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.

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.  Analytical methods are needed to detect leachable in injectable vaccines and related biological products so that the toxicological risk can be assessed.

The first step toward developing analytical methods for leachables is to identify the extractables  from the CCS that could become leachables by doing extraction studies.  Extraction studies are designed to simulate both intended use and “worst case scenario” models to identify as extractables the leachables that could migrate.  Analytical methods are then developed with sensitivity to detect the leachables in the finished product at the threshold determined by the toxicity of the leachable.

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.

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Single-use systems can introduce leachables into a drug product during the manufacturing process.   Therefore all users of single-use systems should evaluate the risk of leachables by performing extraction studies on all components that contact the drug product in single-use systems (e.g. bags, tubing, connectors, filters, etc.).

Similar to container closure systems, extraction studies performed by the user on single-use systems should be done using extraction solvents based upon the drug product that represent the “worst case” scenario.   Usually this will require two solvents of decreasing polarity.   The extraction conditions should be based upon the intended use of the component of the single-use system.   The sample extracts are then analyzed for extractables using the same analytical methods used in an extraction study on a container closure system.

Once the extractables from the single-use system have been identified, the manufacturing process may be modified based on the results of the extraction study to minimize the risk of leachables.   If the risk of the potential leachable cannot be eliminated with process changes, toxicological risk of the leachables or further studies to confirm the actual levels of the leachables may be needed.

Pine Lake Laboratories has extensive experience with performing extraction studies for single-use systems and design a study for your specific application.

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Extractables and leachable testing is required by the CDRH in the FDA for many medical devices. Experimental design for evaluation of extractable and leachables from medical devices can be done based on the most likely route for a leachable to enter the body. One route of entry is for leachables from a medical device to enter a drug product that carries the leachable into a patient.  Examples of medical devices were this is the leachable route of entry include infusion pumps, syringes, and syringe filters. For leachables in this category, both the toxicity of the leachable and the potential impact of the leachable on the drug product need to be considered.  The second route of entry is direct migration of the leachable from the medical device into the patient from direct tissue contact.  Examples of medical devices where this is the leachable route of entry include dental implants, artificial joints, stents, bandages, and contact lens.  For some medical devices, both routes of entry for leachables are possible. Examples of medical devices where both routes of entry are possible include drug releasing implants and catheters. If leachables from a medical device are unlikely to enter the body from one of these two routes, an evaluation of extractables and leachables is probably not necessary.

To address extractables testing for medical devices, in the FDA Modernization Act of 1997, the FDA recognized ISO 10993-12 Titled “Sample Preparation and Reference Materials”.  In this document are clearly defined extraction experiments for extractable and leachable evaluations.  Some of the definitions and experiments in ISO 10993-12 are similar to the definition of an extractable and the forced extraction studies described in the PQRI guidance for E&L testing of OINDP.  Acceptance criteria for extractables and leachables are not defined in ISO 10993-12.

Based upon the similarities between ISO 10993-12 and the PQRI guidance for E&L testing of OINDP, Pine Lake Laboratories has developed a study design for medical devices based upon the route of entry for the leachables.    This study design is available in the technical library as a white paper titled “Extractables and Leachables for Medical Devices: Meeting the 510(k) Requirements.”

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Recent changes in the FDA’s 510(k) requirements for medical devicses has lead to confusion on how to address the request for extractables, leachables and drug compatibility data.  Meeting the expectations of the CDRH can be challenging in that any given study design is not universally applicable to all devices.  A good study design requires elements of the best practices documented in ISO-10993-12, the PQRI guidance for E&L testing of OINDP as well as any specific requests for drug compatibility data from CDRH.

Pine Lake Laboratories has a hybridized study design, incorporating the essential regulatory elements, has been developed and successfully implemented for a variety of medical device applications.  The rationale behind selection of the elements, overall experimental design strategy and interpretation of the resulting are available in the technical library.

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