How to Ensure the Safety of E-Cigarettes

What are e-cigarettes?

E-cigarettes or “e-cigs” are battery operated machines which unlike conventional cigarettes, convert nicotine into vapor instead of smoke, and are often rechargeable. Their cartridges, containing an “e-liquid” mainly comprised of nicotine and other chemicals in smaller quantities, can be replaced by the user. For the discreet consumer, some e-cigs come disguised as a pen or even a USB stick. Moreover, e-cigarettes appeal to the younger consumer as they come in different vapor flavors including mint, coffee, chocolate and various fruit flavors.

New rule proposed for e-cigarettes

In April 2014, the FDA put forth a new rule that would, under the Family Smoking Prevention and Tobacco Control Act of 2009, extend its authority to new tobacco products. Currently cigarettes, cigarette tobacco and smokeless tobacco fall under the agency’s purview. The proposed rule would empower the FDA to regulate, among other tobacco products, e-cigarettes. Under the new rule, e-cigarettes would be regulated under the same provisions that apply to conventional cigarettes such as: the ban on sale to minors and distribution of free samples, marketing of new products only after FDA review, registration of all products with FDA, submission of ingredient list to the FDA and reporting harmful ingredients.

FDA’s analysis of e-cigarettes

So why is the FDA concerned about e-cigarettes? Apart from the worry that the younger generation would be drawn to smoking, there are scientific concerns as well.  In 2009, the agency studied both the cartridges and entire e-cigs of two leading e-cig makers, and analyzed them for nicotine content and other tobacco derived chemicals. You can read a summary of the results here and the report here.

The results indicated a lack of quality control in the manufacturing processes of e-cigs. E-cigs marketed as nicotine-free had small amounts of nicotine in their e-liquids. Cartridges indicating the same nicotine content on their label emitted vapors with different amounts of nicotine. Diethylene glycol, a known ingredient in antifreeze, was found in one of the 18 cartridges tested. Tobacco specific nitrosamines (TSNAs) which are carcinogenic, were found in half of the 18 cartridges. Additionally, tobacco specific impurities, which can prove hazardous to humans, were found in many of these cartridges.

Testing e-cigarettes to ensure their safety

The yet unknown risks of e-cigs and the current non-regulation of these products have propelled the FDA to propose the above-mentioned new rule. E-cigs are claimed to be “safer” by some, promoting the notion that smoking e-cigs is harmless. Even smokers are increasingly switching from conventional tobacco products to e-cigs to aid them in quitting. Hence the escalating use of e-cigs has prompted the FDA to require e-cig makers to report product composition and any hazardous ingredients before these products can be sold to consumers. In fact, a few e-cig makers have already begun characterizing their e-liquids; one even offering consumers the option to receive free batch reports of their product so they can know the exact composition of the e-liquid.

Characterization of the e-liquid and vapor will include testing for nicotine content, nitrosamines and other volatile organics, and heavy metals. This can be easily achieved by analytical chemistry methods using GC/MS, HPLC-UV and ICP-MS. For example, nitrosamines and other volatile organics can be released in the vapor as degradation products of the e-liquid. Forced degradation studies i.e. exposing the e-liquid to extreme heat, light, oxidation and acidic conditions for extended periods of time to represent the worst-case scenario, would “force” degradants to come out. These degradants can then be identified and analyzed by GC/MS. Short-term (1 month) and long-term stability studies (6 months-1 year) can also be used to find out if the e-liquid is degrading over time.

Heavy metals can also leach out of the metal components of the e-cigarette into the vapor inhaled by the consumer. A commonly used heavy metal in e-cigarettes is tin, which makes up solder joints in the cartridge. Tin can be cytotoxic and when inhaled as part of the e-cig vapor, will directly reach the respiratory system of the user. In this case, ICP-MS can be used to detect the presence of even trace amounts of heavy metals and quantify them.

To conclude, the FDA is concerned about the potential hazards of e-cigarettes which prompted it to propose new regulations. To prove the safety of their products in marketing applications, manufacturers of e-cigarettes would benefit from performing rigorous tests such as degradation studies, stability studies, and analyses of degradants and heavy metals.

Pacific BioLabs performs testing of devices, including analytical chemistry. More information on our services can be found here: http://www.pacificbiolabs.com/testing_services.asp

References

Erik Foehr, VP of Analytical, Featured in Drug Development & Delivery Magazine

Erik Foehr, PhD., VP of Analytical Services

Erik Foehr, PhD., VP of Analytical Services

The market for biologics and biosimilars is expected to grow significantly throughout this decade. Given this growth, it becomes essential that contract research labs are able to predict trends and add capabilities and capacity, and that development firms are able to effectively tap into those capabilities.  

Examining predictions of how this market may grow was a March 2014 article in Drug Development & Delivery magazine, Analytical Testing of Biologics and Biosimilars, featuring contributions from key thought leaders in the contract analytical research field including PBL's VP of Analytical Testing, Erik Foehr.

Anyone working on the development of biosimilars can benefit from reading this article -  especially those involved in outsourcing. Some key points:

  • "U.S. demand for biologics is expected to grow 6.5% per year to $102 billion in 2015, up from $74.3 billion in 2011, according to Freedonia Group."

  • "...the most commonly outsourced activity is analytical testing because of the need for highly specialized staff and equipment required to perform assays as well as regulatory agencies wanting more characterization and other data about products. On average, facilities outsource 32% of their analytical testing/bioassays..."

  • Dr. Foehr: "Start-ups may not have had the opportunity to learn from mistakes or successes of other innovators - contract labs share in the experience of a multitude of clients. Therefore, the experienced contract labs can be a tremendous resource to the pharmaceutical industry. As Big Pharma sheds R&D resources and virtual start-ups become the norm, in-house analytical experience and technical capabilities dry up. One of the last pools of experienced, well-resourced chemists is now found in the contract lab sector."

See the entire article: http://www.drug-dev.com/Main/Back-Issues/SPECIAL-FEATURE-Analytical-Testing-of-Biologics-Bi-660.aspx

Material and Chemical Characterization of Devices: Part 1, An Overview

This is the first in a series of posts on material and chemical characterization of medical devices.

At PBL we hear a lot of questions from medical device clients regarding FDA material and chemical characterization requirements. To address, and hopefully alleviate some of this confusion, we’ll be delving into material and chemical characterization  - what these terms mean, what the ISO standards say, what the FDA requirements are, and when certain types of testing are necessary.

Background

Historically, assessing the safety (or biocompatibility) of a new medical device has been done primarily through in vivo biocompatibility testing. This testing looks at whether device components, or extracts from a device, have the capacity to cause irritation, damage, or toxicity in an animal system. This method of testing produces data that has been shown to correlate strongly with human biocompatibility.

However, with the advent of more sensitive analytical equipment, and more robust analytical methods, the FDA and other regulatory bodies are increasingly asking for data on the material and chemical components of devices to complement in vivo biocompatibility studies. By analyzing the device components, and by looking at the types and amounts of chemicals that may migrate from a device to a patient during use, potential toxicities can be predicted. We can then examine these potential toxicities, as well as the in vivo testing data, and better assess overall biocompatibility.

Thus, characterization studies are ultimately performed in order to gain a more complete understanding of a device, and of the risk factors associated with using a device. This also explains why the FDA is placing a greater emphasis on these studies - to better ensure patient safety.

Material Characterization vs. Leachables and Extractables

Material and chemical characterization can be summarized fairly simply: it is characterizing a device so that we know clearly what materials the device is composed of, and characterizing the type and amount of chemicals that may leach out of the device during use.

Material characterization refers to identifying all the component materials of a device. This can include colorants, plasticizers, specific metals, and ceramics, for example. Often, specific information and data on materials can be obtained from material manufacturers. In fact, the ISO 10993 standards, a series of standards on methods to be used to determine the biocompatibility of devices, recommend that as much data as possible be gathered from material manufacturers. Preexisting data can significantly reduce the amount of material characterization testing needed.

Chemical characterization is analogous to leachables and extractables, and these two terms are often used interchangeably in device testing. These studies look at what chemicals may come out of the device in both typical usage (leachables) and when challenged (extractables), and these studies are most often conducted according to ISO 10993-17 and 10993-18.

As mentioned previously, a user of the device may be exposed locally and/or systemically to these chemicals, and it is important for the safety of the potential user to know whether use of the device may produce harmful effects. Once the composition of a device is fully known, a qualified toxicologist can conduct a risk assessment to thoroughly characterize patient risk from exposure to device materials.

ISO 10993 Standards for Characterization Studies

Several sections of the ISO 10993 standard cover aspects of material and chemical characterization studies:

  • ISO 10993-9: Framework for identification and quantification of potential degradation products
  • ISO 10993-13: Identification and quantification of degradation products from polymeric medical devices
  • ISO 10993-14: Identification and quantification of degradation products from ceramics
  • ISO 10993-15: Identification and quantification of degradation products from metals and alloys
  • ISO 10993-16: Toxicokinetic study design for degradation products and leachables
  • ISO 10993-17: Establishment of allowable limits for leachable substances
  • ISO 10993-18: Chemical characterization of materials
  • ISO 10993-19: Physico-chemical, morphological and topographical characterization of materials

Although there are multiple sections of ISO 10993 which address material characterization specifically, the standards clearly state that gathering data from the manufacturer is the best way to characterize a material. For instance, ISO 10993-13, section 5.2 (regarding polymeric materials) states:

“The initial material characterization shall address the bulk polymer and the residuals and additives present in the final device. Because of the difficulties of retrospective analysis, this information is best obtained from the supplier or manufacturer of the material [emphasis mine]. It is important to fully characterize the purity of the polymer and the additives used in the formulation.”

Because it is likely that the majority of material characterization data will be obtained from the manufacturer, subsequent posts will focus more specifically on chemical characterization, how this data can best complement in vivo biocompatibility data to inform on the overall toxicity profile of a medical device, and how this data can be used to assess the potential impact of manufacturing or materials changes.

Pacific BioLabs performs Biocompatibility testing of medical devices, including chemical characterization. More information on our characterization services can be found here: http://www.pacificbiolabs.com/testing_device_characterization.asp

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