EDITOR’S NOTE: The author, Dr. Chris Houston, serves on the PQRI-PODP working group as well as a sub-group for Ophthalmics, which is led by iuvo Chief Scientific Officer Dr. Mary Richardson.
I recently attended the 3rd FDA/PQRI Conference on Advancing Product Quality held March 22-24, 2017 in Rockville, MD. I was invited to speak about pending output from the PQRI Working Group on Extractables and Leachables in Parenteral and Ophthalmic Drug Products (PODP) with respect to best practices in ophthalmic drug products.
For those unfamiliar with PQRI, some background might be useful. As described on their website, PQRI (Product Quality Research Institute) is "a non-profit consortium of organizations working together to generate and share timely, relevant, and impactful information that advances drug product quality, manufacturing, and regulation.” In practice, PQRI working groups are comprised of industrial scientists and regulators (the U.S. Food and Drug Administration and Health Canada are full members) working together to deliver regulatory solutions based on rigorous science. Close collaboration between regulators and the industry is a uniquely appealing aspect of the PQRI framework.
PQRI achieved a significant success in the realm of extractables and leachables (E&L) in September of 2006 when an E&L working group released a recommendation document entitled “Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products”. These drug products, abbreviated as OINDP, represent the highest classified risk to patients from leachables as described by FDA  and, more recently, USP .
In addition to a set of best practices describing the conduct of controlled extraction studies, the team introduced the concept of a Safety Concern Threshold (SCT) defined as the “threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and noncarcinogenic toxic effects.” In other words, the SCT determined the threshold where leachables found in a drug product should be identified and assessed for safety. Leachables present below the SCT would not require further evaluation. For OINDP, the SCT was set to 0.15 µg/day. Given the dose volume and dose frequency of a specific drug product under study, the SCT can be recalculated in terms of drug product concentration (e.g., µg/mL, µg/g) to produce an analytically-useful value called the AET (Analytical Evaluation Threshold). E&L studies would thus be guided by the AET. OINDP manufacturers previously pressed by regulators to push their analytical capabilities ever lower embraced the SCT/AET concept as a scientifically justified, safety-based, and consistent standard for how low they needed to probe their products for leachables.
The PQRI recommendations for OINDP were adopted globally, but did not provide recommendations for other high risk dosage forms such as parenterals (injectables) or ophthalmic solutions and suspensions. This resulted in the formation of the PQRI Parenteral and Ophthalmic Drug Product (PODP) Working Group of which I am a member. The goal of our team was to determine whether concepts from the PQRI-OINDP recommendations might be applicable to PODPs.
For parenteral products, the SCT concept was deemed applicable; however, because parenteral products pose a reduced risk to patient safety from leachables, the SCT for parenterals was set less conservatively than for OINDP at 1.5 µg/day . Thus, by considering the overall risk from leachables as so effectively summarized by USP , the team established a new paradigm whereby SCTs are specific to routes of administration.
Although ophthalmic and parenteral products are lumped together in the 1999 FDA packaging guideline on the basis that they are both generally sterile solutions or suspensions , the PODP team quickly realized that these products cannot be treated identically with respect to E&L. Whereas parenterals are administered directly to tissue or the bloodstream such that systemic toxicity endpoints are a significant concern, most ophthalmic solutions and suspensions are applied topically (e.g., eye drops). When administering microliter quantities of drug product directly to the eye, localized irritation becomes an important safety endpoint and significant systemic exposure of any leachables is less likely. Much of the safety data used to derive SCT values for OINDPs and parenterals was systemic and thus less applicable to ophthalmics. Unfortunately, there is a dearth of ocular toxicity data available in the literature at concentrations relevant to leachables. As a result, the PQRI-PODP Working Group cannot recommend a specific SCT for ophthalmic drug products at this time. We expect that prior reporting practices for leachables exceeding 1 µg/mL (ppm) in ophthalmics will likely continue .
Many ophthalmic drug products are filled into semipermeable containers (often, LDPE) and this fact figures prominently in the pending PQRI-PODP best practice recommendations. Owing to the common use of semipermeable containers, the drug products are susceptible to chemical constituents from secondary (non-product contact) packaging components such as pressure-sensitive labels, patient information inserts, and even unit cartons. The challenges inherent to this scenario include complex partitioning behavior and change control.
In typical scenarios, leachables residing in the primary (product contact) packaging leach directly into the product, eventually achieving equilibrium. Migration from secondary packaging components is more complex. It is not merely a function of the packaging configuration, but also driven by the immediate environment. Environmental factors can result in unexpected outcomes such as inconsistent migration and underestimation of leachable levels under accelerated stability conditions. These factors can confound the unprepared.
Because constituents of secondary packaging components often undergo compositional changes on short timescales (e.g., reformulations or discontinuations of inks and adhesives, changes to preservatives in paperboard, etc.), managing change control of these critical packaging components on marketed products is a significant challenge.
The PQRI-PODP recommendations will advocate simulation studies (extraction studies specifically skewed realistic to forecast likely drug product leachables) as a useful means of managing the more complex partitioning behavior of secondary packaging extractables as well as the need to make timely, data-driven decisions in change control situations. Strategies to manage these scenarios will be forthcoming in the PQRI-PODP recommendations document.
Although a specific publication date has not yet been determined, the guideline is expected to issue in 2017.
For additional information, the original set of presentations made by the PQRI-PODP team can be viewed on the PQRI webpage HERE.
1. U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for Industry: Container Closure Systems for Packaging Human Drug and Biologics. May 1999.
2. United States Pharmacopeia, General Chapters: Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems.
3. Paskiet D, Jenke D, Ball D, Houston C, Norwood D, Markovic I. The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP). PDA J. Pharm. Sci. Technol., 2013, 67 (5), 430-447.
4. Ng L. Current Regulatory Recommendations for Leachables in Ophthalmic Drug Products. Presented at the PQRI Workshop on Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products, February 22-23, 2011.