Leachables and extractables.
The history of the PQRI Leachables and Extractables Working Group began with activities initiated by International Pharmaceutical
Aerosol Consortium (IPAC) and its evolutionary organization IPAC-RS (Regulation and Science). IPAC formed in 1989 with a mission
to address pharmaceutical regulatory consequences of the Montreal and Kyoto Protocols, and their impact on chlorofluorocarbon
propellants used in metered dose inhaler (MDI) drug products. In 2001IPAC-RS was officially formed as a separate consortium
with a mission to advance consensus-based and scientifically driven standards and regulations for all orally inhaled and nasal
drug products (OINDP), with the overall goal of facilitating the availability of high-quality, safe, and efficacious drug
products to patients. In collaboration with the Inhalation Technology Focus Group (ITFG) of AAPS, IPAC-RS formed "technical
teams" to study various scientific and regulatory issues for OINDP, including a Leachables and Extractables Technical Team.
In March 2001, the IPAC-RS/ITFG Leachables and Extractables Technical Team submitted a technical paper entitled "Points to
Consider" to FDA (29). Central to this paper were proposals for: 1) reporting and qualification thresholds for leachables,
and 2) a leachables qualification process.
Based on the "Points to Consider" proposals and FDA's response to them, a formal proposal to develop safety thresholds and
examine best practices for leachables and extractables in OINDP was drafted by IPAC-RS and submitted to PQRI. The proposal
was accepted, and a working group was formed later in 2001, consisting of chemists and toxicologists from FDA, industry, and
academia. Through the PQRI process of hypothesis definition, workplan and study protocol development, laboratory, and other
scientific activities, the PQRI Leachables and Extractables Working Group developed the recommendations, "Safety Thresholds
and Best Practices for Leachables and Extractables Testing in Orally Inhaled and Nasal Drug Products," which was submitted
to PQRI and FDA in fall 2006 (30).
The working group also sponsored a public workshop that focused on its scientific process and proposals held prior to finalization
of the recommendation document in December 2005. After formal submission of the recommendation document, the working group
presented a series of "training courses" based on its work, three of which were held in the United States, one in Europe,
and one in Canada (to Health Canada). Two peer-reviewed scientific publications based on the working group's results and conclusions
have also appeared (31, 32). Currently, the working group is preparing a book on its safety threshold and qualification process
for leachables, and contributing chapters to a second book on pharmaceutical development "best practices" for leachables and
extractables in preparation by IPAC-RS.
Since 2000 there has been an increased level of concern about the potential presence of genotoxic impurities within drug substances.
This resulted, in 2007, with the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) releasing
a final Guideline on the Limits of Genotoxic Impurities, which established the need to restrict levels of such impurities
to a limit of 1.5 ug/day (threshold of toxicological concern (TTC)) (33). Building on this, PhRMA published a paper advocating
the use of a staged TTC for studies of limited duration (34). FDA has also shown considerable interest in this area and released
its own guideline which incorporated a modified staged TTC approach (35).
Within the context of this issue, of particular concern has been the presence of sulfonate esters. There is experimental data
suggesting that a number of sulfonate esters (e.g. methyl methanesulfonate) are potential human carcinogens. This has lead
to concerns over their levels and driven regulatory authorities to ask for these to be tightly controlled in line with the
limit described above.
Sulfonic acids are widely used in synthetic processes to manufacture drug substances (in the form of catalyst, e.g. tosic
acid, and are also formed as a by-product of their use as leaving groups) and in salt formation; sulfonic acids are widely
used as they form very effective (highly crystalline) and safe salts. Elimination of the use of sulfonic acids is highly undesirable
either from a synthetic process or salt formation perspective.
The PQRI working group conducted research studies to first develop highly sensitive analytical test methods to detect sulfonic
acid esters and then employ these methods to study the stability of these compounds under varying conditions, most notably
pH and water content. The outcomes of these studies have contributed significantly to the scientific understanding of the
chemistry of these molecules and provided the industry with a path forward in managing this critical issue.