Injectable Combination Product Development: Facilitating Risk-Based Assessments for Efficiency and Patient Centric Outcomes.

Combination products (CPs), designated by the US Food and Drug Administration, continue to be on the rise, from the innovation of novel medicines and greater demand for injectable home and self-administration. CP qualification, its constituent parts or intended use, will depend upon the regulatory jurisdiction with reference to the product's primary mode of action. In the case of a drug product combined with a device, a consult or collaborative review process involving different Centers within the US Food and Drug Administration may be necessary. Policies and practices from different legislative branches of government will need to be merged for a single application. This presents a challenge for aligning information for the application dossier as it relates to a drug master file or drug-device CP design history file. A common objective for both pharmaceuticals and devices is to identify and evaluate patient risks to be mitigated, controlled, and managed across the drug product lifecycle. These concepts are reflected in the regulatory practices of pharmaceutical quality by design and device design controls. Early stakeholder engagement with this dynamic process between different regulatory paradigms becomes an advantage. This manuscript describes aspects for early planning for injectable drug-device development to facilitate time to market with patient centric solutions.

Achieving "Zero" Defects for Visible Particles in Injectables.

The reduction of visible particles in injectable products is an important element in the consistent delivery of high-quality parenteral products. An important part of this effort is the control of particles that may emanate from the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the Pharmaceutical Manufacturers Forum (PMF), has undertaken the task of developing test methods to assess the cleanliness of primary packaging components used in the manufacturing of sterile injectable products. Further work is focused on end-to-end analysis of the supply chain to identify additional points where particles may enter the finished product workflow. This includes shipment, receipt, transfer, and fill and finishing operations. This information and appropriate corrective actions and control methods, coupled with appropriate patient risk-based acceptance limits, are intended to provide better and more consistent supply of injectable products that meet current compendial and good manufacturing practice (GMP) expectations. Aligning control limits between supplier and pharmaceutical manufacturers will offer further improvement. This paper describes the formation of a task force to address these needs and current progress to date.LAY ABSTRACT: Visible particles must be controlled in parenteral products. Such particles come from many sources including the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the Pharmaceutical Manufacturers Forum (PMF), has formed a task force to review and improve particle measurement methods and perform an end-to-end analysis of how particles may enter into parenteral products. These activities are intended to lead to more consistent control limits for visible particles and ultimately more consistent supply of high quality injectable products.

Holistic Considerations in Optimizing a Sterile Product Package to Ensure Container Closure Integrity.

A new major chapter dealing with container closure integrity was released by the United States Pharmacopeial Convention. Chapter <1207> provides a significant amount of education and guidance concerning test methodologies to prove that a system is integral and safe for use. The test method used is only one of the major considerations in approaching the challenge of proving an integral system. This paper takes a holistic review of all the major considerations needed in qualifying a new vial system for container closure integrity. There is substantial interplay among many aspects in the process of sealing a vial. This review helps to define major risks that need to be considered and mitigated and reinforces the need to understand the maximum allowable leakage limit that is acceptable for a specific drug application. A typical risk-based approach considers materials, test methods, process, people, environment, and equipment. Each of these aspects is considered in some detail along with a recommended process flow for building a best practice, science-based approach. This approach will inform decision making for evaluating the correct combination of components and assuring they are assembled and tested in an appropriate manner. This work, once completed, can be the basis for a vial system platform or specific drug application qualification.LAY ABSTRACT: Container closure integrity is a fundamental requirement of every sterile drug package. With recent upgrading of compendia standards and guidance around this issue, there is an opportunity to better define a best practice approach to a complicated subject. It is important to recognize that there is substantial interplay among the components of the system, the process of assembly, and the test methods that are used. This paper takes a holistic approach to discussing these issues and identifying the risks that must be considered in assuring an integral container over the shelf life of a drug product.

Best practices for extractables and leachables in orally inhaled and nasal drug products: an overview of the PQRI recommendations.

The Product Quality Research Institute Leachables and Extractables Working Group includes pharmaceutical development scientists representing industry, government, and academia. The Working Group was created and constituted to address scientific and regulatory questions concerning the pharmaceutical development process for Orally Inhaled and Nasal Drug Products (OINDP) related to organic extractables and leachables. This effort has resulted in the creation of a detailed "Recommendation Document", which was submitted to the U.S. FDA for consideration in September 2006. The recommendations include proposed safety and analytical thresholds for leachables and extractables, as well as detailed "best practice" recommendations for various aspects of the OINDP pharmaceutical development process, including: materials selection for OINDP container closure system components, Controlled Extraction Studies, Leachables Studies, and Routine Extractables Testing. The Working Group's processes and the detailed and comprehensive recommendations that resulted from those processes, demonstrate that the Product Quality Research Institute collaborative process can result in consensus science-based and data driven recommendations that could have a positive effect on patient care. It is anticipated that the Working Group's recommendations will also contribute to the new "Quality by Design" pharmaceutical development paradigm. This commentary summarizes the best practice recommendations within the context of an overall pharmaceutical development process.