Recipient NameMs. Hyun Eun Lee
Recipient TitleVice President
- Kadesh International
7341 Lincoln Way
Garden Grove, CA 92841
- Issuing Office:
- Division of Pharmaceutical Quality Operations IV
Irvine, CA 92612-2506
VIA SIGNATURE CONFIRMED DELIVERY
May 2, 2019
Ms. Hyun Eun Lee
7341 Lincoln Way
Garden Grove, CA 92841
Dear Ms. Lee:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Kadesh Inc., FEI 3003832984, at 7341 Lincoln Way, Garden Grove, from October 19 to November 7, 2018.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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, based on our review, your products “Puriton Eye Relief Drops” and “Puriton Intimate Disinfection Spray” are misbranded drugs in violation of section 503(b)(4) of the FD&C Act, 21 U.S.C. 353(b)(4), in that their labels fail to bear the symbol, “Rx only.” In addition, your “Puriton Natural Mineral Cleansing Bar Soap” is an unapproved new drug sold in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). A discussion of these violations is included below.
We reviewed your November 21, 2018, response in detail.
During our inspection, our investigators observed specific violations including, but not limited to, the following.
1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
You failed to establish roles and responsibilities of the Quality Unit (QU), and released your ophthalmic drug product without ensuring its sterility.
You manufacture a bulk drug product by mixing (b)(4) which is then sent to contract manufacturers to manufacture a multi-dose, preservative-free, homeopathic ophthalmic drug product without aseptic processing or terminal sterilization. If ophthalmic drugs are not sterile, they pose unacceptable risks to patients including infection and potential for vision loss.
In addition, it is essential that multi-dose ophthalmic drug products contain one or more suitable substances that will preserve a product and minimize the hazard of injury resulting from incidental contamination during use.
Furthermore, you established finished ophthalmic drug product pH specifications of (b)(4) to (b)(4), which was confirmed by FDA laboratory analysis. The alkaline pH of your ophthalmic drug product is similar to that of (b)(4), which creates unacceptable risks to patients including destruction of ocular tissues in the cornea and vision loss.
Inadequate Quality Oversight of Contract Manufacturers
You lack adequate quality oversight. For example, your Vice President signed a waiver to (b)(4) that explicitly approved the contract manufacture of ophthalmic drugs “in a nonsterile room.” When asked by our investigator during inspection if the bulk ophthalmic drug product is filled aseptically, the same Vice President said your firm is unsure because you rely on your contract manufacturers to do everything. FDA inspections of your contract manufacturers verified that your drugs were being filled in facilities that were not capable of manufacturing sterile drugs. Furthermore, when asked during the inspection whether you review records from contract manufacturers, you again indicated that you rely on your contract manufacturers, and that when your contractor sends you finished product you consider it ready for release.
Although the finished drug is manufactured under contract, you, as the product owner, bear ultimate responsibility for ensuring that manufacturing activities conducted on your behalf comply with CGMP requirements. Without an adequate QU, you are unable to ensure that drug products meet required specifications and manufacturing standards for safety, identity, strength, quality, and purity.
See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing modern 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.
In your response you committed to ceasing (b)(4) hiring a CGMP consultant, and taking some corrective actions and preventive actions (CAPA). Your response was inadequate because you failed to address ceasing (b)(4) in the future and to provide supporting documentation of your CAPA. You also failed to provide interim actions during your estimated timeline of (b)(4) to (b)(4) months for your CAPA and to evaluate the effect of your lack of controls on the quality and safety of all drugs distributed on the U.S. market within expiry.
Although you committed to ceasing (b)(4) in response to this letter, provide the following with respect to your other drugs:
o Written clarification of whether you plan to manufacture drugs required to be sterile in the future. Also, describe all drugs that you plan to manufacture or contract out for manufacture in the future.
o Detailed supporting documentation of your CAPA including, but not limited to, your QU procedures and actions taken to establish a robust quality management system.
o Your interim plans for the manufacture and distribution of drug products while you remediate your violations.
o A retrospective evaluation of your drug products that remain on the U.S. market. You should address any drug product quality or patient safety risks including those potentially affected by your lack of adequate quality oversight, and assess the adequacy of investigations into any deviations, out-of-specification results, or other manufacturing quality issues. Include a full CAPA (e.g., notification to customers; recall) for any drug products that may have a quality or safety risk.
o A comprehensive assessment with CAPA to ensure your QU is given the needed authority and resources to effectively discharge its function. The assessment should also include, but not be limited to:
- A determination of whether procedures used by your firm are robust and appropriate
- Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
- Complete and final review of each batch and its related information before the QU disposition decision
- Oversight and approval of investigations and discharging of all other QU duties to ensure safety, identity, strength, quality, and purity of all products
o A comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified, assigned appropriate expiration or retest dates, and incoming material controls are adequate to prevent use of unsuitable containers, closures, and components.
o Regarding the latter, include a detailed plan for ongoing assessments of each lot of component used for production of finished drug product to meet appropriate standards of identity, strength, quality, and purity. Your plans to establish a robust supplier qualification program, including a detailed supplier qualification and audit program that specifies how you ensure that oversight of suppliers is commensurate with risk to finished product.
2. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).
You released your bulk ophthalmic drug product to your contract manufacturers for further processing without preparing batch production or control records. You also failed to document each significant step in the manufacture, processing, packing, or holding of each batch of bulk drug product that you perform. In fact, when asked by our investigator during the inspection, you said that the actual process is confidential and not written down. Without adequate production and control records, you cannot provide data to demonstrate the safety, identity, quality, strength, or purity of any of your drug products.
In your response, you acknowledged the importance of master production records and committed to taking CAPA for all quality-related activities. However, your response was inadequate because you failed to provide supporting documentation of your CAPA. You also failed to provide interim actions during your remediation which you estimate will take (b)(4) to (b)(4) months.
In response to this letter provide the following:
- Detailed supporting documentation of your CAPA including, but not limited to, establishing batch and production control records.
- A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that remediates documentation practices and ensures you retain complete and accurate records.
- A data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production and packaging processes will consistently meet appropriate manufacturing standards and parameters. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, and determining the capability and reliability of each manufacturing process step and control.
3. Your firm failed to establish time limits for the completion of each phase of production to assure the quality of the drug product (21 CFR 211.111).
You failed to establish time limits for any steps during the manufacture of all bulk drug products that you produce. For example, your bulk drug product can be staged for (b)(4) between manufacturing and shipment to your contract manufacturers for filling without any scientific studies and justification. You had no data to demonstrate that your lengthy hold times did not adversely affect the quality of your drugs including bioburden of the bulk formulation of ophthalmic drugs.
In your response, you committed to establishing time limits for each processing step. Your response was insufficient because you failed to provide supporting documentation of your CAPA. You also failed to address your plans for interim actions during your (b)(4) of remediation time.
In response to this letter, provide detailed supporting documentation of your CAPA including their applicability to your contract manufacturers.
FDA Sample Results & Drug Recall
Finished drug product samples manufactured from the bulk drug product produced at your facility were collected for FDA laboratory analysis.
FDA laboratory analysis of multiple lots of collected ophthalmic drug product confirmed they were contaminated with Bacillus spp., high levels of particulate matter, or both. In addition, FDA sample results demonstrated the unacceptable caustic pH of your ophthalmic drug product.
You recalled all lots of “Puriton Eye Relief Drops” after being contacted by the FDA regarding your contaminated ophthalmic drug product.
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.
If you still plan to manufacture drugs, we also recommend a qualified consultant with drug manufacturing experience perform a comprehensive audit of your drug production operation for CGMP compliance and evaluate the completeness and effectiveness of any CAPA you have implemented before engaging in drug production.
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.
Use of Contract Manufacturers
Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors, such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.
You are responsible for the quality of your drugs, regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.
Misbranded Homeopathic Drugs
During the inspection of your manufacturing facility in Garden Grove, CA, FDA collected the product label for your firm’s “Puriton Eye Relief Drops,” the “Puriton Face” brochure, and the “Puriton Natural Steroid Replacer” handout. In addition, FDA reviewed your website, www.puriton.us, where you market and promote “Puriton Intimate Disinfection Spray.” You market both “Puriton Eye Relief Drops” and “Puriton Intimate Disinfection Spray” as homeopathic drug products.
Your “Puriton Eye Relief Drops” and “Puriton Intimate Disinfection Spray” are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended to diagnose, cure, mitigate, treat, or prevent disease, and/or intended to affect the structure or any function of the body. Claims demonstrating the intended uses of your products include, but may not be limited to, the following:
Puriton Eye Relief Drops
From the “Puriton Face” brochure:
- “After surgery (cataract, glaucoma, etc.): 4 or 5 times a day.”
Puriton Intimate Disinfection Spray
From the website www.puriton.us and the “Puriton Natural Steroid Replacer” handout:
- “Chronic cystitis”
- “Vulva genital ulcers”
We recognize that “Puriton Eye Relief Drops” and “Puriton Intimate Disinfection Spray” are labeled as homeopathic drugs with active ingredients measured in homeopathic strengths. Under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), the term “drug” includes articles recognized in the official Homeopathic Pharmacopeia of the United States (HPUS) or any supplement to it. Homeopathic drugs are subject to the same regulatory requirements as other drugs; nothing in the FD&C Act exempts homeopathic drugs from any of the requirements related to adulteration, labeling, misbranding, or approval.
We acknowledge that many homeopathic drugs are manufactured and distributed without FDA approval under enforcement policies set out in the FDA’s Compliance Policy Guide entitled, Conditions Under Which Homeopathic Drugs May be Marketed (CPG 400.400) (the CPG). As its title suggests, the CPG identifies specific conditions under which homeopathic drugs may ordinarily be marketed; thus, in order to fall under the enforcement policies set forth in the CPG, a homeopathic product must meet the conditions set forth in the CPG. One of those conditions is compliance with section 503(b) of the FD&C Act. The CPG states that homeopathic products intended solely for self-limiting disease conditions amenable to self-diagnosis (of symptoms) and treatment may be marketed over-the-counter (OTC). Homeopathic products offered for conditions not amenable to OTC use must be marketed as prescription products.
Section 503(b)(1) of the FD&C Act, 21 U.S.C. 353(b)(1), identifies criteria for determining the prescription status of a product. The above products are prescription drugs as defined in section 503(b)(1)(A) of the FD&C Act, 21 U.S.C. 353(b)(1)(A), because in light of their toxicity or other potentiality for harmful effect, or the method of their use, or the collateral measures necessary to their use, “Puriton Eye Relief Drops” and “Puriton Intimate Disinfection Spray” are not safe for use except under the supervision of a practitioner licensed by law to administer such drugs. Therefore, these products are misbranded under section 503(b)(4) of the FD&C Act, 21 U.S.C. 353(b)(4), in that their labels fail to bear the symbol, “Rx only.”1 The introduction or delivery for introduction of these misbranded drugs into interstate commerce is a violation of section 301(a) of the FD&C Act, 21 U.S.C. § 331(a).
Unapproved New Drug
Your firm’s product, “Puriton Natural Mineral Cleansing Bar Soap” is a drug under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because it is intended to diagnosis, cure, mitigation, treat, or prevent disease, and/or intended to affect the structure or any function of the body. As explained further below, introducing or delivering this product for introduction into interstate commerce violates the FD&C Act.
Examples of claims that establish the intended use of your product include, but may not be limited to, the following:
Puriton Natural Mineral Cleansing Bar Soap
From the “Puriton Face” brochure:
- “Cleansing bar prevents skin diseases…. It has strong inhibitory effect on skin cancer diseases… and exerts excellent effect to prevent atopy and various skin diseases.”
Your “Puriton Natural Mineral Cleansing Bar Soap” is also a “new drug” under section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because it is not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling. Under section 505(a) of the FD&C Act, 21 U.S.C. 355(a), new drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from FDA. No approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355(a), is in effect for this product. Accordingly, the introduction or delivery for introduction into interstate commerce of this product violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Your written response should refer to the Warning Letter number above (CMS 570947).
Please address your reply to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
United States Food and Drug Administration
Irvine, CA 92612
If you have any questions about the content of this letter, please contact Jessica Mu, Compliance Officer, at 949-608-4477 and reference unique identifier CMS 570947 on all correspondence.
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
1 CPG 400.400 states that, in accordance with 503(b)(1) of the FD&C Act, homeopathic drug products offered for conditions that require diagnosis or treatment by a licensed practitioner must bear the prescription legend, “Caution: Federal law prohibits dispensing without prescription.” This CPG was issued by the agency in 1988. In 1997, Congress enacted the Food and Drug Administration Modernization Act (FDAMA); section 126 of FDAMA amended 503(b)(4) of the FD&C Act to require that the label of a prescription drug must bear, at a minimum, the symbol “Rx only.”