical organization, and within the supply chain, takes on a heightened importance. Although oversight of suppliers has always been a responsibility of the drug manufacturer, the dynamic of building more information exchange with suppliers and combination product applicants brings many new challenges.

Similar to QbD, DC for devices is a systematic approach applied to development that begins with predefined objectives and emphasizes product and process understanding and process control based on sound science and quality risk management. DC begins by defining user needs and desires, as well as customer-centered insights. User needs and intended uses are translated into device product attributes and functional requirements—these are design inputs.⁴

Current good manufacturing processes (CGMPS) are detailed in the Code of Federal Regulations 21 CFR 820 for devices, and in 21 CFR 210/211 for drug products. These both apply to the combination product’s manufacturer. However, choosing suppliers familiar with, and actively practicing the critical components of, CGMPs can offer assurance that the drug package components or combination product constituent parts meet key quality system requirements.

FDA requires that a manufacturer oversees and ensures that its suppliers have adequate quality management processes in place. This is specified in the Title 21 CFR: Section 820:50 (Purchasing Control): “Each manufacturer shall establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements.”⁵ With the continued growth of combination products, it is clear that the partnership between suppliers and pharmaceutical and biopharmaceutical manufacturers must continue to develop in a positive way. The exchange of knowledge between suppliers and these manufacturers is extremely important on an ongoing basis.

ICH Q10 extends quality systems responsibilities for drug product manufacturers to any activity they outsource. One particularly important clause states that the organization hiring the contractor should be responsible for assessing the suitability and competence of the contract acceptor to carry out the work required. It also establishes that all responsibilities for quality-related activities between two parties should be specified in a written agreement.⁶ These references are just an example of why information and knowledge exchange between a drug product or combination product applicant and its key suppliers is crucial to the overall success of delivering a consistent and high-quality product to the patient.

The role of packaging systems
Suppliers of the packaging and delivery systems used for drug products have a unique perspective and understanding of risks relating to these systems and should be the starting point for a drug holder to build their knowledge base. For both packaging and delivery systems, safety, performance, and compatibility are all critical features. The understanding of the materials that comprise these products should be the starting point for knowledge transfer. This material understanding should feed into the qualification process of the packaging and delivery systems to be utilized. All this information should inform the risk-based decision making that occurs throughout development. Suppliers should be leveraged as a starting point, and in many cases, a partner, to help exchange information and findings throughout the process.

KM takes on a unique importance in relationship to specific development programs; however, there is also a much broader lens of knowledge exchange in the realm of drug product development, packaging, and successful delivery to the patient. This comes through the exchange of knowledge and experience from an industry perspective. As every organization is challenged with the same changing dynamics, the exchange of best practices and key learnings is beneficial at an industry level to provide improved clarity. This exchange enables forward progress with various technical and regulatory challenges for the industry as a whole and should be the expectation of thought leaders in this space.

Of course, the effective management of an organization’s knowledge assets can improve its competitiveness, adaptability, and chances of success, whether as a market application holder or a supplier to the industry. So, attention and investment in KM will serve an organization well. 

References

1. T. Garcia, G. Cook, R. Nosal,  J Pharm Innov. 3 (2) 60-8 (2008).
2. A.S. Rathore and H. Winkle, Nat Biotechnol. 27 (1) 26-34 (2009).
3. FDA 21 CFR 3.2(e)
4. S. Neadle and I. Vàradi, “Product Development and Manufacturing Challenges for Combination Products,” Americanpharmaceuticalreview.com, Feb. 16, 2018.
5. FDA 21 CFR 820:50
6. ICH Q10

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Fran L. DeGrazio is Vice President of Scientific Affairs and Technical Services at West Pharmaceutical Services, Inc. She has been in the pharmaceutical packaging industry for over 30 years with extensive expertise in the area of delivery of injectable drug products, such as vial/closure combinations, pre-fillable syringe systems and injectable combination products. In her current role, she is focused on providing scientific industry leadership and innovation around West’s new products and services.