- Delivery Method:
- VIA UPS
Recipient NameMr. Stuart Soo
Recipient TitleManaging Director
- Furley Bioextracts SDN BHD
No. 7, Jalan Villaraya, Villaraya Industrial Park 3
23rd Mile, Jalan Sungai Lalang
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-21-56
September 13, 2021
Dear Mr. Soo:
Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of over-the-counter (OTC) drug products. FDA has reviewed the records you submitted in response to our November 5, 2020, request, and subsequent correspondence, for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility, Furley Bioextracts SDN BHD, FEI 3008174509, located at No. 7, Jalan Villaraya, Villaraya Industrial Park 3, 23rd Mile, Jalan Sungai Lalang, 43500 Semenyih, Selangor Darul Ehsan, Malaysia.
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 appear conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).
In addition, PainFix Relief Gel is an unapproved new drug 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 is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(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.
1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).
Your firm manufactured an OTC drug product, PainFix Relief Gel, containing menthol for the United States market. Your response to our request for records and other information under section 704(a)(4) indicated that you did not conduct adequate finished drug product testing on all drug products shipped to the United States.
For example, in response to our request to provide release specifications of products for distribution in the United States and the test methods used to evaluate them, you submitted a certificate of analysis (COA) for your OTC PainFix Relief Gel that indicated you did not conduct adequate testing for the identity and strength of the active ingredient, menthol. You specifically confirmed in subsequent correspondence that you did not perform any identification and assay testing for menthol in the finished drug product that was shipped to the United States.
Without adequate testing, you do not have scientific evidence that your drug product batches conform to appropriate specifications before release.
In response to this letter, provide the following for all drug products imported to the United States:
• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.
o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the U.S. that are within expiry as of the date of this letter.
o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(1).
Based on the records and information you provided, you have not demonstrated that you are testing incoming lots of the active pharmaceutical ingredient (API) used to manufacture your OTC drug products to determine their identity.
For example, in response to our request for information on identity testing for each lot of component, you did not provide evidence of such testing. In response to our follow up request to clarify whether identity testing was performed for the incoming API used to produce PainFix Relief Gel, you provided the COA received from the vendor and stated that identity testing was not performed for the incoming API.
In response to this letter, provide the following for all drug products imported to the United States before and after our 704(a)(4) request:
• 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.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
• 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.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure that describes this COA validation program.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
3. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).
You failed to provide adequate stability data to demonstrate that the chemical properties of your drug products remain acceptable throughout the labeled expiry period.
For example, in response to our 704(a)(4) request for a list of all batches on stability and a list of all stability studies, you confirmed that there was no stability data to support the (b)(4) shelf life for PainFix Relief Gel shipped to the United States. In addition, your e-mail dated March 22, 2021, stated you only “managed to collect the 0th month data”. The Stability Data document attached to the e-mail reported only initial test results and you stated the subsequent testing was placed on hold.
Without appropriate stability data, you cannot ensure your drug products meet established specifications and all pre-determined quality criteria throughout the drug product’s assigned shelf-life.
In response to this letter, provide the following for all drug products imported to the United States:
• A comprehensive, independent assessment and corrective and preventive action plan to ensure the adequacy of your stability program.Your remediation program should include, but not be limited to:
o Stability indicating methods, including both analytical and microbiological test methods
o Stability studies for each drug product in its marketed container-closure system before distribution is permitted
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.
Unapproved New Drug and Misbranding Violations
PainFix Relief Gel is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is 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 it is intended to affect the structure or any function of the body. Specifically, this product is intended for use as an external analgesic.
Examples of claims observed on the PainFix Relief Gel product label and the website, https://painfixbody.com, that is considered labeling that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:
“Drug Facts. . . Topical analgesic. . .Uses. . . temporarily relieves aches and pains of the joints and muscles associated with backache … arthritis … bursitis … tendonitis …cramps …strains…bruises…sprains.” (product label)
“Soreness prevention and relief for joints, muscles, and soft tissues . . .fights inflammation. . .improves circulation . . . Results showed that PainFix significantly reduced existing inflammation and inhibited the onset of new inflammation . . . Each ingredient has not only its own unique healing power, but also works together with other ingredients for a synergistic effect….Key Ingredients. . . Safflower (Carthamus tinctorius)…Rich in anti-inflammatory HYSA compounds…Improves blood circulation…Protects endothelial cells; TibetanRhubarb (Rheum officinale)…Contains emodin, a powerful anti-inflammatory…Used to treat wounds and ulcers; Turmeric (Rhizoma curcumae longae)…Antioxidant and anti-inflammatory…Reduces cartilage degeneration; Myrrh (Commiphora molmol)… Relieves swelling…Anti-inflammatory and analgesic; Mandarin Orange Peel (Citrus reticulata) …Powerful anti-inflammatory…Natural antiseptic and antifungal; Baikal Skullcap (Scutellaria baicalenis)…Powerful antioxidant and antimicrobial…Neuroprotective properties; Chinese Cinnamon (Cinnamoum cassia)…Powerful antioxidant…Inhibits osteoclasts…Antifungal and antibacterial; Basket Fern (Drynaria roosii)…Scientifically proven anti-osteoporotic…Improves bone healing; Aloe vera (Aloe barbadenis)…a rich antioxidant and anti-inflammatory…Reduces risk of joint cartilage degeneration; Wild celery root (Angelica anomala)…Analgesic and antibacterial…Reduces muscle spasms…Relieves headaches; Dragon’s blood (Daemonorops draco)… Promotes tissue regeneration…Traditionally used for sprains; Zedoary (White Turmeric) …Relieves joint swelling; Mastic sap (Pistacia lentiscus) …Relieves joint swelling…Multiple pharmacological properties; and Camphor (Cinnamomum camphora) …used for arthritis…Powerful painkiller.”
This topical external analgesic product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. New drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from 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 this product, as further described below) or under other exceptions not applicable here. No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is 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 your PainFix Relief Gel drug product is GRASE for use under the conditions suggested, recommended, or prescribed in its labeling. Accordingly, this product is an unapproved new drug 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 OTC external analgesic products have been the subject of rulemaking under FDA’s OTC Drug Review. In particular, such products were addressed in the Tentative Final Monograph (TFM) for External Analgesic Drug Products for OTC Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983).
Section 505G of the FD&C Act addresses nonprescription drugs marketed without an approved application. Under 505G(a)(1) of the FD&C Act, 21 U.S.C. 355h(a)(1), category I drugs that were subject to a 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. However, PainFix Relief Gel does not conform to the applicable TFM or any other TFM or proposed rule and does not meet the conditions under section 505G(a)(1) of the FD&C Act for marketing without an approved application under section 505.
The formulation and labeling for PainFix Relief Gel are not consistent with the conditions proposed by the external analgesic TFM. Specifically, your product website presents ingredients Safflower (Carthamus tinctorius), Tibetan Rhubarb (Rheum officinale), Turmeric (Rhizoma curcumae longae), Myrrh (Commiphora molmol), Mandarin Orange Peel (Citrus reticilata), Baikal Skullcap (Scutellaria baicalenis), Chinese Cinnamon (Cinnamoum cassia), Basket Fern (Drynaria roosii), Aloe vera (Aloe barbadenis), Wild celery root (Angelica anomala), Dragon’s blood (Daemonorops draco), Zedoary (White turmeric), Mastic sap (Pistacia lentiscus), and Camphor (Cinnamomum camphora) that are outside the applicable monograph. According to 21 CFR 201.66(b)(2), an “active ingredient” means 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 humans. Although your firm does not specifically list these ingredients as active ingredients, your claims for these specific ingredients such as, Safflower (Carthamus tinctorius)…Rich in anti-inflammatory HYSA compounds…Improves blood circulation…Protects endothelial cells; Tibetan Rhubarb (Rheum officinale)…Contains emodin, a powerful anti-inflammatory…Used to treat wounds and ulcers; Turmeric (Rhizoma curcumae longae)…Antioxidant and anti-inflammatory…Reduces cartilage degeneration; Myrrh (Commiphora molmol)… Relieves swelling…Anti-inflammatory and analgesic; Mandarin Orange Peel (Citrus reticulata) …Powerful anti-inflammatory…Natural antiseptic and antifungal; Baikal Skullcap (Scutellaria baicalenis)…Powerful antioxidant and antimicrobial…Neuroprotective properties; Chinese Cinnamon (Cinnamoum cassia)…Powerful antioxidant…Inhibits osteoclasts…Antifungal and antibacterial; Basket Fern (Drynaria roosii)…Scientifically proven anti-osteoporotic…Improves bone healing; Aloe vera (Aloe barbadenis)…a rich antioxidant and anti-inflammatory…Reduces risk of joint cartilage degeneration; Wild celery root (Angelica anomala)…Analgesic and antibacterial…Reduces muscle spasms…Relieves headaches; Dragon’s blood (Daemonorops draco)… Promotes tissue regeneration…Traditionally used for sprains; Zedoary (White Turmeric) …Relieves joint swelling; Mastic sap (Pistacia lentiscus) …Relieves joint swelling…Multiple pharmacological properties; and Camphor (Cinnamomum camphora) …used for arthritis…Powerful painkiller” 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.None of these ingredients except for camphor are permitted active ingredients under the external analgesic TFM. Furthermore, the combination of these ingredients with menthol is not permitted under the external analgesic TFM.
Additionally, the product labeling for the PainFix Relief Gel includes indications that are not covered under the external analgesic TFM. For example, your product website includes claims such as fighting inflammation, pain relief from bursitis and tendonitis, healing, treating wounds and ulcers, protecting endothelial cells, reducing cartilage degeneration, antimicrobial, neuroprotective properties, relieves headaches, and improves bone healing. These labeled intended uses go beyond merely describing the general intended use for external analgesic products containing active ingredients as set forth in the external analgesic TFM.
PainFix Relief Gel is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee) because PainFix Relief Gel is a nonprescription drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but does not comply with the requirements for marketing under that section and is not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.
The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
You acknowledged that you did not prepare a process validation protocol or qualify your (b)(4) and filling equipment. Your Batch Production Record did not include documentation of each significant step in the manufacturing process. Without established procedures for production and process controls, you are unable to ensure stable manufacturing operations and consistent drug quality.
See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and elements of process validation at https://www.fda.gov/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf.
Your firm’s quality systems are inadequate. See 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/media/71023/download.
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.We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.
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.
The violations cited in this letter are not intended to be an all-inclusive list of violations associated with your drug product. You are responsible for investigating and determining the causes of any these violations and for preventing their recurrence or the occurrence of other violations.
Note that FDA placed all drug products manufactured by your firm on Import Alert 66-40 on May 7, 2021, as the methods used in and controls used for the manufacture, processing, packing, or holding of these products do not appear to conform to current good manufacturing practices within the meaning of section 501(a)(2)(B) of the FD&C Act. Drugs and drug products that appear to be adulterated or misbranded may be detained or refused admission without physical examination pursuant to section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).
All drugs and drug products manufactured by your firm may remain listed on this import alert until there is evidence establishing that the conditions that gave rise to the appearance of this violation have been resolved, and the Agency has confidence that future entries will be in compliance with the FD&C Act. This may include an inspection before the Agency considers the appearance of adulteration to be addressed.
Correct any violations promptly. FDA may withhold approval of any new drug 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 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 correct your 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.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3008174509 and Joseph Lambert, Pharm.D.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
CC (via email& UPS):
Manoj Zachariah, U.S. Agent
Liberty Management Group, Ltd
75 Executive Dr Ste 114
Aurora, IL 60504-8150