A Note on Chemical Characterization

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According to the ISO standard 10993, a medical device should be biocompatible i.e. not induce any adverse effects when it comes in contact with the patient. The standard provides a specific roadmap for planning a thorough biocompatibility study program for a device using both in vivo and in vitro techniques. But before evaluating the final or prototype device for biocompatibility, information should be gathered with regard to the “fitness of purpose” of the material(s) selected for the manufacture of the device. To begin, questions like the following can be asked. What are the chemical constituents of the material(s)? Will the chemical, physical, biological and other characteristics of the material(s) have any effects on the toxicological profile of the device? In other words- is the device in its entirety, safe? 

Extractables and Leachables

Chemical characterization essentially consists of two main tests. The first test is for extractables, which are substances, both organic and inorganic that can be “extracted” from the test material in the presence of a solvent under controlled conditions, and may be indicators of potential leachables. The second test is for leachables, which can leach out from the material during normal use via contact with liquids (including water or aqueous solutions). These chemicals can pose a potential risk to patients and hence should be detected before the final production and marketing of the device.

Analytical Instrumentation

GC (gas chromatography) and GC/MS (gas chromatography/mass spectrometry) are used for analyzing these chemicals and such work is routinely conducted by Pacific BioLabs’ analytical lab, where our team of chemists designs the most appropriate extraction conditions for a device after considering the device material, use of the device, and the solvent. Moreover, our analytical team can also characterize the chemical’s identity and concentration using HPLC, and can also conduct routine tests including moisture determination by Karl Fischer, pH, conductivity, viscosity and osmolarity.


ISO 10993-18:2005 Biological evaluation of medical devices – Part 18: Chemical characterization of materials

PK Studies at PBL

Pharmacokinetic (PK) and Toxicokinetic (TK) analysis is an important aspect of drug development.  These studies may be exploratory in nature or more extensive and formal.  Understanding the bioavailability, exposure, half-life, clearance and metabolism of your drug may be the difference between success or failure in the clinic. Pacific BioLabs has integrated toxicology and analytical services departments that can coordinate the in-life and bioanalytical aspects of a PK study

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Pacific BioLabs operates GLP compliant systems and validated instrumentation.  We have several LC/MS/MS systems as well as ELISA platforms to provide sensitive, high throughput evaluation of drug concentration in a variety of matrices.  Stability studies and metabolite identification can be conducted to understand the strengths and liabilities of your compound.

We can quickly develop and validate a sensitive, accurate and robust PK assay in a number of different matrices from different species.  We have experience working with plasma, serum, urine, CSF, and tissue.  Our chemists will optimize the extraction conditions to provide a reproducible and robust method.  Non-GLP exploratory PK assays can be implemented in a few days and use 4-6 reference standards, internal standard, and quality control samples.  Pivotal GLP compliant Toxicokinetic studies require method validation protocols, validation reports and analytical SOP.  We have the systems and Quality resources in place to guide your project, comply with the latest regulatory requirements and ensure high quality, timely data.

Learn more about PBL's PK studies or request a quote

AM2PED Grant to Accelerate California Bay Area Biomanufacturing

Source: NIST

Source: NIST

Last week I was privileged to be able to participate in a focus group for California East Bay biomanufacturing.

The purpose of the focus group was to generate ideas on how best to utilize the $2.2 million in Federal grant funds given to the East Bay Economic Development Alliance (among others) in the form of the AMP2ED Grant.

According to Manex Consulting, one of the partner organizations for the grant, "The Advanced Medical/Biosciences Manufacturing Pipeline for Economic Development (AM2PED) will build a regional innovation ecosystem for technology transfer, economic development, and workforce development in medical device and bio-science manufacturing along the I-80/880 Corridor of the Inner San Francisco East Bay Area."

For those who might not be aware, the San Francisco Bay Area is one of the strongest and most innovative clusters for biotech and medical device innovation in the world. And the East Bay region contains 469 bioscience companies, generating over $6 billion per year. As a CRO, PBL serve this cluster both in development testing, and also in lot release testing - thus we function as part of the supply chain for many local manufacturers.

It was in this capacity, as part of the bioscience manufacturing supply chain that PBL was able to provide perspective that will hopefully lead to the encouragement of more small companies and bioscience manufacturing in the East Bay region.

If you are part of a small company here in the East Bay, you would be well-served by learning more about some of the resources available to you here - including the Tech Futures Group (techfuturesgroup.org), a nonprofit that helps support small tech companies.

All in all, it's exciting to be part of the innovation taking place here, and to support so many of this region's bioscience companies.


UC Berkeley News Center: http://newscenter.berkeley.edu/2012/11/28/new-grant-will-accelerate-job-creat...

Manex Consulting: http://www.manexconsulting.com/blog/?p=182

BBL Contributes to Successful Phase 3 Trial of BioMarin Orphan Drug

Keratan Sulfate

Keratan Sulfate

Bay Bioanalytical Laboratory (BBL), recently acquired by Pacific BioLabs (PBL), provided important biomarker data to the successful Phase 3 trial of GALNS for Morquio Syndrome (http://investors.bmrn.com/releasedetail.cfm?ReleaseID=718462). “We are very proud of our contribution to the success of this innovative treatment for an orphan disease,” said Bob Cunico, Principal Scientist and founder of BBL.

“BBL’s work on the GALNS trial is a fine example of the sophisticated analytical expertise we can now offer to all of PBL’s clients,” said Tom Spalding, President of PBL. “We are excited to add these capabilities to our existing services in Toxicology and Microbiology.”

In 2007, BioMarin Pharmaceuticals approached BBL to develop and validate a novel LC/MS/MS method to measure plasma and urine concentrations of Keratan Sulfate. Keratan Sulfate is a glycosaminoglycan (GAG) that accumulates in the cells and tissues of patients afflicted with Morquio Syndrome.  The children and young adults with the disease have a defective enzyme (GALNS) and cannot properly process certain GAGs. The GAGs accumulate and cause damage to muscles, bone, and other organs.

BioMarin sought the bioanalytical expertise of BBL to measure Keratan Sulfate in blood and urine to support their preclinical and clinical studies of GALNS. The effort between BBL and BioMarin was extensive and resulted in peer reviewed publications from Bob Cunico and Erik Foehr, a successful IND submission, and now a Phase 3 trial that demonstrated the efficacy of the GALNS treatment. The urinary biomarker data demonstrated a dramatic and statistically significant decrease in urinary keratan sulfate with weekly treatment with GALNS.

The work involved many team members from BBL, including excellent analytical skills of Jayoung Ohh, timely and expert support by the QA group, Kate Lancaster and Samantha McCoy, as well as logistics and lab support by Steve Guthrie and Andrea Parungao.


Martell LA, Cunico RL, Ohh J, Fulkerson W, Furneaux R, Foehr ED. (2011.) Validation of an LC-MS/MS assay for detecting relevant disaccharides from keratan sulfate as a biomarker for Morquio A syndrome. Bioanalysis 3(16):1855-66.

Toxicologists Weigh in on Biocompatibility

Medical Device biocompatibility, once considered just a "box-checking" activity, continues to become more complex. This was the focus of a talk at the 2012 American College of Toxicology Annual Meeting entitled "The Unique World of Safety and Toxicology Testing of Medical Devices."

Drug Toxicology Versus Device Toxicology

Drug safety testing focuses on dose responses in vivo and in vitro, whereas device safety testing focuses on device failure and the toxicology of the materials making up the device. Although even the most complex device and most involved biocompatibility testing program doesn't come close to the requirements for a new chemical entity, the toxicology of the materials still does need to be adequately addressed.

Risk assessment for medical devices is based on the chemical nature and known toxicity of a device's constituent materials, the prior use of the materials and any records of their use, and the biological safety data generated by in vivo and in vitro testing.

The Changing Nature of Biocompatibility Testing

Historically, biocompatibility testing has been an exercise in determining the type of device and testing required according to ISO 10993, and then performing only that specific testing. However, since each device is unique, simply conducting the recommended biocompatibility studies may not be sufficient to allow for an adequate scientific and regulatory review of the device.

The choice of animal species may be affected by the type of device - for instance, artificial joint replacements may be best evaluated in certain strains of sheep.

Finally, biocompatibility testing should always be conducted according to Good Laboratory Practices (GLP). There once was some question about this, but the most recent FDA draft guidance for industry on 510(k) submissions made clear that GLP testing is a requirement.

It is important to be aware that as the regulatory environment changes, biocompatibility testing may continue to become more involved, and each device may require a testing program very specific to it. A lab with an established history of testing, or a consultant with device toxicology experience may be able to help with putting together an appropriate testing program.