Primer: GLP and Medical Device Studies

GLP regulations

Here at PBL, we work with many medical device companies, and no matter whether these companies are new or established, there still seems to be common questions among them. Namely: how exactly do the GLP regulations apply to medical device studies?

This uncertainty, and, in many cases, confusion, likely stems from a lack of clarity in the GLP regulations themselves, as well as a sometimes ambiguous stance from the FDA on when GLP should be applied to medical device studies.

Based on our experience, here's a quick primer on how we find GLP can best be applied to medical device studies.

Which Medical Device Studies Should be Conducted GLP?

A quick look into the FDA GLP regulations (21 CFR part 58) reveals that GLP is only applicable when conducting nonclinical laboratory studies. This is key, because many studies don't qualify as nonclinical, and thus don't need to be conducted according to GLP.

"A nonclinical laboratory study is an in vivo or in vitro experiment in which a test article is studied prospectively in a test system under laboratory conditions to determine its safety (21 CFR 58.3(d))."

Studies that are not done for the purpose of determining the safety of a device thus do not need to be conducted according to GLP.  There is occasionally a misperception that a GLP study is "better" than a non-GLP study or a study conducted according to GMP (Good Manufacturing Practices.) And this misperception can lead to study sponsors requesting GLP when it is not needed, adding unnecessary cost and length to a study.

Based the understanding that GLP is for nonclinical studies only, here are some common medical device studies and our recommendations on whether GLP is applicable.

Biocompatibility (both in-vivo and in-vitro): GLP

Validation Studies (sterilization validations, reusable device cleaning validations): either non-GLP or GMP (GLP is most likely not needed)

Exploratory Studies: GLP not needed (conduct these studies non-GLP)

Chemical Characterization Studies (such as ISO 10993-18 Chemical Characterization): GLP (most likely) not needed

Routine Lot Testing (bioburden, endotoxin, sterility): Conduct according to GMP*

*GMP is short for Good Manufacturing Practices

What Device Characterization Data is Needed for a GLP Study?

If a device study does need to be conducted GLP, then characterization data for the device (the test article) must be gathered, and this data becomes part of the GLP study.

GLP regulations require the following:

“The identity, strength, purity, and composition or other characteristics which will appropriately define the test or control article shall be determined for each batch and shall be documented. Methods of synthesis, fabrication, or derivation of the test and control articles shall be documented by the sponsor or the testing facility (21 CFR 58.105(a)).”

This language seems to be more targeted to pharmaceuticals than medical devices, so determining what data is needed for a device can be tricky. In our experience, here is what we find to be most appropriate:

  • Description of the device

  • Types of materials the device is made of (method of manufacture and name of the manufacturer of any polymers, colorants, metals, etc.)

  • Methods of manufacture and synthesis of the final device (i.e. injection molding) and location of manufacturing facilities.

  • Lot number (if applicable).

Stability data is also required, which is somewhat analogous to the device's shelf life or usable life. If this data has not been determined yet, it typically is sufficient for the manufacturer to provide a letter with an assurance that the device as tested during the relevant GLP study is within it's usable life.

For more information, and to better understand some of the FDA's stances on GLP and medical device studies, we recommend the FDA’s Draft Guidance for Industry and Food and Drug Administration Staff - The Applicability of Good Laboratory Practice in Premarket Device Submissions: Questions & Answers.

Additionally, a medical device specialist at Pacific BioLabs may be able to help assist with questions for your specific device testing project. Contact PBL to see if we may be able to help.

A New Era for Compounding Pharmacies

FDA Registration, New Regulations, and GMP Standards

Historically, pharmacies have been able to compound drugs for individual patients or in small batches. These compound pharmacies create and mix drugs customized to specific patient needs,  based on a prescription written by a physician. They abide by state regulations, as well as section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), and are overseen by the state boards of pharmacy.

In the last decade these pharmacies have outgrown their guidelines, simply because of the demand for compound drugs. What once was done on a per-patient basis grew into bulk production of compounded drugs, and this has serious consequences.

Adverse Events Linked to Contaminated Compounded Drugs

When Los Angeles experienced a meningitis outbreak in 2001 due to a compounded drug, the rules and regulations that govern compounding pharmacies became a topic of debate. This incident provoked health officials to request implementation of stricter laws for compounding pharmacies. There were several prominent concerns, including: the production and distribution of compounded drugs -- in a high volume -- without a prescription, maintaining sanitary environments during the manufacturing process, and lack of reporting adverse affects.

These issues again became a focal point in October 2012, when the New England Compounding Center (NECC) in Massachusetts manufactured and released a contaminated compound drug. This drug was responsible for a fungal meningitis outbreak, accounting for “infections in 750 individuals and the deaths of over 60 people,” according to the National Conference of State Legislatures. This incident prompted enactment of the Drug Quality and Security Act (DQSA) in November 2013, amending the FD&C Act, and including the significant addition of Section 503B, covering rules for bulk outsourcing facilities.

New regulations specified in the DQSA

1)    Compounding Pharmacies that distribute a high volume of compounded drugs, without prescription, have the option to register as an “outsourcing facility” (section 503B). This makes a clear distinction between traditional pharmacies compounding on a per patient basis, and the bulk production outsourcing pharmacies. The primary distinctions are that outsourcing facilities are now regulated by the FDA, and these facilities can now manufacture bulk compounded drugs without the need to be patient specific.

The FDA states that these facilities:

  • Must comply with Current Good Manufacturing Practice (CGMP) requirements
  • Be inspected by the FDA according to a risk-based schedule
  • Must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound

Compounding pharmacies that do not register as an outsourcing facility will still be required to comply with section 503A.  Each state is required to put a system in place to improve communication between the state boards of pharmacy and the National Association of Boards of Pharmacy (NABP). This system aims to promote a better regulation of these pharmacies. If a compound facility doesn’t comply with section 503A, the offense must be reported to the state boards of pharmacy.

2)    There will be new labeling requirements for compounded drugs. According to section 503B, labels should include:

  • A statement saying, “This is a compounded drug” and “Not for resale”
  • Information about the outsourcing facility
  • All pertinent details regarding the compounded drug (i.e. expiration date, active and inactive ingredients, manufacture date, storage and handling instructions, quantity, etc.)

3)    Per Title II: the drug supply chain will be strengthened by a “track and trace” system for prescription drugs. The goal is to have nationwide drug serial numbers that provide federal officials, manufacturers, repackagers, wholesale distributors, and dispensers with transaction information that will make it easier to investigate suspicious products.
How does the FDA plan to implement these new laws?
Besides becoming actively involved in inspecting high-risk compound pharmacies, the FDA has released documents to help implement the new rules mentioned above. According to the FDA, these documents consist of a draft interim guidance, a proposed rule, a and final guidance.

Draft Interim Guidance

When new rules are put into place, there can be an overwhelming amount of questions about compliance. The draft interim guidance helps pharmacies that register as outsourcing facilities comply with CGMP requirements, specifically focusing on sterility assurance of sterile drug products and the general safety of compound drug products.

Proposed Rule

A “proposed rule” would update the list of drug products considered unsafe or ineffective and therefore prohibited for use by outsourcing facilities and traditional compound pharmacies.

Final Guidance

This document reiterates section 503A for the pharmacies that do not register as outsourcing facilities. It also outlines what punitive actions that will be taken if compliance with section 503A is not met.

Expected Testing for Outsourcing Facilities

Outsourcing facilities are expected to adhere to the cGMP requirements in Title 21 of the Code of Federal Regulations Part 210 and 211 (21 CFR 210 and 211) until the FDA creates guidelines specifically designed for outsourcing facilities. According to 21 CFR 211.160(b), components of the compounded drug and the final drug product must “conform to appropriate standards of identity, strength, quality, and purity”. The facilities must also have “a system for monitoring environmental conditions” per section 211.42(c)(10)(iv).

If the facility does not have its own testing laboratories they will rely on 3rd party testing from laboratories that are approved by the FDA. These laboratories will conduct the necessary testing required, such as, but not limited to, Stability Testing (per section 211.166), Pyrogen and/or Sterility Testing (per section 211.165) and Environmental Monitoring. Other testing for potency, identity and concentration may also be required to ensure the safety of the drug product before released to the public.

Overall, the heightened regulations on compound pharmacies and the new addition of outsourcing facilities that the DQSA provides will safeguard the manufacturing of compound drugs.

Pacific BioLabs supports testing on compounded drugs that is required by 21 CFR 210 and 211. More information on our testing services can be found here: http://www.pacificbiolabs.com/testing_services.asp

References

1.    “Compounding and the FDA: Questions and Answers.” 2 Dec. 2013. Web. 6 Aug. 2014.
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm339764.htm#happens
2.    “FDA Implementation of the Compounding Quality Act.” 25 April 2014. Web. 6 Aug. 2014. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm375804.htm
3.    “FDA outlines expectations for human drug compounders, including registered outsourcing facilities.” 10 July 2014. Web. 6 Aug. 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403507.htm
4.    “CFR - Code of Federal Regulations Title 21.” 1 April 2013. Web. 18 Aug. 2014. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1
5.    Morgan, Rachel B. “Oversight of the U.S. Drug Supply.” 2 Dec. 2013. Web. 6 Aug. 2014. http://www.ncsl.org/research/health/regulation-and-oversight-of-the-u-s-drug-supply-h-r-3204-the-drug-quality-and-security-act.aspx#compounding%20quality%20act
6.    Drug Quality and Security Act. 27 Nov. 2013.
https://www.govtrack.us/congress/bills/113/hr3204/text or http://www.gpo.gov/fdsys/pkg/BILLS-113hr3204enr/pdf/BILLS-113hr3204enr.pdf
7.    Vivian, Jesse C. “New Rules for Compounding Drug Products.” 19 Feb. 2014. Web. 6 Aug. 2014. http://www.uspharmacist.com/content/d/pharmacy_law/c/46717/

How to Ensure the Safety of E-Cigarettes

What are e-cigarettes?

e-ciggarette

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.

lab-analysis

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