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WARNING LETTER

Soleo MARCS-CMS 567046 — 13/12/2018

Soleo - 567046 - 12/13/2018

Product:
Drugs

Recipient:
Recipient Name
Mr. Ji Hyun Min
Recipient Title
Chief Executive Officer
Soleo

24 Sandan-Ro

Pyeongtaek-Si, Gyeonggi-do
17746
South Korea

Issuing Office:
Center for Drug Evaluation and Research

United States


Via UPS Warning Letter 320-19-07
Return Receipt Requested

December 13, 2018


Mr. Ji Hyun Min 
Chief Executive Officer
Soleo
24 Sandan-Ro
Pyeongtaek-Si, Gyeonggi-do 17746
REPUBLIC OF KOREA

Dear Mr. Min:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Soleo at 24 Sandan-Ro, Pyeongtaek-Si, Gyeonggi-do, from August 6 to 9, 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, as formulated and labeled, “GEN+LE THERAPY Shampoo” is an unapproved new drug in violation of section 505(a) of the FD&C Act (21 U.S.C. 355(a)). Introduction of such a product into interstate commerce is prohibited under section 301(d) of the FD&C Act (21 U.S.C. 331(d)). 

We reviewed your August 23, 2018, response in detail. 

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

1.  Your firm failed to conduct at least one test to verify the identity of each component of a drug product. 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 (2)).

You lacked testing of incoming raw materials, including active pharmaceutical ingredients and components, used in manufacturing of your Gentle Therapy Shampoo over-the-counter (OTC) drug product, for their identity, strength, and other appropriate quality attributes. Instead, your firm relied solely on your suppliers’ certificates of analysis (COA) without establishing the reliability of the suppliers’ analyses through appropriate validation.

In your response, you stated that you “will try to proceed by purchasing the experimental equipment also so that we [Soleo] can directly analyze the ingredients contained in the raw material”.

Your response is inadequate because you failed to provide a detailed procedure for conducting raw material testing, a target date for implementation, and a plan of action in the interim. 

In response to this letter, provide:

  • Chemical and microbiological quality control specifications you will use to approve the release of each incoming lot of components for use in manufacturing. 
  • A description of how you will conduct at least one specific identity test for each incoming component lot, regardless of a COA validation program
  • A description of how you will test each component lot for conformity with all appropriate specifications for strength, quality, and purity. If you intend to accept any testing results from your supplier’s COA in lieu of your testing of each component lot for purity, strength, and quality, specify how you plan to establish the reliability and consistency of your supplier’s test results for these attributes through initial validation (followed by periodic re-validation). Include your standard operating procedure that describes this COA validation program. 
  • A summary of test results obtained from full testing of reserves samples of active pharmaceutical ingredient lots used in the manufacture of your drug product that were distributed to the U.S. market and within expiry. 
  • A comprehensive independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified and are assigned appropriate expiration or retest dates. Also determine whether your controls for incoming material lots are adequate to prevent the use of unsuitable containers, closures, and components.

2.  Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

Your firm did not validate analytical test methods used to determine assay for the active ingredients in your drug product before release for distribution. Your notebook and high-performance liquid chromatography (HPLC) report included different instrumentation parameters for the same active ingredient analysis. For example, in the HPLC report the flow rate and injection amount for biotin was 0.8 mL/minute and 5 µL, while in the notebook these parameters were recorded as 1 mL/minute and 10 µL.

In your response, you stated, “In the main component analysis, other components besides the main component will be subjected to quantitative analysis and qualitative analysis through an external analysis institution”.

Your response is inadequate because you did not provide sufficient information regarding the validation of your test methods, including a timeframe to complete method validation and which analyses your third-party will be conducting. You also did not provide an interim plan of action.
See United States Pharmacopeia (USP) General Chapter <1225>, Validation Of Compendial Procedures and USP General Chapter <1226>, Verification Of Compendial Procedures for typical performance characters that should be considered for validation and verification of analytical test methods.

In response to this letter, provide:

  • An independent assessment of all test methods used by your firm to ensure they have appropriate instructions, method suitability criteria, and validation (or verification, for USP compendial methods) to determine whether they are fit for purpose. 
  • Your plan of action to complete validation (or verification, for USP compendial methods) for all analytical test methods used in association with drug products shipped to the United States. 
  • A comprehensive independent review of your entire laboratory system and a corrective action and preventive action plan that ensures full remediation of the laboratory operation. For example, the review of your laboratory system should include, but not be limited to, the suitability of all laboratory equipment, a fully remediated calibration program, staff competencies, supervisory oversight, data systems, and other elements of laboratory control.
  • A summary of your procedures for qualifying and overseeing the adequacy of contract facilities that test the drug products you manufacture.
  • A summary of test results obtained from testing retain samples of all batches of your drug product within expiry. You should test all appropriate quality attributes including, but not limited to, identity, strength, and purity of finished drug products. If your testing for any previously released batch yields out-of-specification results, indicate the corrective actions you will take, including notifying customers and initiating recalls.

3.  Your firm failed to establish 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)). 

You failed to conduct process performance qualification for your OTC drug product, which contains four active ingredients. You did not demonstrate that your manufacturing process is reproducible and controlled to consistently yield drugs of uniform character and quality. You also did not conduct equipment qualification.

In your response, you stated that you will prepare and record weighing and manufacturing instructions and will have quality oversight during the manufacturing process.

Your response is inadequate because you failed to provide a detailed process performance qualification protocol and an overall program for assuring ongoing maintenance of a validated process.

In response to this letter, provide:

  • Your process performance and equipment qualification protocols.
  • Reports with timelines for completion for all drug products distributed to the U.S. market.
  • A detailed summary of your approach for routinely monitoring intra- and inter-batch variation to ensure an ongoing state of control.

See FDA’s guidance document Process Validation: General Principles and Practices for approaches that FDA considers appropriate elements of process validation at http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.

4.  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)).

You do not have stability data to support your firm’s 36-month expiration date for your OTC drug product. You failed to demonstrate that the chemical properties of the active ingredients in your drug product remain acceptable throughout the labeled 36-month expiry period. Therefore, there is no assurance that your drug product can maintain its stability through its expiration period.

In your response, you stated that in the future, you will create and execute data to determine the appropriate expiration date at the stage of new development. You also stated that you will add analysis items to existing stability tests to determine if “functional ingredients are retained in the future.” 

Your response is inadequate because you did not include a stability protocol or test results to demonstrate that your drug product met its specifications throughout the labeled expiration period.

In response to this letter provide your plan, with timelines, to develop and implement a complete drug stability program. This plan should include an assessment of the stability by testing retain samples of your drug product currently on the U.S. market within expiry. Indicate the corrective actions that you will take, including notifying customers, if your testing of any previously released batches yields an out-of-specification result.

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 evaluate your operations and 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 effectiveness of any corrective action and preventative action plan you have implemented. 

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all violations and ensuring ongoing CGMP compliance.

Unapproved New Drugs
“GEN+LE THERAPY Shampoo”

Examples of claims observed on your product label, and on your labeling which includes your product website, https://marumus.com/gentle-therapy-shampoo.html, for “GEN+LE THERAPY Shampoo” that establish the intended uses of the product as defined in 21 CFR 201.128 include, but may not be limited to, the following:

  • Label Claims:

“Prevents Hair Loss ... Hair Loss Prevention ... Anti-Dandruff” 

  • Website Claims:

“Is your dandruff out of control? The solution is GEN+LE THERAPY SHAMPOO & TREATEMENT ... Anti-Dandruff ... A inveterate Dandruff goes away in a short time ... Hair Loss Prevention ... Biotin helps your hair grow ...”

Based on the above claims, “GEN+LE THERAPY Shampoo” 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 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 as a hair growth, hair loss prevention, and anti-dandruff drug product. 

Under 21 CFR 310.527, OTC drug products intended as an external hair grower, such as “GEN+LE THERAPY Shampoo”, that are labeled, represented, or promoted for external use as a hair grower or for hair loss prevention are regarded as new drugs within the meaning of section 201(p) of the FD&C Act and require an FDA-approved application prior to being marketed. 

In addition, drug products intended for the treatment of dandruff, such as “GEN+LE THERAPY Shampoo” are subject to the Final Rule for Drug Products for the Control of Dandruff, Seborrheic Dermatitis, and Psoriasis (21 CFR 358, Subpart H). However, the formulation for “GEN+LE THERAPY Shampoo” is not consistent with the formulation requirements that describe acceptable active ingredients for drug products for the treatment of dandruff. Specifically, biotin, niacinamide, and dexpanthenol do not comply with the acceptable active ingredients in 21 CFR 358.710. 

Thus, as formulated and labeled, “GEN+LE THERAPY Shampoo” does not comply with the final rules described above. Furthermore, we are not aware of sufficient evidence to show that “GEN+LE THERAPY Shampoo”, as formulated and labeled, is generally recognized as safe and effective. Therefore, this product is a new drug within the meaning of section 201(p) of the FD&C Act (21 U.S.C. 321(p)). As a new drug, “GEN+LE THERAPY Shampoo” may not be legally marketed in the United States absent approval of an application filed in accordance with section 505(a) of the FD&C Act (21 U.S.C. 355(a)). “GEN+LE THERAPY Shampoo” is not the subject of an FDA-approved application and therefore, the current marketing of this product violates section 505(a) of the FD&C Act (21 U.S.C. 355(a)). Introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act (21 U.S.C. 331(d)). 

Conclusion

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.

FDA placed your firm on Import Alert 66-40 on November 26, 2018.

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer. 

Failure to correct these violations may also result in FDA continuing to refuse admission of articles manufactured at Soleo at 24 Sandan-Ro, Pyeongtaek-Si, Gyeonggi-do, into the United States under section 801(a)(3) of the FD&C Act (21 U.S.C. 381(a)(3)). Under the same authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).

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. 

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

Christina Alemu-Cruickshank
Compliance Officer 
U.S. Food and Drug Administration
White Oak Building 51, Room 4212
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA

Please identify your response with FEI No. 3009699696.

Sincerely,

/S/

Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research