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  1. Warning Letters

WARNING LETTER

Custom Research Labs Inc. MARCS-CMS 616184 —

Delivery Method:
Via Email
Product:
Drugs
Recipient:
Recipient Name
Mr. Steven Kim
Recipient Title
Chief Executive Officer
Custom Research Labs Inc.

432 W. Alondra Blvd.
Gardena, CA 90248-2425
United States

steve@customresearchlabs.com
Issuing Office:
Division of Pharmaceutical Quality Operations IV

United States

WARNING LETTER

July 8, 2022

Dear Mr. Kim:

The U.S. Food and Drug Administration inspected your drug manufacturing facility, Custom Research Labs Inc., FEI: 3008268262, at 432 W. Alondra Blvd., Gardena, from June 1 to June 4, 2021.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

In addition, “(b)(4),” “(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer” are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a), and are misbranded under sections 502(c) and (ee) of the FD&C Act, 21 U.S.C. 352(c) and (ee). Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.

We reviewed your June 10, 2021, response to our Form FDA 483 in detail.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).

Your firm failed to test incoming active pharmaceutical ingredients (e.g., camphor and menthol) and other components (e.g., deionized (DI) water) used to manufacture over-the-counter drug products to determine their identity, purity, strength, and other appropriate quality attributes. For active pharmaceutical ingredients (API), you relied solely on certificates of analysis (COA) from suppliers where you have not established their reliability. In addition, you have not shown that your water system can consistently produce water suitable for drug manufacturing, and, at a minimum, meets the USP monograph for purified water and appropriate microbial limits.

For example,

Inadequate API Testing

Your firm relied on the COA from unqualified suppliers of camphor and menthol. These components are used in the manufacture of your (b)(4) drug product. The FDA requires identity testing for each component lot used in drug product manufacturing, and you can only rely on the COA for other component attributes by appropriately validating the supplier’s test results at appropriate intervals.

In addition, you did not ensure all specifications of your components were in conformance with USP. For example, the COA specification for impurity testing for halogens of camphor gum USP states “CONFORMS TO USP.” However, the USP monograph for camphor gum has a quantitative acceptance criterion for halogens and the quantitative result was not provided. Also, you provided the COA for menthol USP, which lacked impurity testing data for limit of nonvolatile residue and related compounds as required per the USP monograph.

In your response, you stated that both camphor and menthol have been validated by a third-party laboratory “through assay.” Your response is inadequate because you failed to demonstrate that all appropriate tests for camphor and menthol were performed or that appropriate validation of the supplier’s test results was conducted. Further, you did not address the discrepancies between your third-party laboratory’s COA and USP specifications.

Inadequate Component Water

Your firm has not shown that your DI water is suitable for aqueous-based dosage form drug product manufacturing, and, at a minimum, meets the USP purified water monograph and appropriate microbial limits. Further, your firm lacked sufficient testing of your DI water system. Inadequate water system design is a repeat observation from your 2016 FDA inspection. For example,

• Your firm has no record of testing water for Total Organic Carbon (TOC). In your response you stated, "All products produced since March 2020, have passed micro testing ensuring there are no TOC issues." You committed to purchase a TOC meter but failed to provide a timeline for the purchase and validation of the equipment. Further, the vendor stated in the TOC meter proposal provided in your response that, based on the current design of the system, TOC will most likely not meet the specification and that a recirculation pump must be added to keep the TOC low. Your response lacked details on whether you will establish appropriate TOC specifications and ensure your water system is adequately designed to meet those specifications.
• Since March 2020, your firm failed to monitor conductivity of your water used as a component in your drug products. You also failed to establish a specification for conductivity. Your response failed to address the lack of a conductivity specification.

Furthermore, your firm’s water system point-of-use ports yielded elevated bioburden counts of 1.3 x 106 and 2.3 x 104 total plate count (TPC)/ml for water used as a component in your drug products. Your action limit was (b)(4) TPC/ml. Your associated investigations did not adequately determine potential root cause(s) to fully investigate product impact. Your response did not address bioburden failures that lacked adequate investigation. Also, in multiple instances, the pH of your water system Line (b)(4) was out of specification with results ranging between 3.59 and 4.73. Your pH specification was (b)(4). In your response, you stated that, batches manufactured during this period were reviewed and there was no evidence that batches were affected. However, you did not provide data to substantiate this claim.

Without routine water monitoring of an appropriately designed system, you cannot ensure that your water meets minimum microbiological and chemical standards suitable for the manufacture of your drug products.

In response to this letter, provide:

• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.

• A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.

• A procedure for your water system monitoring that specifies routine chemical and microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.

• A comprehensive, independent assessment of your water system design and maintenance including the sanitization process. In addition, provide a summary of the qualification protocol(s) for your component water system. Also, include a summary of any improvements made to your system design and program for routine control and maintenance.

2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

Your firm failed to validate the manufacturing process for (b)(4) drug product currently in distribution. This is a repeat observation from your 2016 FDA inspection.

In your response, you stated that the validation of your (b)(4) drug product was not completed yet because you “require (b)(4) batches before we can validate a formula,” and only two batches have been completed. However, as observed during the inspection, there are at least (b)(4) batches manufactured using an unvalidated process and currently in distribution. Your response is inadequate because you failed to conduct an assessment or identify corrective actions to address unvalidated drug products currently in distribution.

In response to this letter, provide:

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

• A timeline for performing appropriate process performance qualification for each of your marketed drug products, including how you will ensure proper validation prior to distribution of drugs.

3. 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)).

Your firm lacked stability data to support the expiration dates for your (b)(4) drug product which is currently in distribution. This is a repeat observation from your 2016 FDA inspection. Instead, to support the two-year expiration date of your drug product, you provided data from a different formulation of (b)(4) that failed its long-term stability study and was stopped at the three-month time point because of changes in viscosity. The long-term stability test report determined the need for reformulation.

In your response, you explained that because a retain sample of (b)(4) drug product passed microbiology and assay testing, the two-year expiration date was justified for the drug product. However, the retain sample tested was the formulation that failed its long-term stability study for viscosity. Further, you did not provide testing to ensure the retain sample met all specifications required during your stability studies such as odor, pH, and viscosity. Your response is inadequate because you failed to provide a report that ensures adequate stability studies have been conducted for all drug products.

Without an adequate stability program, you cannot confirm that your drug products will meet established specifications and all pre-determined quality criteria throughout their shelf life.

In response to this letter, provide the following:

• A comprehensive, independent assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
  o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
  o Stability-indicating methods.
  o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
  o Detailed definition of the specific attributes to be tested at each station (timepoint).

• All procedures that describe these and other elements of your remediated stability program.

4. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your quality unit (QU) failed to review batch records before releasing drug product for distribution. Your QU procedure specifies that the Quality Assurance designee is responsible for reviewing all manufacturing, production, and quality records. However, during the inspection, one of your QU employees stated that the shipping and production department had released drug product batches before the batch record had been reviewed by the QU. It was also stated that your firm is trying to catch up on back logged batch record reviews. During the inspection, we observed that drug product batch records were incomplete at the time of release for (b)(4) Lot (b)(4), and (b)(4) and for (b)(4) Lot (b)(4).

In your response, you stated that all pending batch record reviews have been completed and that you revised your record review procedure to include batch sheet approval and other controls. However, your response failed to provide details of the outcome of that review. Your response is inadequate because you failed to identify appropriate corrective actions when the QU released drug products before batch record completion to ensure that drug products met established specifications for identity, strength, quality, and purity.

Your response demonstrated a lack of CGMP understanding and the lack of adequate quality oversight and control from incoming products to finished product.

Your inspectional history indicates that your quality unit is not fully exercising its authority and responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

In response to this letter, provide:

• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
  o A determination of whether procedures used by your firm are robust and appropriate
  o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
  o A complete and final review of each batch and its related information before the QU disposition decision
  o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products

Unapproved New Drug and Misbranding Violations

Unapproved New Drug Violations

“(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer” are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21, U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, “(b)(4),” and “(b)(4) are topical products intended for use as external analgesics. “(b)(4) HAND SANITIZER” (8 oz and 16 oz) and “BAK-OFF Instant Hand Sanitizer” are topical products intended for use as consumer topical antiseptics. Examples of claims from the products’ labeling, including websites listed on product labels, that provide evidence of the intended uses (as defined by 21 CFR 201.128) of these products include, but may not be limited to, the following: From your website (b)(4):

On your website homepage:
(b)(4)

On your website for “HOW IT WORKS”:
(b)(4)

“(b)(4) HAND SANITIZER” (8 oz and 16 oz)
“Easy To Use Spray + Surface Disinfectant . . . Uses1 ● for handwashing to decrease microbial contamination on the skin ● may be reapplied during the day as required ● for disinfecting surfaces” [from your product label]

“BAK-OFF Instant Hand Sanitizer”
“Lavender Oil . . . Rosemary Leaf Oil . . . Geranium Flower Oil . . . Antimicrobial Properties . . . Uses To decrease bacteria on the skin ▪ Recommended for repeated use” [from your product label]
“Made in California from Ethically Sourced Cosmetic Grade Ingredients with Antimicrobial Properties : . . . ● Aloe Vera . . . ● Lavender Oil . . . ● Rosemary Leaf Oil . . . ● Geranium Flower Oil . . . ●Specially Denatured Alcohol 70% vv” ” (from (b)(4))

As described below, “(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer” are “new drugs” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in their labeling. New drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from the FDA, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless they are lawfully marketed under section 505G of the FD&C Act (which is not the case for these products, as further described below) or under other exceptions not applicable here. No FDA-approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for these drug products, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that “(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer” drug products are GRASE for use under the conditions suggested, recommended, or prescribed in their labeling. Accordingly, these drug products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).

External Analgesic Drug Products

“(b)(4)” and “(b)(4)” are topical external analgesic drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Under section 505G(a)(1) of the FD&C Act, 21 U.S.C. 355h(a)(1), category I drugs that were subject to a tentative final monograph (TFM) that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330 are deemed to be GRASE and not “new drugs,” as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM and comply with all other applicable requirements. We note that over-the-counter (OTC) topical external analgesic products were addressed in the TFM for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983) and subsequent rulemakings. Under 505G(b)(8) of the FD&C Act, the 1983 external analgesic TFM, in combination with subsequent rulemakings, was deemed to be a final administrative order. However, “(b)(4),” and “(b)(4)” do not conform to the conditions of use specified in the final administrative order for the reasons described below.

The active ingredients, in your products, “(b)(4)” and “(b)(4),” i.e., (b)(4), and (b)(4), are not active ingredients included in the final administrative order for topical external analgesics. Although the product labeling does not specifically list these ingredients as active ingredients, the website claims for these ingredients, such as “With (b)(4), and (b)(4) temporarily reduces inflammation and pain,” “(b)(4) Used in homeopathic medicine as a treatment for bruises, sprains, pains, and other wounds,” “(b)(4) Alternative pain relief method applied to the skin for relief from sore muscles, aching joints, pain or inflammation” and “(b)(4) Natural pain reliever that can stimulate circulation to promote healing,” demonstrate that these are each an “active ingredient” as defined in 21 CFR 201.66(b)(2) because each ingredient is intended to furnish pharmacological activity.2

Furthermore, your “(b)(4)” and “(b)(4)” products fall under section 505G(a)(5) of the FD&C Act (21 USC 355h(a)(5)), because the FDA has determined that counterirritant external analgesic drug products with the active ingredient eucalyptus oil are not GRASE under a final determination issued under 21 CFR part 330.3 Therefore, these products are new drugs under FD&C Act 201(p).

Your “(b)(4)” is labeled for use as a counterirritant drug product because it includes claims associated with muscular aches and pains. The labeled active ingredient, (b)(4), falls below the allowable dosage range of 3% -11% for this active ingredient when used as a counterirritant in the 1983 TFM (48 FR 5862 at 5868).4 Further, the product labeling for “(b)(4)” includes the claim of fibromyalgia pain as an indication, which is not an indication that is permitted consistent with the conditions of marketing under the topical external analgesic final administrative order. This labeled intended use goes beyond merely describing the general intended use for external analgesic products as set forth in the final administrative order.

In addition, the FDA is not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that “(b)(4),” and “(b)(4)” drug products are GRASE for use under the conditions prescribed, recommended, or suggested in their labeling. Moreover, there is no evident basis under the FD&C Act under which these products would be legally marketed without an approved application. Accordingly, these products are unapproved new drugs marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section and 301(d) of the FD&C Act, 21 U.S.C. 331(d).

Topical Antiseptic Drug Products

Based on the above labeling claims, “(b)(4) HAND SANITIZER” (8 oz and 16 oz) and “BAK-OFF Instant Hand Sanitizer” are topical products intended for use as topical antiseptic drug products. As described below, these topical antiseptic drug products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).

We note that over-the-counter (OTC) topical antiseptic products had been the subject of rulemaking under the Agency’s OTC Drug Review. In particular, such products were addressed in a tentative final monograph (TFM) entitled “Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Health-Care Antiseptic Drug Products,” Proposed Rule, 59 FR 31402 (June 17, 1994) (1994 TFM), as further amended by “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,” Proposed Rule, 81 FR 42912 (June 30, 2016) (Consumer Antiseptic -Rubs Proposed Rule). Over the course of these rulemakings, three active ingredients (benzalkonium chloride, ethyl alcohol (ethanol), and isopropyl alcohol) were classified as Category III for use in consumer antiseptic rub products, meaning that additional safety and effectiveness data are needed to support a determination that a drug product containing one of these active ingredients would be GRASE for use in a consumer antiseptic rub. Additionally, OTC consumer antiseptic washes were addressed in “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Proposed Rule, 78 FR 76444 (December 17, 2013) (Consumer Antiseptic Washes Proposed Rule) and “OTC Safety and Effectiveness of Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Final Rule, 81 FR 61106 (September 6, 2016). We note that ethyl alcohol is not one of the active ingredients that was classified as Category III for use as an active ingredient in a consumer antiseptic wash. Under the Consumer Antiseptic Washes rulemaking, ethyl alcohol was determined to be ineligible for evaluation under the OTC Drug Review for use as an active ingredient in consumer antiseptic washes.

Section 505G of the FD&C Act addresses nonprescription drugs marketed without an approved application. Under 505G(a)(3) of the FD&C Act, drugs that were classified as Category III for safety or effectiveness in a TFM that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330 – and that were not classified as Category II for safety or effectiveness – are not required to have an approved application under section 505 in order to be marketed, as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM, including the active ingredient, and comply with all other applicable requirements.

However, “(b)(4) HAND SANITIZER” (8 oz and 16 oz) and “BAK-OFF Instant Hand Sanitizer” do not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rubs Proposed Rule and the 2013 Consumer Antiseptic Washes Proposed Rule, nor any other TFM, proposed rule or final rule. Thus, neither “(b)(4) HAND SANITIZER” (8 oz and 16 oz) nor “BAK-OFF Instant Hand Sanitizer” meets the conditions under section 505G(a)(3) of the FD&C Act for marketing without an approved application under section 505.

As previously noted, statements on the “(b)(4) HAND SANITIZER” (8 oz and 16 oz) label suggest both that the product is a consumer antiseptic wash and a consumer antiseptic rub. However, ethyl alcohol (in any concentration) is not an active ingredient permitted for use in a consumer antiseptic hand wash under the 2013 Consumer Antiseptic Washes Proposed Rule as further amended in the 2016 Final Rule.

In addition, Lavender Oil, Rosemary Leaf Oil, and Geranium Flower Oil are clearly represented as active ingredients in the labeling of your “BAK-OFF Instant Hand Sanitizer” drug product.5 Specifically, your product labeling for “BAK-OFF Instant Hand Sanitizer” features on the Principal Display Panel (PDP) “Lavender Oil . . . Rosemary Leaf Oil . . . Geranium Flower Oil . . . Antimicrobial Properties.” Your labeling further emphasizes these ingredients are intended to have a therapeutic effect with the statements “Our Hand Sanitizer with Antimicrobial Properties is carefully formulated with natural and botanical non-toxic ingredients that moisturize and are gentle for the skin, but 99% effective against germs.” As noted above, Lavender Oil, Rosemary Leaf Oil, and Geranium Flower Oil are not active ingredients in any applicable final monograph or TFM for purposes of establishing eligibility for lawful marketing without an approved application under section 505G of the FD&C Act. Therefore, “(b)(4) HAND SANITIZER” (8 oz and 16 oz) and “BAK-OFF Instant Hand Sanitizer” do not conform with the TFM, or the applicable requirements.

We are not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that “(b)(4) HAND SANITIZER” (8 oz and 16 oz) and “BAK-OFF Instant Hand Sanitizer” drug products are GRASE for use under the conditions prescribed, recommended, or suggested in their labeling. Moreover, there is no evident basis under the FD&C Act under which these products would be legally marketed without an approved application. Accordingly, these products are unapproved new drugs marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a).

Misbranded Drug Violations

In addition, “(b)(4) HAND SANITIZER” (8 oz and 16 oz) is misbranded under section 502(c) of the FD&C Act, 21 U.S.C 352(c), because the product’s Drug Facts panel contains extraneous information that goes beyond the required directions described in the rulemakings mentioned above. Specifically, 21 CFR 201.66(d)(7) states that additional information not described in the content requirements for OTC drug products should not appear in the Drug Facts panel. However, the Uses section for your product’s Drug Facts panel includes language such as “for disinfecting surfaces” that is not consistent with the uses provided for in the applicable rulemakings for consumer antiseptic rubs and consumer antiseptic washes.

Further, “(b)(4) HAND SANITIZER” (8 oz and 16 oz), and “BAK-OFF Instant Hand Sanitizer” are misbranded under section 502(ee) of the FD&C Act, 21U.S.C. 352(ee), because they are nonprescription drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but do not comply with the requirements for marketing under that section, and are not the subjects of applications approved under section 505 of the FD&C Act, 21 U.S.C. 355.

Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(a) of the FD&C Act, 21 U.S.C. § 331(a).

Quality Systems

Your firm’s quality systems are inadequate. See the FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Additionally, we note that you manufacture several OTC drug products, “(b)(4)” and “(b)(4)” that are labeled with a Drug Facts panel in which the purpose identifies these products as a “Pain Reliever.” While we acknowledge that neither product currently appears to be available for purchase or distribution in the US, we want to advise you of their regulatory status under 505G of the FD&C Act, 21 U.S.C. 355G. “(b)(4)” and “(b)(4)” are considered to be drugs as defined under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C) because they are intended for use as external analgesics. Section 505G of the FD&C Act, 21 U.S.C. 355h governs nonprescription drugs marketed without an approved application. These products prominently feature cannabidiol (CBD) on the principal display panel and include statements such as, “(b)(4) CBD.” Although CBD is labeled as an inactive ingredient in the labels of “(b)(4)” and “(b)(4),” the labeling for these products clearly represents CBD as an active ingredient.6 Currently, a nonprescription drug product containing CBD cannot be legally marketed without an approved new drug application, regardless of whether the CBD is represented on the labeling as an active ingredient or an inactive ingredient. To date, no CBD-containing drug has met applicable FDA requirements to be legally marketed for nonprescription use. Nonprescription drug products that include CBD as an active ingredient are not generally recognized as safe and effective and are new drugs which require an approved application to be legally marketed.

Furthermore, even if CBD could be considered an inactive ingredient in a nonprescription drug product, that product would still need an approved new drug application to be legally marketed, because the product would not meet the general requirements for nonprescription drug products under section 505G of the FD&C Act. In particular, such product would not meet the general requirement with respect to the safety and suitability of inactive ingredients under 21 CFR 330.1(e)7. Additionally, an inactive ingredient should not exert pharmacological effect8 and must be safe when used at the intended dosage.9

We note that CBD also cannot legally be sold in a conventional food or dietary supplement product. Please see the following for more information: FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD) and Warning Letters and Test Results for Cannabidiol-Related Products.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

Failure to address violations may also cause the FDA to withhold issuance of Export Certificates. The FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Please identify your response with the unique identifier: CMS# 616184

Send your electronic response to ORAPHARM4_Responses@FDA.HHS.GOV with ATTN: CDR Steven E. Porter, Jr. or mail your written response to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506

If you have questions regarding this letter, please contact LCDR Rumany Penn, Compliance Officer, at (949) 608-4409, or by email at Rumany.Penn@fda.hhs.gov.

Sincerely,
/S/

Lance M. De Souza
Acting Director, Division of Pharmaceutical Quality Operations IV

Cc:

David V. Ward
President
Custom Research Labs Inc.
432 W. Alondra Blvd.
Gardena, CA 90248-2425
david@customresearchlabs.com

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1 We note that your “(b)(4) HAND SANITIZER” labeling contains conflicting information about whether it should be used as a consumer antiseptic rub/consumer antiseptic wash or consumer antiseptic rub. The term “hand sanitizer” generally refers to consumer antiseptic rubs and the Drug Facts labeling of your product both indicates that the product is to be used for handwashing (presumably with water) and suggests that it should be used without water (i.e., “wet hands thoroughly with product” followed by the statement “briskly rub hands together until dry.” “(b)(4) HAND SANITIZER,” however, does not conform to the requirements for either a consumer antiseptic rub or a consumer antiseptic wash as discussed in this letter.

2 Under 21 CFR 201.66(b), an active ingredient is a component of a drug intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.

3 On November 7, 1990, FDA issued a final rule establishing that OTC counterirritant external analgesic drug products containing certain active ingredients, including eucalyptus oil, are not generally recognized as safe and effective. 55 FR 46920. FDA’s final determination was codified in regulations at 21 CFR 310.545(a)(10)(ii). Under section 505G(k)(2)(A) of the FD&C Act, the non-monograph conditions in 21 CFR 310.545 in effect on the day before the date of enactment of the CARES Act (i.e., March 26, 2020) were deemed to be a final administrative order. The final administrative order is entitled “Non-Monograph Conditions NM900: Drug Products Containing Certain Active Ingredients Offered Over-the-Counter for Certain Uses” (See Order ID OTC 000007, available at OTC Monographs@FDA, https://www.accessdata.fda.gov/scripts/cder/omuf/).

4 As noted earlier, the 1983 external analgesic TFM, in combination with subsequent determinations, was deemed to be a final administrative order under 505G(b)(8) of the FD&C Act.

5 Under 21 CFR 201.66(b), an active ingredient is a component of a drug intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.

6 See Tentative Final Monograph (TFM) for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983). CBD was not included as an active ingredient under this TFM. Under 21 CFR 201.66(b), an active ingredient is a component of a drug intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.

7 21 CFR 330.1(e) requires that “the product contains only suitable inactive ingredients which are safe in the amounts administered and do not interfere with the effectiveness of the preparation or with suitable tests or assays to determine if the product meets its professed standards of identity, strength, quality, and purity.”

8 See e.g., 21 CFR 314.3(b) and 21 CFR 210.3(b)(7), which define an active ingredient as “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man.” All other components of a finished drug product are considered inactive ingredients (see 21 CFR 314.3(b), 21 CFR 210.3(b)(8)).

9 See 21 CFR 330.1(e)

 
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