FDA Decision to Exempt Certain Class II Devices from 510(k) Premarket Notification

On July 11th, 2017 the FDA announced that they have determined that certain class II device will no longer meet the premarket notification requirements under section 510(k) of the Federal Food, Drug and Cosmetic Act.  This published list of devices is in accordance to the 21st Century Cures Act and will decrease the regulatory burden on the medical device industry. 

There are a number of factors that the FDA considers when determining whether a 510(k) is necessary to provide reasonable assurance of the safety and effectiveness of a class II device.  These factor are:

  1. The device does not have a significant history of false or misleading claims or of risks associated with inherent characteristics of the device.

  2. The characteristics of the device necessary for its safe and effective performance are well established.

  3. Changes in the device that could affect safety and effectiveness will either be readily detectable before causing harm or not increase the risk of injury, incorrect diagnosis or ineffective treatment.

  4. Any changes to the device will not be likely to result in a change to the device’s classification.

The FDA points out that an exemption from the 510(k) requirement does not mean that the device is exempt from any other statutory or regulatory requirement.     

The FDA document announcing these exemptions can be found here.  The majority of the document is comprised of three tables outlining the class II device exemptions.  Table 1 lists the devices that no longer require premarket notification under section 510(k) of the FD&C Act.  Table 2 lists the devices which contain partial exemptions and are subject to the general limitations to the exemptions found in the .9 section of Part 862 and 892 of Title 21 of the CFR.  Table 3 list devices classified as Radioallergosorbent (RAST) immunological test systems that no longer requires a 510(k) premarket notification but is subject to Section .9 of Part 866 of Title 21 of the CFR.  



Maximum Tolerated Dose (MTD) – An effective preclinical dose determination strategy

The path to drug approval involves drug discovery and drug development. In drug discovery, compounds are screened for favorable biological activity against a target(s) and lead compounds are chosen to be moved forward through drug development. Drug development evaluates these candidates for toxicity and ADME properties. An important part of preclinical drug development is to define the dose and schedule for Phase I clinical trials (First In Man).

Before conducting in vivo PK and ADME studies to determine the dosing schedule, the dose has to be defined. There are typically five options for defining a dose: Maximum Tolerated Dose (MTD), Maximum Feasible Dose (MFD), limit dose (1000mg/kg), exposure saturation, and dose providing a 50-fold margin of exposure. The most common of these, the maximum tolerated dose, is defined as the highest dose of a drug that does not cause unacceptable side effects or overt toxicity in a specific period of time.  These side effects can range from mild effects such as reduced weight gain, moderate effects such as weight loss up to 20% or substantial effects such as unresponsiveness. The MTD can be determined by acute toxicity studies, short duration dose escalation studies and dose ranging studies. These studies are designed with a minimum number of animals and include toxicological endpoints such as clinical observations and clinical pathology, for example blood tests for liver function. This maximum tolerated dose is then used for longer-term safety assessments. The rationale for using the MTD in long term studies is to maximize the likelihood of detecting any chronic disease effects or other hazards of a drug candidate. It is also more humane to determine the MTD before conducting any PK or ADME studies to minimize animal morbidity.  Maximum tolerated dose studies are not designed to cause mortality, therefore death is not an appropriate end point.    

It is not essential to demonstrate the MTD in every study, in some cases one of the other methods such as MFD, limit dose, exposure saturation or 50X margin of exposure would be more appropriate.  All of these options for determining the high dose for toxicology studies are described in ICH M3(R2), Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.

Pacific BioLabs performs preliminary toxicity studies in vivo to determine appropriate dosage, frequency and route of administration. Our toxicology team has extensive knowledge and experience to help our clients determine maximum tolerable dose (MTD) for their novel compounds for single and multiple dosing.  Visit PBL’s in vivo toxicology webpage to learn more.


Insulin and Glucagon Bioassays

PBL supports testing for a wide array of diabetes medications

PBL supports testing for a wide array of diabetes medications

With the prevalence of diabetes increasing worldwide at unprecedented rates in recent decades, the development of relevant drug therapies have expanded as well. Medications for regulating blood glucose levels are available in numerous permutations, and innovations in drug dosage and delivery methods appear frequently on the market.

Chief among the pharmaceuticals/injectables used in diabetes management is insulin, which lowers glucose levels.  Glucagon, on the other hand, increases glucose levels and is often used for the treatment of hypoglycemia.

Both insulin and glucagon are pancreatic hormones secreted in response to changes in blood glucose.  Recombinant insulin and glucagon can be mass-produced as a protein therapeutic, which can be modified to create analogs of the original proteins with certain desirable activity profiles.

The determination of biological potency plays a key role in the development and control of biological and biotechnology-derived products. Chapters <121> and <123> of USP outline procedures for testing the bioidentity and biopotency of synthetically produced insulin and glucagon.


Before synthetic insulin and glucagon products are used in clinical settings, they undergo a number of tests to verify their activity, concentration, and efficacy. These tests, called bioassays, vary in complexity and scope and may assess either quantitative or qualitative characteristics of the substance

· Biopotency tests quantitatively measure a product’s biologic activity

· Bioidentity tests qualitatively determine the identity of a compound by examining its physiological effects.

Standard bioassay procedures for the pharmaceutical industry are outlined in the U.S. Pharmacopeia and National Formulary (USP-NF).


Procedures for insulin assays are usually performed in conformance to USP <121>. Both the bioidentity and biopotency tests described in this chapter involve the rabbit blood sugar method, where four test groups of rabbits receive an injection of either a standard insulin solution or one of several sample solutions diluted to different potencies, and their blood glucose levels are measured periodically for several hours afterwards. A day to a week after the first injection, the rabbits receive a dose from another one of the insulin solutions, and their blood glucose is measured again. The rabbits’ response to the injections is extrapolated from these measurements, and this data can be used to calculate the potency of the sample solutions (not less than 15 USP units/mg to meet the bioidentity test requirements). These computed potencies are further analyzed in the biopotency test to establish a relative value with a 95% confidence interval; in order to meet the criteria of the test, this confidence interval must fall within +/- 10% of the computed potency value.

The USP requires a minimum of two replicates for this assay, though it generally takes 4-6 replicates to meet the specified confidence interval.


The bioidentity test for glucagon outlined in USP <123> is a challenging ex vivo procedure in which the drug’s effects are assessed on a primary culture of rat liver cells. As glucagon stimulates liver cells to convert glycogen to glucose, measurements of the rat cells’ glucose release indicate the extent of the product’s biologic activity. The potency can be calculated with statistical methods and comparisons detailed in other USP chapters. In order to meet the requirements of the bioidentity test, the glucagon sample must have a potency of not less than 0.80 USP rGlucagon Unit/mg.


Having over 18 years of experience in performing Insulin Bioassays, Pacific BioLabs expert panel of scientists – have extensive experience dealing with several product pipelines and have been actively involved with providing inputs for the writing of USP chapter <121> and <123>.

Our aim is to provide our clients with a combination of knowledge, rigor in our quality systems, personalized attention that is hard to find in the contract research world and help bring your product to marketYou can also learn more about our capabilities at our Compendial Bioassays and our In Vivo Bioassays pages.


1. Herman WH, Zimmet P. Type 2 diabetes: An epidemic requiring global attention and urgent action. Diabetes Care. 2012 [accessed 2016 July 15];35:943-944. http://care.diabetesjournals.org/content/35/5/943

2. 2016 U.S. Pharmacopoeia-National Formulary [USP 39 NF 34]. Volume 1. Rockville,Md: United States Pharmacopeial Convention, Inc; 2015. <121> Insulin assays;123.

3. 2016 U.S. Pharmacopoeia-National Formulary [USP 39 NF 34]. Volume 1. Rockville,Md: United States Pharmacopeial Convention, Inc; 2015. <123> Glucagon bioidentity tests; 198.



USP 661 Plastic Packaging: Introduction to <661.1> and <661.2>

Systems used to package therapeutics products – often called “Packaging Systems”, are generally constructed and composed from materials that may include glass, metals, plastics and elastomers/homologous polymers with a range of molecular weights and several additives.

These systems are usually in contact with the pharmaceutical product at some point during manufacturing, storage or administration and cause a big concern for safety.

A packaging system that contains or comes in contact with a pharmaceutical product needs to conform to USP 661.1 and 661.2 guidelines

A packaging system that contains or comes in contact with a pharmaceutical product needs to conform to USP 661.1 and 661.2 guidelines

Standards that address the safety and efficacy impact of interactions between the packaging systems and pharmaceutical products must consider diverse materials of construction and should include relevant and appropriate test methods and specifications for these materials.  1

The preexisting USP 38/NF 33 Chapter 661 contained analysis and qualifying methods for plastic packaging materials which included identification tests and physiochemical tests, but did not fully address the safety and efficacy of the material for its intended use. 2

Starting May 1, 2016, the new USP 39/NF 34 chapter 661.1 and 661.2 series characterize the materials better to provide more meaningful and rigorous analysis of the polymers that compose packaging materials <USP 661.1> and packaging systems <USP 661.2>.

What are the new chapters and what concerns do they address?

There are two separate chapters which were added to the May 2016 revision of USP <661>:

  • <661.1> Plastic Materials of Construction, determines whether a material has been well-characterized, for its intended use, and is designed to ensure that the material characteristics match the relevant performance requirements.

This chapter solely applies to individual plastic and raw materials, and contains tests, methods and specifications for cyclic olefins, polyethylene, polypropylene, polyethylene terephthalate, polyethylene terephthalate G, and plasticized polyvinyl chloride.1

The term “plastic packaging system” refers to the sum of packaging components which together contain the pharmaceutical product, the sum of which may include:

1. Primary packaging components: Those that directly contact the product at some time during the product’s manufacturing, distribution storage or use.

2.Secondary packaging components: Those that may interact with the pharmaceutical product’s manufacturing, distribution storage or use, although the component does not directly contact the pharmaceutical product.

What do these changes mean for packaging systems already in use and are commercially available?

The purpose of <661.1> is to increase the likelihood that a packaging system will be suitable for use by providing data about its material(s) of construction; whereas the purpose of <661.2> is to establish that the packaging system is suitable for use.

The new changes will only affect packaging systems which have not yet gained regulatory approval for use with a to-be marketed pharmaceutical product. If the packaging system is currently being used with a pharmaceutical product that is currently on the market, it does not require testing to the new requirements.

However in case of modifications, if a new material has been introduced, or if a material has changed then the packaging system will have to be re-tested. If the packaging system is changed in a way that does not alter its materials, then it does not need testing.

What tests would be performed to identify the material characteristics as required in <661.1> and <661.2>?

The testing matrix would primarily depend on the composition of the packaging system.

For <661.1> it may include any of the following tests (or a combination of them):

The characterization is done by identity, biocompatibility (biological reactivity), General physicochemical properties and additives and extractable metals.

  • Biological reactivity
  • IR
  • Thermal analysis
  • Extraction (possible solvents: water, toluene, alcohol)
  • Acidity or alkalinity
  • Absorbance
  • TOC
  • Metals (ICP- MS), HPLC (as required for the additive composition) 3

For <661.2> the focus is on suitability for use with respect to patient safety, and therefore the testing regimen would be inclusive of the establishment of the packaging system’s : 

  • Biocompatibility (biological reactivity)
  • Physiochemical properties (water extraction, acidity or alkalinity, absorbency, TOC)
  • Chemical safety assessment required involving the Extractables/Leachables profiling and the Toxicological risk assessment of the test data.

The <661.2> chapter applies specifically to plastic packaging systems and should not be applied to materials from which plastic packaging systems are constructed. 4

However, if the dosage form or conditions of use are moving from a ‘low risk’ to a ‘high risk’ dosage form, then the packaging system will need to be tested. This is because the <661.1> materials testing for ‘high risk’ dosage forms is more extensive than those for ‘low risk’.

How can Pacific BioLabs help you?

Starting August 2016, Pacific BioLabs offers testing services catering to the USP 661.1 and 661.2 chapters. Our objective is to help you determine the required testing for your materials and the ideal testing matrix so you will be able to plan ahead for your product.

Please reach out to BusinessDevelopmentStaff@pacificbiolabs.com for more info and one of our staff members will get back to you as soon as possible.

NOTE: Additional chapters have been proposed recently and are under review:

<661.3> Plastic Components and Systems used in Pharmaceutical Manufacturing, addresses the qualification of plastic components used in the manufacture of both pharmaceutical and biopharmaceutical active pharmaceutical ingredients (APIs) and drug products (DPs), and was open to public comment till July 31, 2016.

<661.4> Plastic Medical Devices Used to Deliver or Administer Pharmaceutical Products addresses the material characterization of plastics used in the manufacturing process and medical devices and still under development.  


1.  http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/stim_article_661_final.pdf

2.   https://hmc.usp.org/sites/default/files/documents/HMC/GCs-Pdfs/c661.pdf

3.   http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/m8008.pdf

4.  http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/m8009.pdf

5.   http://www.usp.org/frequently-asked-questions/plastic-materials-construction-and-plastic-packaging-systems-pharmaceutical-use




Current FDA guidance indicates that drug interactions should be "defined during drug development, as part of an adequate assessment of the drug's safety and effectiveness."(1) While in vivo drug interaction studies are typically necessary during late-stage development, in vitro drug interaction studies can sometimes serve as a cost-effective substitute to more costly in vivo drug interaction studies in earlier stages of development. Hence along with pharmacokinetic studies, studies designed to investigate drug-drug interactions represent an important step in the drug development process for new chemical entities.

Pacific BioLabs was recently approached by a client in need of quantitative HPLC test methods for 25 different pharmaceuticals as part of an in vitro drug interaction study. Each drug was to be quantified within three separate buffer formulations designed to simulate in vivo conditions. The list of pharmaceuticals included compounds displaying a broad range of chemical structures, each of which would be expected to display unique retention behavior on an HPLC system. In addition, many of the compounds were to be prepared in only trace quantities representative of bodily concentrations observed in a clinical setting.

Method development began with a chalkboard assessment of the chemical properties of each compound to estimate the most suitable HPLC conditions. A thorough literature search was conducted to examine parameters used in previously published methods. The compounds were subsequently divided into three categories corresponding to molecules with high, intermediate, and low polarity. Basic method conditions were then developed for each of the three categories: a shallow gradient (phosphate buffer/acetonitrile) with a C8 column for high polarity molecules, a moderate gradient (phosphate buffer/acetonitrile) with a C8 column for intermediate polarity molecules, and a steep gradient (H2O + formic acid/acetonitrile + formic acid) with a C18 column for low polarity molecules. These conditions served as a starting point from which more specific conditions for each compound could be adjusted and optimized as necessary.


Often common in method development, the occurrence of a number of stumbling blocks necessitated the application of some creative workarounds. Many of the low-polarity molecules displayed poor aqueous solubility even after repeated dilution. In these cases, addition of a small amount of DMSO to the aqueous buffers permitted successful dissolution. On the other end of the polarity scale, some compounds displayed little or no retention on C8/C18 columns.  A pentafluorophenyl (PFP) column, which has a unique bonded-phase that interacts with polar compounds, demonstrated adequate retention for an exceptionally high-polarity compound which failed to retain after repeated adjustments of mobile phase pH and gradient conditions. Adequate detection of compounds present in trace concentrations was accomplished through optimization of UV-wavelength and on-column focusing, although one compound present in extremely low concentrations required MS/MS detection.

Optimal method conditions developed at PBL were qualified to ascertain linearity, accuracy, precision, and benchtop stability. In the end, three of the compounds displayed insufficient benchtop stability and one of the compounds was dropped by the client, leaving a grand total of 21 successfully completed HPLC methods. The successful development of these methods – the majority of which were completed in roughly three months’ time – demonstrates Pacific BioLabs’ capability to respond to client needs with both scientific expertise and timeliness.

For more information about method development services and other contract research services please see our analytical services brochure or inquire by telephone at +1 510 964 9000.

1 "Draft Guidance: Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations." FDA, Feb. 2012.