I. Shay Cosmetics Inc - 552754 - 10/29/2018

WARNING LETTER

VIA SIGNATURE CONFIRMED DELIVERY

October 29, 2018

Mr. Mehdi Ehsan
CEO and Owner
I. Shay Cosmetics Inc.
1024 East Del Amo Boulevard
Carson, California 90746

Dear Mr. Ehsan:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, I. Shay Cosmetics Inc. at 1024 East Del Amo Boulevard, Carson, California, from November 27 to December 7, 2017.

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).

We received your undated response on January 3, 2018, and reviewed it in detail.

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

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

You did not conduct adequate investigations into out-of-specification (OOS) test results.

a. You did not investigate an epinephrine HCl assay OOS result for the over-the-counter (OTC) drug product (b)(4), lot (b)(4). The OOS result was (b)(4)% (specification was (b)(4) ± (b)(4)%), which is substantially less active ingredient than what is claimed on the label. Your certificate of analysis (COA) indicates that the product met the acceptance criteria.

In your response, you stated the specification for epinephrine HCl will be “corrected to reflect [the] test result.” Your response was inadequate because you did not explain how you determined the specification was incorrect. We note that other documents used the original specification, including the product label claim, your COA, and the specification used by the contract testing laboratory performing the assay analysis.

b. On May 30, 2017, your customer, (b)(4), reported bloated bottles of 3% hydrogen peroxide from lots (b)(4), (b)(4) and (b)(4). In August 2017, you manufactured and released lot (b)(4) while your investigation into this critical quality defect was pending. We note that in August 2017 you also manufactured but subsequently rejected lot (b)(4) due to the bloated bottle complaints associated with other lots. Labels on 3% hydrogen peroxide bottles state, “If the bottle expands, don’t sweat it; it’s natural.” However, bloating of the bottles is a product quality defect and may be associated with degradation of hydrogen peroxide.

In your response, you committed to continuing the investigation into the bloated 3% hydrogen peroxide bottles. We also note that during the FDA inspection, you committed to stopping shipment of this product until you concluded the investigation.

c. Your firm did not assess the impact of OOS total dissolved solids testing results from the deionized water system that occurred from May through July 2016. The results were OOS on (b)(4) out of (b)(4) days.

Your firm has a history of manufacturing finished drug products with water that does not meet the minimum quality standards for topical and oral drug products. Water is a major ingredient in many of your drug products, which include aqueous-based dosage forms. It is essential that you employ a robustly designed water system and that you effectively control, maintain, and monitor the system to ensure it consistently produces water suitable for pharmaceutical use. You reportedly modified your water system since relocating to your current facility, although it was not validated at the time of our inspection.

In your response, you committed to evaluate the impact of these OOS results on finished products. However, you did not specify how you will perform this evaluation. We note you did not address in your response how you will ensure that the water you use in drug manufacturing will meet the requirements of the USP monograph for purified water and appropriate microbial standards. You did not submit protocols or timelines for your water system validation. You also did not assess how your failure to validate your water system affected the quality of products you released to the U.S. market that are within expiry.

Your response is inadequate because you did not propose any corrective actions and preventive actions (CAPA) to address your repeated failure to conduct thorough investigations into OOS test results and unexpected discrepancies.

For more information about handling failing, OOS, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.

In response to this letter, provide:

• A comprehensive, independent assessment of your overall system for investigations of deviations, atypical events, complaints, OOS results, and failures. Your CAPA should include, but not be limited to improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA effectiveness.

• A retrospective assessment of all drug product lots within expiry to determine whether they meet their purported quality standards. For each lot that does not meet its purported quality standards, provide your plan to take appropriate action(s) (e.g., notifying customers or product recalls). For instance, regarding water quality, you should assess how failures of tests such as total dissolved solids and the use of an unvalidated water system affected the quality of finished products within expiry.

• A comprehensive, independent evaluation of the water system design, including a thorough CAPA plan to remediate and validate a suitable water system.

• An effective program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets Purified Water, USP monograph specifications, and appropriate microbial limits. Regarding the latter, a total count limit significantly tighter than (b)(4) CFU/ml would be appropriate for products produced by your firm.

• Detailed procedures for validating, maintaining, controlling, and monitoring your water system.

• The executed protocol, all test results, and the final report supporting validation of your water system.

2. Your firm failed to establish a quality control unit and procedures applicable to the 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, including drug products manufactured, processed, packed or held under contract by another company. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit (21 CFR 211.22(a) and (d)).

Your inspectional history indicates that your quality unit is not able to fully exercise its authority and/or responsibilities. On instructions from the CEO, your quality unit made decisions to release products that did not meet one or more critical quality attributes. Although multiple products failed finished product specifications (e.g., assay, pH), the COAs reported failing results as passing, as instructed by you.

This practice is unacceptable. When a drug product lot fails its minimum quality specifications, your quality unit is responsible for ensuring the lot is rejected.

Your firm must provide the quality unit with appropriate authority, sufficient resources, and staff to carry out its responsibilities and consistently ensure drug quality.

Your quality control unit does not follow your written standard operating procedure, SOP QA 18 Quality Control Unit: Production of OTC Product. For example, your SOP states that (b)(4). However, the executed batch record of (b)(4) lot (b)(4) included batch sizes, as well as citric acid and epinephrine HCl quantities that were inconsistent with the master batch record.

Your response was inadequate. You did not provide an adequate CAPA plan. You stated that you are appropriately qualified to function as the firm’s quality control unit. You committed to (b)(4), although you did not explain the qualifications for the position or what authority that person will have to perform the duties assigned to the position. You also did not commit to ensuring the quality control unit follows established procedures.

In response to this letter, provide:

• Your plan to ensure personnel functioning in the quality control unit are qualified to perform its duties and will have the authority to execute them.

• Your plan to ensure all procedures, including those applicable to the quality control unit, comply with CGMP, are established, and are followed.

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 such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

Your stability testing program is inadequate because you assigned an expiration date of 2 years to a product even though (b)(4) lot (b)(4) failed to meet specification in multiple instances. During the accelerated testing performed by your firm to justify your expiration date, this product failed the appearance specification at the 1-, 2-, and 3-month test points and the assay specification at the (b)(4) test point for your initial batch. This batch was released for distribution by your quality unit on (b)(4), with a 2-year expiration date.

During the inspection, the CEO indicated failing testing results are not necessarily indicative of product stability.

In response to this letter, provide:

• A list of all OOS stability test results for products manufactured in the past five years. Include the product name, active pharmaceutical ingredients (API), quality attributes, specifications, results, stability study conditions (e.g., temperature and humidity), test points (e.g., 1-month, 2-month), dates of test points, date(s) of manufacture, and lot release dates.

• Your investigation into each stability failure for all products within expiry to ensure that all products will meet their quality attributes throughout their labeled shelf life.

• A full summary of stability data results for all batches tested, with each time interval, attributes tested, the testing methods used, and the written stability protocol that was followed. Include testing of all microbiological and chemical attributes, and any updated test data used to determine whether the integrity of your container-closure systems (and the sterility of products, as applicable) is maintained throughout their shelf life.

• A comprehensive assessment and CAPA to ensure the adequacy of your stability program. Your CAPA should include, but not be limited to a remediated SOP describing your stability program; stability-indicating methods; stability studies to support each drug product in its container-closure system before distribution is permitted; 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; and specific attributes to be tested at each station.

4. 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)).

Your firm does not perform a specific identity test for each drug component. For example, the identity test results for hydrogen peroxide 50% API lot (b)(4) were determined by comparing a Fourier-transform infrared spectroscopy (FTIR) scan with a second scan of the same API and lot.

You also did not test API to determine their conformance to purity, strength, and other appropriate specifications. Your firm released API for use in drug product manufacturing based on the COA from your supplier without establishing the reliability of the suppliers’ analysis through appropriate validation.

Furthermore, your procedure is inadequate because it allows you to qualify vendors without establishing the reliability of API assay data. Contrary to your procedure, you are not performing identity and purity testing to qualify vendors. According to your procedure, the strength of hydrogen peroxide API will be “extrapolated” from finished product testing. However, you do not perform assay testing for 3% hydrogen peroxide finished products.

In your response, you indicated the quality unit failed to detect the comparison of two identical samples for the identification of API and allowed “the negligence to occur.” You committed to retrain your staff and to hire new quality control unit personnel. However, you did not commit to investigating the root cause of the “negligence” or to implement appropriate CAPA. You also did not provide any CAPA to address deficiencies in your vendor qualification procedure.

In response to this letter:

• Investigate the root cause for personnel not following written procedures to test components, and implement CAPA to prevent recurrence. Explain how you will ensure CAPA effectiveness.

• Provide your revised procedures for ongoing receipt and disposition of all component lots, including but not limited to API, to ensure they possess their purported identity, purity, strength, and other appropriate specifications.

• Provide a comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified; whether they are assigned appropriate expiration or retest dates; and whether incoming material controls are adequate to prevent the use of unsuitable containers, closures, and components.

5. 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 batch record for 3% hydrogen peroxide does not include identity and strength testing for the active drug substance used in your finished drug products.

In response to this letter, provide:

• Your plan to ensure complete finished product testing.

• A list of all finished products for which the identity and strength of each active drug substance was not determined before release. Include an assessment of product quality and potential impact to patients for each lot of finished product within expiry and identified as untested for active drug substance identity and strength before release.

• Your plan to promptly test all distributed drug products within expiry that were not fully tested before their release.

• For each lot of finished drug product that was manufactured without active drug substance identity and strength testing before release, identify the actions you will take going forward to prevent adverse impact to patients, and the time frames in which these actions will be taken.

Responsibilities as a Contractor

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 drugs you produce as a contract facility, regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document, Contract Manufacturing Arrangements for Drugs: Quality Agreements, at https://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf.

Quality Systems Guidance

Your firm’s quality systems are inadequate. For guidance on establishing and following CGMP compliant quality systems, see FDA’s guidances: Q8(R2) Pharmaceutical Development, at https://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf; Q9 Quality Risk Management, at https://www.fda.gov/downloads/Drugs/Guidances/ucm073511.pdf; and Q10 Pharmaceutical Quality System, at https://www.fda.gov/downloads/drugs/guidances/ucm073517.pdf.

Repeat Violations and Observations at Facility

FDA cited similar CGMP violations and observations in previous communications:

• An untitled letter dated July 10, 2008

• Warning Letter 03-13, dated October 22, 2012

• Previous inspections dated September 13 to 23, 2010; February 1 to 21, 2012; and March 6 to 14, 2013

You proposed specific remediation for these violations and observations in your responses to our previous communications. These repeated failures demonstrate that your facility’s oversight and control over the manufacture of drugs is inadequate.

CGMP Consultant Recommended

Because you failed to correct repeat violations, 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 fully resolving all deficiencies and ensuring ongoing CGMP compliance.

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.

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.

We request that you contact Maria Kelly-Doggett by email (Maria.Kelly-Doggett@fda.hhs.gov) within five days of receipt of this letter to schedule a regulatory meeting.

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 Kelly.Sheppard@fda.hhs.gov or mail your reply to:

Kelly D. Sheppard
Acting Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612

Please identify your response with unique identifier 552754.

Sincerely,
/S/

Kelly D. Sheppard
Acting Director, Division of Pharmaceutical Quality Operations IV