1. The Link between OINDP and PDP Best Practice Recommendations
The essential hypothesis upon which the PDP effort was based is that the “good science” best demonstrated practices that were established for the OINDP pharmaceutical development process can be extrapolated to container closure systems for PDP. In 2013, seven years after the initial release of the OINDP recommendations, a commentary on these recommendations was published by Norwood, et al. [1]. The authors were closely involved in the development and subsequent implementation of the OINDP recommendations. While noting that “although the PQRI (re OINDP) recommendations, including the safety-based thresholds and best practices, have been generally accepted by both industry and regulators for inhalation drug products” the authors also observed that “certain questions and concerns have been raised since their initial release.” Two of these concerns involved:
- Best practices for controlled extraction studies
- Extension to other drug product types – “The AET Challenge”
Regarding controlled extraction studies, it was observed that the laboratory extraction studies accomplished by the PQRI OINDP Working Group to assist in the development and illustration of their recommendations, were designed with metered dose inhaler (MDI) rubber and plastic componentry in mind [2]. The MDI model was chosen “because the MDI is the only drug product type in which there is an almost certain 1:1 correlation … between critical component extractables (i.e., potential leachables) and actual identified leachables.” Although there was no intention on the part of the OINDP group to exclude extraction techniques and extraction solvents more applicable to componentry related to other dosage forms, a gap clearly existed in the OINDP extraction study work, in relating these studies directly to other dosage forms. The PODP Working Group recognized these gaps and undertook extraction studies using extraction techniques and solvent systems more appropriate for these dosage forms and their largely aqueous formulations. The test articles in the extraction studies were plastic and elastomeric materials of construction chosen to represent PDP packaging components and systems. The results of these extraction studies have been reported [3], and were used to assist the PDP group in developing their recommendations, extrapolating the OINDP recommendations to PDP dosage forms, and generalizing the OINDP recommendations for other dosage forms beyond PDP. Therefore, PDP general recommendations 3 and 4 are:
Extractables assessments and extraction studies for PDP may be considered as appropriate for specific application to materials of construction, finished components, and complete packaging systems (i.e., container closure systems).
- Extractables assessments and extraction studies for PDP packaging systems should include aqueous-based extraction solvents with appropriate consideration of extraction pH, organic solvent content, and other appropriate extraction conditions (e.g., extraction time, extraction temperature, extraction technique, and sample-to-solvent ratio).
It is also recommended that extractable studies for CCS used with complex drug products should consider appropriate solvent propensity to establish the extractable profile to guide optimization of nontargeted screening methods for placebo or leachables.
Note: Examples of complex drug products include complex API (e.g., polymeric compounds, peptides), complex formulations (e.g., liposomes, emulsions, suspensions), complex routes of delivery (e.g., topical), complex dosage forms (e.g., long-acting injectables), and complex drug-device combinations (e.g., prefilled syringes, autoinjectors).
Concurrent with development of the PQRI PDP Recommendations, the USP developed three informational general chapters related to extractables and leachables (4–6). These include the following:
USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems. 2015 [4].
USP <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems. 2015 [5].
USP <1664.1> Orally Inhaled and Nasal Drug Products. 2015 [6].
The USP is a PQRI member, and several members of the Expert Committee that created these general chapters were also members of the PQRI OINDP and PODP Working Groups, therefore it is reasonable that these general chapters reflect the consensus science-based thinking of PQRI. The PQRI OINDP recommendations are generally reflected in these chapters. For example, as stated in USP <1663>:
“In order to assess…risks and manage the potential issues posed by leachables, it is necessary to know the identities and the levels to which leachables will accumulate in the finished drug product over its shelf-life. These two pieces of information can be used to establish the magnitude of patient exposure (dose) and therefore the safety risk posed by an individual leachable, as well as the likelihood of any compatibility issues involving the drug product.
Since the pharmaceutical packaging/delivery system is the primary source of potential leachables, it is generally appropriate that any leachables assessment be preceded by an extractables assessment performed on the packaging/delivery system, its primary and certain critical secondary packaging components that are noncontacting but potentially interacting, and/or packaging and delivery system materials of construction; consistent with regulatory guidelines and best-practice recommendations.” [4]
The term “Extractables Assessment” refers to the process by which chemical entities are extracted from a test article (e.g., material of construction, component, finished packaging system), detected through chemical analysis of extracts, identified through structural analysis, and quantitated. Extractables assessments necessarily involve an “Extraction Study” (Controlled Extraction Study) and result in the creation of “Extractables Profiles” (e.g., the list of identified and unknown organic and inorganic extractable chemical entities, amount present, and level of confidence in the identity). These concepts and principles have been investigated and included in development of the PQRI PDP Recommendations. There are various reasons for accomplishing extractables assessments (e.g., materials characterization and selection, identification of potential leachables, etc.) and these are listed in detail in USP <1663>. Comprehensive datasets typically include the identity and estimated amount of detectable organic and inorganic extractable chemical entities, indication of criteria for confidence level in identification of chemical entities, and supporting analytical data such as chromatograms, mass spectra, NMR spectra, etc. These principles remain unchanged from the original PQRI OINDP Recommendations.
