GMP, Healthcare Institutions, Life Sciences, Medical Devices, Pharma

FWQRC™ intended to provide a decision pathway for drug & medical devices manufacturers in their first steps towards implementation of eCTD publishing and submission

Hi, Welcome to FWQRC™ Regulatory Focus News Letter

About Blog: FWQRC™ Regulatory focus pharma news, views and analysis of healthcare in a rapidly changing world. Not only do we keep you connected with the latest trends in pharma, we can also help you develop and bring to life your own thoughts, ideas and inspirations to enable you and your business to become key pharma influences

Many of us aware that eCTD is mandatory for DMF submissions from Jan 2020.

  • At the beginning of the decision process it is very important to make an evaluation of the current submission processes (“where are we”) in comparison with the eCTD requirements (“where do we need to be”).
  • The conclusions drawn from this analysis, together with a careful evaluation of the boundary conditions within the company are the basis for the definition of the User Requirements Specifications (URS). 
  • In the URS all the needs and boundaries of the expected processes are described and this information is used to find the optimal solution.Three possible solutions are described in detail, with their related advantages and disadvantages
  1. In-house software,
  2. Software as a Service (SaaS) and
  3. Outsourcing  
  • The last step of the process is the implementation of the chosen solution.
  • It has to be considered whether a consultant should help with the creation of this URS document. Especially for the generation of the new processes the experience of a consultant can be helpfulThe URS is part of the official validation documentation according to GAMP and should be established for any new system
  • Selection of solution
  • Once the URS has been finalised, the most suitable solution has to be found.  For this analysis the URS requirements should be classified in some way, e.g. “crucial” and “nice to have”.
  • The three possible solutions (In-house Software, Software as a Service and Outsourcing) are described in detail in the following sections.  Table 1 compares the most relevant characteristics of the 3 solutions, Table 2: Running an eCTD software system in-house: advantages and disadvantages and Table 3: Host system option: advantages and disadvantages

Table 1: Comparison of the 3 solutions

ItemIn-House softwareSoftware as a ServiceOutsourcing
Freedom of configurationHigh limitedNo
Responsibility for update and MaintenanceHighNoNo
IT support in-house needed YesNoNo
Link to other IT systems in-house possibleYesNoNo
Initial costs High LowNo
Ongoing costs In-houseYesYes
Lead timeLongMediumShort
ScalabilityDepends on set-upEasy Easy
Need of resources and competence for use of eCTD softwareYesYesNo
confidentiality / data security issuesNoYesYes

Table 2: Running an eCTD software system in-house: advantages and disadvantages

AdvantagesDisadvantages
Full freedom for configurationHigh initial costs for setting up the system
Free choice of hardware and software componentsRelatively long lead time needed to set up the system
The software is part of the company-owned software and fits into the IT concept of the companyFull responsibility for update and maintenance
Everything stays in house (no data-transfer via internet / confidentiality etc.)Personnel for technical set-up and maintenance must be available.
Link-up to other IT-systems possible (e.g. SAP) 
Maintenance costs stay in-house 
On-going costs are lower compared to the host software or outsourcing options 

Table 3: Host system option: advantages and disadvantages

AdvantagesDisadvantages
Speed: time from the decision to a pilot eCTD is often shorter compared to the in-house software solutionDependency on an external partner which increases if also the DMS shall be hosted
Lower cost for initial implementation as there is no or a smaller initial investment (e.g. initial set-up, user and software licenses, maintenance)Data transfer via internet (confidentiality, upload / down load capacity)
Scalable: ability to scale as business needs changeData hosted at an external company (confidentiality)
No on-going system maintenanceLimited freedom for software configuration
 On-going costs for renting the system/service

Table 4: Outsourcing option: advantages and disadvantages

AdvantagesDisadvantages
Speed: time from the decision to a pilot eCTD is very shortDependency on an external partner for each project and throughout the life cycle of a submission
No initial investment and no reoccurring costs for system maintenance and technical supportOn-going costs for each service during the whole lifecycle of a product/submission (initial submission(s), variations etc.)
No direct costs for software, licenses, hardware, system validation and maintenance, trainingData transfer (confidentiality, upload / down load capacity)
No need to establish, maintain technical knowledge in building and publishing eCTDs, no need for respective in-house resources (eCTD builder/publisher)Data hosted at an external company (confidentiality)
Scalable: ability to scale as business needs change 
Can also substantially-reduce risk of failed initial submissions 
  • There are 4 main scenarios that can drive the decision for outsourcing
  1. there is no in-house software available to build / publish eCTDs or
  2. the in-house capacities are too little
  3. to gain experience for the creation of eCTD ready documents and eCTD submissions in-house
  4. the number of eCTD submissions is too small, seldom use of the system
  • Conclusion: The option with the lowest impact on processes and systems in a company is outsourcing. There are various different extents of outsourcing. Common to all is that the external partner will provide the necessary infrastructure / software as well as the personnel to prepare the eCTD.

Stay in connected with FWQRC™ for implementation of eCTD publishing & submission

GMP, Life Sciences, Regulatory Focus News Letter, Rules

FDA Finalizes Rule to Go From Paper to Electronic Devices Submissions

Hi, Welcome to FWQRC Regulatory Focus News Letter.

Here we are going to discuss about the finalised rule for the submission process.

As part of an effort to improve the US Food and Drug Administration’s (FDA) medical device submission process, the agency on Friday issued a final rule to remove the requirements for multiple paper copy submissions and replace them with a single electronic submission.

The agency said the rule, proposed in September 2018 and will take effect in 30 days, is in response to an executive order from the Trump Administration in 2017 made famous as the “one-in, two-out” order. FDA’s rule is meant to improve the device premarket submission program and create a more efficient submission system.

“The requirement for a single submission in electronic format applies to all submission types that fall within the provisions listed in section 745A(b) of the FD&C Act; under this final rule, FDA is only amending those regulations that specifically mention paper and/or multiple copies of such regulatory submissions and are not consistent with this final rule,” FDA said.

The agency responded to four comments on the proposal but did not update the rulemaking. The agency noted that the final rule will produce cost savings for firms without imposing any additional regulatory burdens for submissions or affect the agency’s ability to review submissions.

“Firms will incur minimal administrative costs to read and understand the rule. We expect the economic impact of this regulation to be a total net costs savings yielding positive net benefits,” FDA said.

The agency also noted that submissions in electronic format can include those created and submitted on CD, DVD or flash drive and mailed to FDA.

For premarket approval applications (PMAs), the final rule changes one section to take out a section requiring an applicant to submit three copies of any updated safety and effectiveness report for pending applications.

FDA also previously required that PMAs be submitted in six copies, each bound in one or more numbered volumes, but that language has been removed with this final rule.

In another section, FDA removes the requirement that a PMA applicant has to provide copies of information that it believes to be trade secret or confidential commercial or financial information in the PMA.

FDA in September also published a draft guidance with “both binding and nonbinding provisions”

Please contact FWQRC for electronic submissions. (+91 8072483812)

Healthcare Institutions, Life Sciences, Regulatory Focus News Letter, Rules

Final Rule to Collect Antimicrobial Sales and Distribution Information by Animal Species

Hi, Welcome to FWQRC Regulatory Focus News Letter

Here we are going to discuss about the final rule to collect Antimicrobial Sales and Distribution information by Animal Species

The FDA has issued a final rule to obtain more detailed information about antimicrobials sold or distributed for use in food-producing animals by including estimates of sales data by species. The additional data will improve understanding about the extent to which antimicrobials are sold or distributed for use in major food-producing species and help the FDA further target its efforts to ensure judicious use of medically important antimicrobials. It will also assist the agency in measuring the effectiveness of those efforts.

The final rule requires animal drug sponsors to submit species-specific estimates of antimicrobial sales for cattle, swine, chickens, and turkeys. The final rule also includes a provision to improve the timeliness of FDA’s annual summary report of these sales data by requiring the FDA to publish its annual summary report of antimicrobial sales and distribution information by December 31 of the following year.

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Healthcare Institutions, Life Sciences, Pharma, Regulatory Focus News Letter

BIOSIMILAR DRUGS

Good Morning, Welcome to FWQRC Regulatory Focus News Letter

Today We are going to review the benefits and concerns on biosimilar drugs

Pathway for approvals was initiated in 2009.

Ten years later (or less than five years since the first FDA approval of a biosimilar), and just 42% (11 out of 26) of FDA-approved biosimilars have launched. But in the next three months , a clutch of new biosimilars will hit the market, including new ones in oncology, hinting at a wave of uptake.

For instance, Pfizer is expected to launch three biosimilars soon: one for Avastin (bevacizumab) later this month, one for Rituxan (rituximab) next month, and one in February for Herceptin (trastuzumab). Two other trastuzumab biosimilars may also launch soon, which would mean more than 60% of biosimilars approved in the US will have launched by early next year.

The rising number of launches, combined with an increasing amount of quick uptake, may put biosimilar foes on their heels.

For instance, Neulasta (pegfilgrastim) biosimilars have found recent success, with Coherus’ Udenyca (pegfilgrastim-cbqv) and Mylan and Biocon’s Fulphila (pegfilgrastim-jmdb) capturing 25% market share in just over a year, according to a report released last week from Bernstein.

Similarly, a sign of rapid uptake can be seen with Amgen’s Mvasi (bevacizumab-awwb), which has captured 10% of the Avastin market in just four months.

“Biosimilars are growing their market share and leading to meaningful price erosion over time; with the more recent biosimilar launches showing a lot of success – reflecting perhaps the growing market sophistication of the biosimilar companies,” former FDA Commissioner Scott Gottlieb, referring to the Bernstein report, noted recently.

And in the future, Humira (adalimumab) and Enbrel (etanercept) biosimilars (seven approved, zero launched int he US) may look more like outliers in a larger pool of approvals and subsequent launches. By contrast, in the EU, Humira biosimilars have already captured 35% of the multi-billion-dollar market in one year, and biosimilars have captured 50% of the Enbrel market in about three years, according to Bernstein.

The US Remicade (infliximab) biosimilar market is also an eyesore (Bernstein refers to it as “essentially a failed market”) as the two biosimilar entrants have only amassed 12% market share in more than two years. Amgen’s infliximab biosimilar was recently approved last week and may hit the market soon. And Johnson & Johnson said the Federal Trade Commission has launched an investigation into its contracting practices for Remicade, although similar investigations in Canada and the UK yielded little.

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Contact FWQRC™ for GMP Training, Auditing by QP, eCTD, GAP Analysis, Risk Assessment, CAPA, CSV, Method development/Validation, ADE/PDE Values, Facility & Product Registrations

GMP, Life Sciences, Pharma, Regulatory Focus News Letter

MUTUAL RECOGNITION AGREEMENT (MRA) FROM A GLOBAL PERSPECTIVE

Hi, Welcome to FWQRC Regulatory Focus New Letter

Here we are going to measuring the Impact of the Pharmaceutical Annex to the U.S./EU Mutual Recognition Agreement

When we first began discussing the prospects of a mutual recognition agreement with the European Union, in which EU member state (EUMS) regulators and the FDA would agree to rely on each other’s factual findings from their good manufacturing practice (GMP) inspections of drug facilities, the potential benefits seemed obvious.

European drug makers to benefits from MRA

By relying on each other’s expertise and ability to conduct GMP inspections under the Pharmaceutical Annex to the U.S./EU Mutual Recognition Agreement, we expected to avoid duplicate inspections of the same facilities, especially for facilities with a strong record of compliance. And these efficiencies would allow us to reallocate our inspectional resources to areas of higher risk. Of course, we knew we would have to wait until the agreement was implemented before we could confirm these assumptions.

Developing the MRA took time and resources. Beginning in 2014, FDA experts were sent to Europe to observe EU officials audit each of the 28 EUMS inspectorates to assure that they could conduct inspections at a standard similar to a U.S. inspection. In addition, we had to establish confidentiality commitments with each regulator to allow for the sharing of non-public information contained in inspection reports and be assured that each EUMS had a framework for preventing conflicts of interest that provided a similar level of protection as those in place at FDA. The FDA completed this work for the most common type of drug manufacturing inspections in July 2019.

The FDA and the EU have been collecting data on the operational impact of the MRA ever since the first countries were found capable on November 1, 2017, and the numbers are quite promising. So far the EU has conducted 29 inspections at FDA’s request and the FDA has conducted 14 inspections at the EU’s request. Moreover, FDA has deferred 157 inspections in the EU after review of the inspectional information provided by our trusted partners. We anticipate seeing an even greater impact now that the MRA has been implemented in all 28 EU countries for human drug products.
The need for such metrics was one of the recommendations from the National Academies of Sciences, Engineering, and Medicine (NASEM) in a recent report. FDA had asked an Ad Hoc NASEM committee to examine mutual recognition and mutual reliance agreements around the world (some dating back many years) and the committee found a surprising lack of data on the successes and challenges of these programs. To address that information gap, the committee called on regulatory authorities to create a results framework with clear indicators, metrics, and processes for monitoring and evaluating these programs. Such information would increase understanding of the program’s public health benefits and enable benefit-risk analyses over time, the report’s authors said.

We certainly agree that more data is needed on the U.S./EU MRA, beyond the operational data we’re collecting now. In fact, we’re working with our EU partners to explore what additional metrics might be informative. Having sufficient data will help the FDA decide not only how to allocate our inspectional resources, but also the scope and breadth of future mutual recognition and mutual reliance agreements that might include other categories of inspections and product types, such as veterinary medicines. Since these other categories often involve different inspectorates in Europe than those audited for human pharmaceuticals, implementation could take some time. Yet, eventually, with metrics in place, we could confirm their benefits as well, allowing manufacturers to avoid unneeded inspections while ensuring that medicines are safer for patients.

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Contact FWQRC™ for GMP Training, Auditing by QP, eCTD, GAP Analysis, Risk Assessment, CAPA, CSV, Method development/Validation, ADE/PDE Values, Facility & Product Registrations

GMP, Pharma

Asia Regulatory Roundup: China Opens Food and Drug Center of Excellence

Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia.


TGA Suspends Ranitidine Medicines Ahead of Possible License Cancellations

The Therapeutic Goods Administration (TGA) has suspended 23 ranitidine medicines from the Australian Register of Therapeutic Goods (ARTG). TGA suspended the products for six months but thinks there are grounds to ultimately cancel the medicines from the ARTG altogether.

Last month, TGA presented results from tests on 34 ranitidine medicines sold by 10 companies. The tests, which covered 135 batches, suggested most ranitidine medicines available in Australia contained more than 0.3 parts per million (PPM) of N-nitrosodimethylamine (NDMA), meaning they breached the internationally agreed limit for the carcinogen. Back then, TGA said it was considering “suspending the registration for products which cannot demonstrate adequate safety and quality.”

Now, TGA has revealed its response to the high levels of NDMA. The Australian regulator has put 23 ranitidine medicines on a six-month suspension that will run from 16 December to 16 June. Apotex, Arrow Pharma and Sandoz are among the companies with products affected by the suspension.

Ranitidine products absent from the list of suspended medicines include two ARTG entries sold by Arrow Pharma under the Chemists’ Own brand. The products were two of five ARTG entries with batches TGA found to contain levels of NDMA below 0.3ppm. Batches taken from two other Arrow Pharma ARTG entries and one Sandoz entry also passed the TGA test but were still suspended.

TGA uses suspensions to protect patients while giving manufacturers the chance to address issues with their products. In the case of the ranitidine medicines, if the affected companies fail to make changes to reassure TGA of the safety of their products, they face the prospect of losing their place on the ARTG permanently.

In the section on the grounds for suspension for each of the 23 products, TGA wrote that, “It is likely there are grounds for cancelling this medicine from the ARTG … on the basis that the quality of the goods is unacceptable.” The affected manufacturers now have a little more than six months to stop that happening, although in some cases TGA extends suspensions to give companies more time to fix problems with their products

GMP, Life Sciences, Pharma, Rules, Warning Letters

Regulatory focus news letter on USFDA Warning letters – Monthly Update (Nov 2019)

A summary of USFDA Warning letter is presented below for quick reference

  • In total 27 USFDA Warning letters were issued in the month of November 2019.
  • 11 out of 27 related to various Pharmaceutical industries ( CGMP/Finished Pharmaceuticals/Adulterated )across the Globe
  • 15 are related to Unapproved New Drugs/Misbranded/Cannabidiol (CBD) Products
  • 01 is related to unapproved new drugs/misbranded

Find below some of the warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211

MARCS-CMS 581785 — SEPTEMBER 10, 2019

1. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

2. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

3. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

Hazard Analysis and Risk-Based Preventive Controls (21 CFR 117, Subpart C)

1. Your hazard analysis did not identify a known or reasonably foreseeable hazard for each type of food manufactured, processed, packed, or held at your facility to determine whether there are any hazards requiring a preventive control, as required by 21 CFR 117.130(a)(1). Specifically, your hazard analysis does not identify the hazard of recontamination with environmental pathogens at all steps where ready-to-eat (RTE) food is stored and processed while exposed to the environment in your facility after the (b)(4) step, such as at the “(b)(4),” “(b)(4),” and “(b)(4)” steps.

2. You did not identify and implement sanitation preventive controls to provide assurances that any hazards requiring a preventive control (i.e., recontamination with environmental pathogens) will be significantly minimized or prevented and the food manufactured, processed, packed, or held by your facility will not be adulterated under section 402 of the FD&C Act, as required by 21 CFR 117.135(a)(1) and (c)(3), as evidenced by the following:

a. From April 2019 to May 2019, you found five (5) environmental samples positive for L. monocytogenes in the environment in Zone 3, including areas within your RTE production area where RTE food is exposed to the environment. In addition, FDA laboratory analysis of environmental sample #1088400 collected at your facility on May 21, 2019, revealed that one (1) environmental swab in Zone 3 was positive for L. monocytogenes

b. Your written corrective action procedure for your “Environmental Microbial Sampling SOP,” issued 3/19/2019, states that “(b)(4).” However, between April 2019 and May 2019, you identified five positive environmental samples of L. monocytogenes, and you do not have records to show that you conducted an investigation of the potential source or cause of contamination.

Find below some of the warning letters related to Unapproved drugs / Misbranded products

Dietary Supplement Labeling

Information on your website at https://koicbd.com suggests that you intend to market your “KOI CBD Infused Shot” product as a dietary supplement that contains CBD because the “KOI CBD Infused Shot” is described as a “supplement.” However, your product cannot be a dietary supplement because it does not meet the definition of a dietary supplement under section 201(ff) of the FD&C Act, 21 U.S.C. 321(ff). FDA has concluded, based on available evidence, that CBD products are excluded from the dietary supplement definition under sections 201(ff)(3)(B)(i) and (ii) of the FD&C Act, 21 U.S.C. 321(ff)(3)(B)(i) and (ii). Under those provisions, if an article (such as CBD) is an active ingredient in a drug product that has been approved under section 505 of the FD&C Act, 21 U.S.C. 355, or has been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, then products containing that substance are outside the definition of a dietary supplement.1 There is an exception if the substance was “marketed as” a dietary supplement or as a conventional food before the new drug investigations were authorized; however, based on available evidence, FDA has concluded that this is not the case for CBD. FDA is not aware of any evidence that would call into question its current conclusion that CBD products are excluded from the dietary substance definition under sections 201(ff)(3)(B)(i) and (ii) of the FD&C Act, but you may present FDA with any evidence bearing on this issue.

Unapproved New Drugs

Based on our review of your website, your “CBD HEALING BALM,” “CBD VAPE OIL,” “FULL SPECTRUM CBD TINCTURE,” “KOI LOTION,” “KOI CBD Gummies,” and “KOI CBD Infused Shot” products are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or intended to affect the structure or any function of the body.

Examples of claims observed on your website, https://koicbd.com, that establish the intended use of your products as drugs include, but may not be limited to, the following:

On your webpage titled “8 Proven Benefits of CBD”:

  • “CBD RELIEVES PAIN AND INFLAMMATION”
  • “studies show that CBD prevents human experimental psychosis and is effective in open case reports and clinical trials in patients with schizophrenia, with a remarkable safety profile.”
  • “Not only does the research show that CBD benefits including being effective in fighting breast cancer cells, data also suggest that it can be used to inhibit the invasion of lung and colon cancer, plus it possesses anti-tumor properties in gliomas and has been used to treat leukemia.”
  • “CBD LOWERS INCIDENCE OF DIABETES”

On your webpage titled “IS CBD RIGHT FOR YOU?”:

  • “several pre-clinical reports showing anti-tumor effects of CBD…have found reduced [cancer] [sic] cell viability, increased cancer cell death, decreased tumor growth, and inhibition of metastasis.”

On your webpage titled “CBD AND OPIOID ADDICTION”:

  • “CBD FOR OPIOID ADDICTION”
  • “A potential new treatment for opioid addiction has been found in a new review of previous research of cannabidiol (CBD).”

On your webpage titled “10 LITTLE KNOWN USES FOR CBD”:

  • “PTSD”
  • “Fibromyalgia”
  • “Schizophrenia”
  • “Diabetes”
  • “MS”
  • “Crohn’s Disease”
  • “Opioid Addiction”
  • “The advantage of cannabidiol as a potential treatment for opioid addiction is that it doesn’t give users a high and thus doesn’t involve a risk of misuse.”

Your “CBD HEALING BALM,” “CBD VAPE OIL,” “FULL SPECTRUM CBD TINCTURE,” “KOI LOTION,” “KOI CBD Gummies,” and “KOI CBD Infused Shot” products are not generally recognized as safe and effective for the above referenced uses and, therefore, the products are “new drugs” under section 201(p) of the FD&C Act, 21 U.S.C. 321(p). New drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from the FDA, as described in sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a). FDA approves a new drug on the basis of scientific data and information demonstrating that the drug is safe and effective. There are no FDA-approved applications in effect for any of the above mentioned products.

Misbranded Drugs

Your “CBD HEALING BALM,” “CBD VAPE OIL,” “FULL SPECTRUM CBD TINCTURE,” “KOI LOTION,” “KOI CBD Gummies,” and “KOI CBD Infused Shot” products are also misbranded within the meaning of section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1), in that their labeling fails to bear adequate directions for use. “Adequate directions for use” means directions under which a layperson can use a drug safely and for the purposes for which it is intended. (See 21 CFR 201.5.) The aforementioned products are offered for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written so that a layperson can use these drugs safely for their intended purposes. FDA-approved prescription drugs that bear their FDA-approved labeling are exempt from the requirements that they bear adequate directions for use by a layperson. However, your products are not exempt from the requirement that their labeling bear adequate directions for use, 21 CFR 201.100(c)(2) and 201.115, because no FDA-approved applications are in effect for them. The introduction or delivery for introduction into interstate commerce of these misbranded drugs violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

Prohibited Act under 301(ll) and Adulterated Human Foods

We note that your “KOI CBD Gummies” product appears to be promoted as a conventional human food. Specifically, your website refers to the gummies as “delicious, edible CBD snacks.” However, you should be aware that it is a prohibited act under section 301(ll) of the FD&C Act, 21 U.S.C. 331(ll), to introduce or deliver for introduction into interstate commerce any food to which has been added a drug approved under section 505 of the FD&C Act or for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public. Based on available evidence, FDA has concluded that the prohibition in section 301(ll) applies to CBD. There is an exception if the substance was marketed in food before the drug was approved or before the substantial clinical investigations involving the drug had been instituted. However, based on the available evidence discussed above, FDA has concluded that this is not the case for CBD. FDA is not aware of any evidence that would call into question its current conclusion that section 301(ll) of the FD&C Act prohibits the introduction into interstate commerce of any food to which CBD has been added, but you may present FDA with any evidence bearing on this issue.

You should also be aware that, as defined in section 201(s) of the FD&C Act (21 U.S.C. 321(s)), the term “food additive” refers to any substance the intended use of which results in its becoming a component of any food, unless the substance is generally recognized as safe (GRAS) among qualified experts under the conditions of its intended use, or unless the substance meets a listed exception.2

Food additives require premarket approval based on data demonstrating safety. Any food additive that has not been approved for its intended use in food is deemed to be unsafe under section 409(a) of the FD&C Act (21 U.S.C. 348(a)), and causes the food to be adulterated under section 402(a)(2)(C)(i) of the FD&C Act, 21 U.S.C. 342(a)(2)(C)(i). Introduction of an adulterated food into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

There is no food additive regulation which authorizes the use of CBD. We are not aware of any information to indicate that CBD is the subject of a prior sanction (see 21 CFR Part 181). Furthermore, we are not aware of any basis to conclude that CBD is GRAS for use in conventional foods. FDA’s regulations in 21 CFR 170.30(a)-(c) describe the criteria for eligibility for classification of a food ingredient as GRAS. The use of a food substance may be GRAS based on either scientific procedures or, for a substance used in food before 1958, through experience based on common use in food (see 21 CFR 170.30).

We know of no basis for general recognition of safety for CBD based either on scientific procedures or common use in food prior to January 1, 1958. Based on our review of published, scientific literature, existing data and information do not provide an adequate basis to conclude that the use of CBD in food meets the criteria for GRAS status. Many unanswered questions and data gaps about CBD toxicity exist, and some of the available data raise serious concerns about potential harm from CBD. Our review of publicly available data associated with the one FDA-approved CBD drug, as well as our review of published scientific literature, identified potential for liver injury from CBD and potentially harmful interactions with certain drugs. In addition, studies in animals have shown that CBD can interfere with the development and function of testes and sperm, decrease testosterone levels, and impair sexual behavior in males. Therefore, based on our review, the use of CBD in conventional food products does not satisfy the criteria for GRAS status under 21 CFR 170.30.

FDA is not aware of any other exception to the food additive definition that would apply to CBD for use as an ingredient in a conventional food. Therefore, CBD added to a conventional food is a food additive under section 201(s) of the FD&C Act and is subject to the provisions of section 409 of the FD&C Act. Under section 409, a food additive is deemed unsafe unless it is approved by FDA for its intended use prior to marketing. CBD is not approved for use in any conventional food. Food containing an unsafe food additive within the meaning of section 409 is adulterated within the meaning of section 402(a)(2)(C)(i). Therefore, to the extent that you intend to market this products as a food, your “KOI CBD Gummies” product is also adulterated within the meaning of section 402(a)(2)(C)(i) of the FD&C Act. Introduction of an adulterated food into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

Unapproved New Animal Drugs

During our review of your website, https://koicbd.com, FDA determined that your firm is marketing the unapproved new animal drugs “KOI Naturals CBD Spray for Pets” and “KOI CBD Soft Chews.” Based on our review of your website, your “KOI Naturals CBD Spray for Pets” and “KOI CBD Soft Chews” products are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in animals and/or intended to affect the structure or any function of the body of an animal. Further, as discussed below, these products are unapproved new animal drugs and marketing them violates the FD&C Act.

Examples of claims observed on your firm’s website https://koicbd.com that show the intended uses of these products include, but are not limited to, the following:

On your webpage titled “Is CBD Oil Good for Pets”:

  • “Do you have a pet who is exhibiting notable discomfort? Consider giving them CBD oil to alleviate their symptoms.”
  • “So although it helps to alleviate pain, there is no risk of addiction or psychoactive side effects.”

These products are “new animal drugs” under section 201(v) of the FD&C Act, 21 U.S.C. 321(v), because they are not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs, as safe
and effective for use under the conditions prescribed, recommended, or suggested in the labeling.

To be legally marketed, a new animal drug must have an approved new animal drug application, conditionally approved new animal drug application, or index listing under sections 512, 571, and 572 of the FD&C Act, 21 U.S.C. 360b, 360ccc, and 360ccc-l. These products are not approved or index listed by the FDA, and therefore these products are considered unsafe under section 512(a) of the FD&C Act, 21 U.S.C. 360b(a), and adulterated under section 501(a)(5) of the FD&C Act, 21 U.S.C. 351(a)(5). Introduction of these adulterated drugs into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

301(ll) and Adulterated Animal Foods

Moreover, to the extent that you market any of your products containing CBD as animal food, you should be aware that it is a prohibited act under section 301(ll) of the FD&C Act, 21 U.S.C. 331(ll), to introduce or deliver for introduction into interstate commerce any animal food to which has been added a drug approved under section 505 of the FD&C Act or for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public. Based on available evidence, FDA has concluded that the prohibition in section 301(ll) applies to CBD, as described above.

You should also be aware that, as defined in section 201(s) of the FD&C Act (21 U.S.C. 321(s)), the term “food additive” refers to any substance the intended use of which results in its becoming a component of any animal food, unless the substance is generally recognized as safe (GRAS) among qualified experts under the conditions of its intended use, or unless the substance meets a listed exception.3

There is no animal food additive regulation that authorizes the use of CBD. We are not aware of any information to indicate that CBD is the subject of a prior sanction (i.e., a sanction or approval granted prior to the enactment of the Food Additives Amendment of 1958 under the FD&C Act, the Poultry Products Inspection Act, or the Meat Inspection Act). Furthermore, we are not aware of any basis to conclude that CBD is GRAS for use in animal foods. FDA’s regulations in 21 CFR 570.30(a)-(c) describe the criteria for eligibility for classification of an animal food ingredient as GRAS. The use of an animal food substance may be GRAS based on either scientific procedures or, for a substance used in animal food before 1958, through experience based on common use in animal food (see 21 CFR 570.30). We know of no basis for general recognition of safety for CBD based either on scientific procedures or common use in animal food prior to January 1, 1958. Based on our review of the publicly available literature, the data and information necessary to support the safe use of CBD in animal foods are lacking. In fact, literature reports have raised safety concerns for animals consuming CBD, including, but not limited to, male reproductive toxicity and liver toxicity. Therefore, based on our review, the use of CBD in animal products does not satisfy the criteria for GRAS status under 21 CFR 570.30.

Under section 409 of the FD&C Act, 21 U.S.C. 348, an animal food additive is deemed unsafe unless it is approved by FDA for its intended use prior to marketing. CBD is not approved for use in any animal food. Animal food containing an unsafe food additive within the meaning of section 409 is adulterated within the meaning of section 402(a)(2)(C)(i) of the FD&C Act. Introduction of an adulterated animal food into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).