At the completion of the extraction studies, a list of extractables is generated. The challenge at this point is to select which extractables present a toxicological risk and thus should be monitored as leachable.
To evaluate the toxicity of each observed extractable, the safety concern threshold (SCT) is used. The SCT is the absolute highest acceptable exposure of a patient to a leachable in drug product and is usually expressed in terms of µg of leachable per day. If an SCT is not known, the recommended SCT by the PQRI should be used. The PQRI selected this SCT as representing a threshold below which leachables would have negligible safety concerns from carcinogenic and non-carcinogenic toxic effects. For orally inhaled and nasal drug products (OINDP), the PQRI recommended SCT is 0.15 µg of each individual leachable per day. For parenteral and ophthalmic drug products (PODP), the PQRI recommended SCT is 1.5 µg of each individual leachable per day.
To apply the SCT to a given drug product, an analytical evaluation threshold (AET) is calculated based on the SCT of an individual leachable, the number of doses of the drug product administered per day, the number of doses contained in the container closure system (CCS), and the weight of the CCS (can also use volume of drug product in the CCS). The AET is defined as follows:
AET = (SCT/number of doses per day) x (doses per CCS/weight of CCS) x uncertainty factor
The AET will have units of µg/g unless other units were used in the calculation. Surface area of the component of the CCS or volume of drug product in the CCS instead of the weight may be applicable in some situations. The uncertainty factor is an adjustment for the confidence in the identification and quantitation of the extractables needed for OINDP. For all other types of drug products, the uncertainty factor is not needed.
All extractables above the AET should either be selected to be monitored as a potential leachable or submitted for a toxicological assessment to determine a compound specific SCT
Leachables from container closure systems (both primary and secondary packaging component) that migrate into injectable vaccines and related biological products can have a potentially negative impact on safety and efficacy. To assess the risk from leachables, extraction studies are designed to simulate both intended use and “worst case scenario” models to identify as extractables the leachables that could migrate. At the end of the extraction study, an assessment of the observed extractables is done to determine if the risk justifies the need for additional leachables studies.
At Pine Lake Laboratories, we have extensive experience performing extraction studies on container closure systems commonly used for injectable vaccines and related biological products. The extraction study design followed at Pine Lake Laboratories for injectable vaccines and related biological products is based upon the PQRI guidance for Parenteral and Ophthalmic Drug Products.
Before starting to evaluate drug compatibility and leachables from the infusion pump or other medical devices intended to deliver a drug, an FDA approved drug(s) intended for use with the device must be selected. If the device is intended for just one drug, like an insulin pump, the selection of the drug is obvious. If the device can be used with multiple drugs and multiple routes of administration, select a total of three drugs that are commonly used from the three most common routes of administration. For example, if evaluating an infusion pump that is intended to deliver drugs intravenously and as an epidural, pick two common drugs for intravenous infusion and one for epidural infusion. Once the drug(s) has been selected, pick the simplest formulation of the drug to evaluate drug compatibility and leachables.
Pharmaceutical companies had been using the “less than lifetime” thresholds of toxicological concern (TTC) from ICH M7 as alternatives to the conservative 1.5 µg/day PQRI safety concern threshold (SCT) for calculations of the analytical evaluation threshold (AET) used in extractables and leachables testing. FDA has accepted this alternative calculation for most dosage forms, with the exception of orally inhaled and nasal drug products. Well, at the PQRI PODP Workshop at USP Headquarters on April 18 and 19, PQRI announced that its final E&L best practices for parenteral drug products will state that the AET should only be calculated using the 1.5 µg/day SCT. The concern raised by the PQRI toxicology sub-team was that the ICH M7 TTC values for less than lifetime patient exposure were all above the PQRI qualification threshold (QT) of 5 µg/day. This is the threshold for leachables that have sensitization and irritation markers. The fear was that extractables and leachables that could potentially be sensitizers would not be reported and qualified by a toxicologist if the AET was calculated using higher TTC values. The ICH M7 TTC values can be used for the qualification of leachables that are carcinogens when the patient dosing is less than lifetime. For example, if a leachable detected above the AET was a carcinogen and resulted in patient exposure of 15 µg/day…then this leachable could be qualified for dosing regimens involving less than 365 days, since the TTC for this exposure duration is 20 µg/day. There was some dialogue between the participants at the PQRI workshop (which included FDA) of possibly raising the SCT to 5 µg/day for less than lifetime exposure since this would be supported by the ICH M7 thresholds for carcinogens and the PQRI QT.
Did you know that leachables testing is the exception and not the rule for evaluating and qualifying pharmaceutical manufacturing equipment? Most equipment vendors have a full set of extractables testing data for their manufacturing components generated in many different model solvent systems that bracket the pH, polarity, and ionic strength of most aqueous based drug products. The vendor extractables testing is typically performed according to the “white papers” issued by the Bioprocess Systems Alliance (BPSA) and the BPOG. A scientific based assessment comparing the extractive power of the drug product that will be manufactured using the equipment to the vendors conditions of contact in the extractables testing has to be performed to demonstrate that the vendor extractables profiles were generated under “worst case” conditions. At the PharmaEd Resources E&L Conference in Philadelphia on March 28-29, Dr. Edwin Jao, from FDA, confirmed this practice in his presentation entitled “Equipment Compatibility Issues for Manufacturing of Liquid Dosage Forms— FDA/OPF’s Perspective.” Any “gaps” identified in the correlation of the vendor extractables data to the conditions used in manufacturing the drug substance and/or drug product can be addressed utilizing a simulated-use extraction study. This testing subjects a given component used in the equipment train to a model solvent or placebo under the typical conditions of contact encountered during manufacturing. Pro-active flushing of filters and tubing, points of dilution in the manufacturing process, and purification techniques (such as recrystallization and diafiltration) can also be used to reduce the leachables risk for manufacturing equipment.
Residual solvents are organic volatile impurities in drug substances and drug products that are byproducts of manufacturing. Drug manufacturers need to ensure that these residual solvents are at or below acceptable levels.
The USP <467> sets the concentration limit for each solvent. Solvents are grouped according to their toxicity levels and potential adverse effects. Class 1 solvents are known to cause unacceptable toxicities or to have environmental effects and should be avoided in the manufacturing process. Class 2 solvents are nongenotoxic animal carcinogens, and concentrations of these compounds should be limited. Class 3 solvents are less toxic and should be used when practical.
Gas Chromatography with valve-and-loop headspace analysis is used for identification and quantification of residual solvents in drug substances and drug products.
Following USP <467>, three analytical procedures are used for identification and quantification of the residual solvents:
At Pine Lake Laboratories, we have extensive experience in the determination of residual solvents in a wide variety of drug substances, excipients or drug products.
In addition to bioanalysis of small molecule drugs in plasma, at Pine Lake Laboratories we also have extensive experience developing bioanalytical methods by LC-MS/MS for drugs in tissue and other biological matrices. In general, tissues present a more complicated matrix than biological fluids but a well-designed mixed mode solid phase extraction method can usually handle the additional challenges of biological tissues. Below are examples of biological fluid and tissue matrices in which we have successfully developed methods:
All drug products sold in the U.S. will have to comply with the limits set by USP<232>, and drug substances and excipients will have to be tested and reported for elemental impurities. January 1 of this year USP has established as the date of applicability of the Elemental Impurities Limits General Chapters. Under GMP drug quality and regulatory requirements, elemental impurities will have to be monitored for all existing drug products, APIs, and excipients – not just for the 15 elemental impurities of USP<232>, but for the full 24 elemental impurities of Q3D.
Pine Lake Laboratories can assist you in meeting this requirement.
In addition to evaluating the risk of leachables from a medical device used to deliver a drug, the compatibility of the drug product with the medical device also needs to be demonstrated. Analytical assay methods are needed to demonstrate the stability and compatibility of the drug product. If available, the USP method for the drug product should be used. If a USP method is not available for the drug product, an analytical assay method will need to be developed and validated.
Once the analytical methods are in place, the drug compatibility experiment can be described in the following steps:
If an analytical method for assay, related substances and degradation products of a combination product is intended to evaluate stability, the method will need to be proven to be stability indicating. If the combination product contains a new drug, a forced degradation study will be needed. If the combination product contains a generic drug, literature references to known degradation pathways and impurities can be used to evaluate if the method is stability indicating. However, if the combining process is significantly different from the literature references, additional degradation pathways may need to be explored experimentally.
Pine Lake Laboratories is a state of the art facility fully equipped to identify unknown degradation products and process impurities. We have successfully used our GC-MS, UPLC-QToF and ICP-MS to aid our clients in identifying unknown compounds. In the past we have adapted client’s methods to be MS compatible to aid in identification. If needed, we can even perform fraction collection to collect enough of the unknown to confirm the identity by NMR.
Pine Lake Laboratories is a GLP/GMP compliant analytical and bioanalytical contract testing laboratory. Our lab, located in Bristol, CT, is FDA registered and inspected and DEA licensed for Schedules 1 through V.
