Peptides present some unique challenges for the bioanalysis by LC-MS/MS of these compounds in plasma and other biological matrices. One main challenge for LC-MS/MS bioanalytical methods for peptides is to get similar sensitivity and specificity compared to methods for small molecules. The challenge presented by peptide for sensitivity and specificity are due to the following properties common to most peptides:
Despite these inherent challenges from peptides, at Pine Lake Laboratories we have developed and validated LC-MS/MS bioanalytical methods for peptides that met the required sensitivity and specificity. We have used mixed mode solid phase extraction to help reduce background from similar peptides while still maintaining good recovery of the target peptide. When properly tuned and with optimized chromatographic conditions, our Waters Xevo TSQ UPLC-MS/MS instruments can achieve the needed sensitivity.
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.
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.
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.”
The main difference between analytical methods for single entity combination products (SECPs) and traditional drug product formulations like oral or parenteral dosage forms is the sample preparation. For most methods the sample preparation will need to be developed to be unique and specific to the SECP but usually involves complicated multi-step procedures. Based upon the SECP, sample preparations of SECPs often involve extensive extraction for complete recovery of the drugs. In addition, depending upon the size of the SECP and the location of the drug, the SECP may need to be disassembled or reproducibly cut, which can be a significant challenge when the SECP is made from hard plastics or metals.
“We recognize this purchase is a significant milestone and growth opportunity for our staff and the Bristol community,” said Pine Lake Laboratories President, Kurt Moyer, Ph.D. “We plan to continue NSF International’s legacy of scientific and technical expertise and to serve our global clients. Moving forward as Pine Lake Laboratories, with our group of scientists and professionals, we will continue to grow our operations, enhance technologies and help our clients produce safer pharmaceuticals and medical devices here in Bristol.”
Along with Dr. Moyer, the Pine Lake Laboratories’ core leadership team includes group leaders Ulyana Matyugicheva and Cassandra Tellarini.
Dr. Moyer has more than 25 years of experience in pharmaceutical development. In his previous role as Director of Research at NSF International, he led all analytical, bioanalytical, and extractables and leachables studies. Prior to joining NSF International, he worked with Sanofi-Aventis as a senior research scientist and DuPont Pharmaceuticals as a senior research investigator. Dr. Moyer earned a Ph.D. in biochemistry from Villanova University and a bachelor of science in chemistry from Millersville University of Pennsylvania.
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.
Single entity combination products (SECP) present unique analytical challenges compared to the other types of combination devices. Most notably, in a SECP the combining process and sterilization will most likely create impurities and degradants no observed in the individual component. This is especially common for SECP contains drugs.
In addition, an SECP may have specific design features that need to measure to ensure proper functioning of the product. For example, measuring the rate of the release of a drug could be a critical performance feature requiring a specific analytical method to evaluate.
Pine Lake Laboratories has a proven record of developing and validating analytical methods for single entity combination products. We also have the necessary equipment and expertise to identify degradation products and impurities that are unique to single entity combination products.
The FDA Guidance for Industry Titled “Current Good Manufacturing Practice Requirements for Combination Products (January 2017)” defines a combination product as “a product composed of two or more types of medical products (i.e. a combination of a drug, device, and/or biological product with another).” There are three types of combination products: single entity, co-packaged and cross labeled.
A single entity combination product has at least two components (i.e. drug/device, biologic/device, drug/biologic or all three) that are chemically or physically combined to form a single entity. Examples of single entity combination products would be a prefilled syringes or a drug coated surgical implant.
A co-packaged combination product has at least two components packaged together as a single unit. Examples of co-packaged combination products are surgical kits and drug products packaged with infusion sets.
With a cross labeled combination product, each component is packaged separately and is intended only for use with an approved second product. An example of a cross labeled combination product would be a light activated drug requiring a light emitting device.
Pine Lake Laboratories has experience with analytical methodologies to support all forms of combination products.
To help fulfill unmet medical needs, sophisticated drug delivery systems are being developed with many innovative combinations of pharmaceuticals, biologics and medical devices. While these combination products have enormous potential, they also present unique challenges in development and approval. One challenge for combination products is the development and validation of analytical methods to assess the quality, safety and stability of combination products. Please see our technical library for a free white paper titled “Analytical Methods for Single Entity Combination Products” This white paper will focus on the analytical methods needed for single entity combination products.
Pine Lake Laboratories has a proven track record in developing and validating methods used to insure the quality of combination devices, especially combination pharmaceutical medical devices. Our experience allows us to adapt validation strategies and assist in testing designs to meet the unique challenges of combination devices.
Our experience with methods for combination products includes:
We have the capacity to perform routine analyses once the methods are validated and can assist in investigations of unexpected results. We have also successfully transferred methods to clients manufacturing site laboratories.
All work performed in compliance with FDA GMP.
We provide bioanalytical methods development, validation and sample analysis in our FDA-GLP registered facility in Bristol, CT.
We support all types of preclinical studies from early discovery (ADME, PK, TK) through long-term chronic in all species. Pinelake bioanalysis group has many years of methods development experience in complex matrices such as brain, spleen, spinal cord and vaginal tissue, in addition to the traditional matrices of blood, plasma and urine.
Sample data is processed and reported using Watson LIMS software. All reports are delivered as “ready to file” documents. We also offer full API characterization as well as formulation concentration and stability analysis.
Preclinical and Clinical Bioanalysis
Sample Analysis
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.
