The evaluation of extractables and leachables has become an increasingly important aspect in the Quality by Design (Qbd) initiative of FDA in the area of drug product design, including the selection of materials used in the drug product production process and the selection of container and closure systems used for product packaging to help maintain product safety, quality, and efficacy. This paper describes a general approach to designing extractables and leachables studies—based on the Product Quality Research Institute (PQRI) recommendations to FDA for Orally Inhaled and Nasal Drug Products (OINDP)—to evaluate and qualify the bioprocess materials used in a disposable manufacturing environment.1
In the method described here, disposable materials are extracted with solvents of various polarities, using various extraction techniques. The resulting respective extractions then are evaluated with various techniques, including liquid chromatography/mass spectrometry (LC/MS), gas chromatography/mass spectrometry (GC/MS), high-performance liquid chromatography (HPLC), gas chromatography (GC), and inductively coupled plasma/mass spectrometry (ICP/MS). This paper also presents analytical thresholds of extractables for the evaluation of disposable materials. In addition, case studies are presented to exemplify the specific study designs and procedures that can be used to fully evaluate, characterize, and qualify certain specific disposable materials used in the bioprocess industry.As pharmaceutical and biological technologies move into the twenty-first century, emerging global regulations are focusing on risk management and integrated quality systems.2–5 The FDA, the International Conference on Harmonization (ICH), and other regulatory bodies have joined forces to promote and facilitate discussions about and the implementation of risk management and integrated quality systems into pharmaceutical and biological manufacturing processes.6–8
The consideration and evaluation of extractables and leachables is a key aspect in the development of disposable bioprocess materials because these compounds, which can originate from the pharmaceutical container and closure packaging's processing and bulk storage supply systems, may adversely affect the safety or efficacy of the final drug product. Extractables are compounds that can be extracted from source materials using appropriate solvents under vigorous laboratory conditions. Leachables are compounds present in drug products caused by leaching from container, closure, or processing components. Therefore, leachables can be considered a subset of extractables.
The process begins with the judicious selection of manufacturing components, and with the proactive design of process qualifications and validation requirements for materials in a disposable bioprocess. The majority of disposable materials used in single-use bioprocesses are various types of plastics which tend to leach out foreign materials over time; therefore, a detailed extractables and leachables study that is designed from an analytical point of view is needed. This paper presents a roadmap to guide the manufacturing process. This roadmap begins with the selection of components in terms of the extractables and leachables (E/L) reports and documentation. Reports and documentation are required to support viable, valid, and qualified processes that meet current good manufacturing practice (cGMP) requirements for a disposable bioprocess.
In its component quality test matrices,9 the Bio-Process Systems Alliance's classification identifies consensus quality tests for each of the four most commonly used classes of disposable components:
Selecting the right material acceptable for use in a disposable bioprocess for components in any of these subclasses can eliminate most potential extractables and leachables because of the removal of materials that fail to satisfy such standards as listed in the US Pharmacopeia (USP) 27, monograph c88: Biological Reactivity Tests, In Vivo: Classification of Plastics, Class VI.