New LSR Forms at PBL

Pacific BioLabs' LSR forms receive a significant update

We're pleased to announce that PBL's Laboratory Service Request forms, which are used to initiate testing, have been redone completely to enhance usability. There are several notable new features of these LSRs:

  • Filled out versions of the forms can now be saved, to make it faster and easier to start repeat, frequently-done testing.
  • Digital signatures are now accepted - LSRs can now be filled out, signed, and emailed electronically.
  • New formatting makes it easier to enter long descriptions or more complete information - such as when entering custom instructions.

The new LSRs can be found here: PBL LSR page.

We recommend using these new LSRs instead of the old versions, and hope that you find these changes useful.

What is Stability Testing?

According to the ICH guideline Q1A(R2) adopted by the FDA and EMA, the goal of stability testing is to demonstrate “how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity and light..”. To support a stability study, analytical methods using HPLC, LC/MS and GC are used to test for degradation products apart from tests to determine the sterility of the substance and whether the container or packaging of the final commercial product is compromised. 

Understandably, the FDA and other regulatory agencies require this data as part of a registration application for the drug substance or product. Usually, pharmaceutical companies begin stability studies during clinical trials and manufacturing and some even continue these studies after gaining approval.

Pharmaceutical companies arrive at optimum storage conditions and the expiration date of a drug substance or drug product which can be seen commonly on drug labels after collecting stability data over months to years. This data includes the effects of environmental conditions which can significantly alter the physicochemical characteristics, biological activity and other attributes of the drug substance or product. Stability studies are performed for medical devices and raw materials as well.

The ICH Q1A(R2) is a good place to begin since it recommends factors and tests to be considered for a stability data package and draws upon other guidance documents such as “Photostability Testing of New Drug Substances and Products” specific to different aspects of a stability program.

To conclude, monitoring the effects of environmental conditions on the quality of a drug product, substance, medical device and raw material is important to ascertain it is suitable for use by consumers or in manufacturing. Pacific BioLabs supports both long term and accelerated stability programs by providing storage in different conditions according to ICH guidelines and analytical and microbiology testing services. For more information, please visit our Stability Testing page.

References:

ICH Q1A(R2) Stability Testing of New Drug Substances and Products, November 2003

ICH Q1B Photostability Testing of New Drug Substances and Products, November 1996

 

The Importance of Immunogenicity Testing in Biotherapeutic Development

Immunogenicity, defined as the ability of a substance to produce an immune response, is key to a successful and safe biopharmaceutical drug development program. Therapeutic Antibodies, enzyme therapies, peptides and combination products can elicit an immune response that may impact their safety and efficacy.

Example of an ELISA assay plate

How Biologics Create an Immune Response

Many types of substances administered to the human body may pose a chance of eliciting an immune response. However, biotherapeutics can be especially immunogenic because the large size of these molecules can trick the body into thinking that they are foreign invaders, triggering action by the immune system. These large molecules can also denature, which changes their profile, or aggregate, creating even larger particles. Ultimately, these characteristics can change or increase a biotherapeutic’s immunogenicity profile.

New technologies have been created - for example, PEGylation –to reduce the immunologic effect of biotherapeutics. However, the efficacy of these attempts to reduce immunogenicity varies. It is for this reason that testing for immunogenicity of a product in development is so important. Furthermore, immunogenicity testing is still necessary in a biosimilar development program. This is because the small changes in the manufacturing of biotherapeutics can effect large changes in their immunogenicity profile. Thus biosimilars, which almost invariably will be manufactured under different conditions than their parent biologics, still need to be tested for immunogenicity.

What is Immunogenicity Testing

Immunogenicity assays provide a way to measure the potential immune responses of biologics and biosimilars. Often a single biologic will require a panel of assays to produce a thorough picture of potential immunogenicity. The FDA stipulates that assays should be designed in such a way that they provide sufficient sensitivity, are free from confounding interference, can detect physiological consequences, and account for potential risks based on the profile of the therapeutic and the target patient population.

By designing assays with these factors in mind, it is possible to gather predictive data about the strength and type of immune response that a drug may produce in humans.

Types of Immunogenicity Analysis

For some biologics, a total antibody assay (to measure the antibodies that are part of the immune response) that includes screening, confirmatory and titer components will be sufficient to develop an immunogenicity profile.  In other cases a neutralizing antibody assay or cell based bioassay may be necessary and informative. ELISA (enzyme-linked immunosorbent assay) is also a useful method to detect antibody-antigen complexes.

In addition, aggregation potential of a biotherapeutic can be measured using size-exclusion chromatography and HPLC combined with laser-light scattering. This can help to provide a fuller picture of the overall immunogenic profile of a compound.

The goal of all these tests is, ultimately, to predict the clinical effect of patient immune responses to biotherapeutics. The role immunogenicity plays in drug development is an important one. As such, a well thought out and well executed program is a key to producing safe and efficacious biologic therapies.

To learn more about Pacific BioLabs Immunogenicity Testing Services, visit www.pacificbiolabs.com or contact us at 510-964-9000.

You can also view a PDF download of PBL's Immunogenicity Testing Services.

Sources

Genetic Engineering and Biotechnology news: Proposed Standards for Immunogenicity Testing - http://www.genengnews.com/gen-articles/proposed-standards-for-immunogenicity-testing/4145/

ANP Tech: Immunogenicity Testing and Immunogenicity Assays - http://anptinc.com/index.php?option=com_content&view=article&id=136&Itemid=104

FDA: Immunogenicity of Protein-Based Therapeutics - http://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm246804.htm

Wikipedia: Immunogenicity - http://en.wikipedia.org/wiki/Immunogenicity

A Note on Chemical Characterization

glass molecule.jpg

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.

Reference:

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

beaker and vials.png

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