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Delivery Method:

Recipient Name
Mr. Krasen Kyurkchiev
Recipient Title
Chief Executive Officer

Madara Boulevard 48
9700 Shumen

Issuing Office:
Center for Drug Evaluation and Research | CDER

10903 New Hampshire Avenue
Silver Spring, MD 20993
United States

February 28, 2020

Warning Letter 320-20-27

Dear Mr. Kyurkchiev:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, FICOSOTA LTD., FEI 3014115921, at Madara Boulevard 48, Shumen, Shumen, from September 2 to 5, 2019.

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 product is 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 reviewed in detail your September 25, 2019, response to om Form FDA 483.

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

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 failed to perform critical quality control tests of finished drug products prior to shipment to the U.S. market. For example, our inspection found you lacked identity and strength testing for each batch of your over-the-counter (OTC) finished drug product "(b)(4)" for its labeled active pharmaceutical ingredient (API) (b)(4).

Testing of each batch for identity and strength, and all other appropriate quality attributes prior to release, is the final in a series of essential CGMP controls that ensure a drug product meets appropriate specifications.

In response to this letter, provide:

• A comprehensive 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.

• A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch 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 United States 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, t~e rapid corrective actions, such as notifying customers and product recalls.

2. 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) & (2)).

Your firm failed to adequately test your incoming raw materials, including API and other components, for identity, purity, strength, and quality. You relied on your supplier's certificate of analysis (COA) in lieu of testing each component lot for purity, strength, and quality. However, you did not establish a supplier qualification program to assess (i.e., initially and periodically) the reliability of your suppliers' test results for these attributes.

In response to this letter, provide:

• A comprehensive 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 lot controls are adequate to prevent the use of unsuitable containers, closures, and components.

• The chemical and microbiological quality control specifications you use to test each incoming lot of component to determine suitability for 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 (b)(4) 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.

3. 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).

During the inspection, our investigator observed that your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC drug product. For example, your QU failed to ensure that:

• QU responsibilities to approve and reject API and drug products were defined.

• All testing was performed and reviewed by the QU prior to batch release.

• An ongoing program for monitoring process control was established to ensure stable manufacturing operations and consistent drug quality.

• Master production records and batch production records with detailed manufacturing steps and parameters were adequate and approved.

• An annual ptoduct review program was established.

• Adequate procedures for out-of-specification (00S) were established, and any unexplained discrepancies or failures of a batch or any of its components to meet any of its specifications, were thoroughly investigated.

In addition, your QU was not independent from production. For example, your written procedure allows your production manager to make final batch release decisions.

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

• A validation plan for ensuring a state of control throughout the product lifecycle, including a timeline for performing appropriate process performance qualification, description of your program for monitoring lot-to-lot variation to ensure an ongoing state of control, and process performance and equipment qualification protocols.

• A comprehensive review and remediation plan for your OOS result investigation systems. Provide a corrective action and preventive action (CAPA) plan to improve OOS handling. Your CAPA plan should include but not be limited to the following:
  o Quality unit oversight of laboratory investigations 
  o Identification of adverse laboratory control trends
  o Resolution of causes or laboratory variations
  o Initiation of thorough investigations of potential manufacturing causes when a laboratory cause cannot be conclusively identified
  o Adequately scoping of each investigation and its CAPA
  o OOS investigation procedures with these and other remediations

• A risk assessment for any drug products in the U.S. market within expiration date for which an OOS result was obtained. Take appropriate actions, including customer notifications or recalls, if drug quality may be compromised.

4. Your firm failed to establish 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 stability program is inadequate because your procedure does not require a long-term stability study for your OTC drug product "(b)(4)." Although you informed our investigator that your product has a three-year expiration date, your stability program lacked chemical and microbial testing of your stability samples. During the inspection, you provided minimal data to support long-term stability of your OTC product.

In response to this letter, provide:

• A comprehensive assessment and CAPA plan.to ensure the adequacy of your stability program. Your CAPA plan should include, but not be limited to:
  o Stability indicating method
  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.

• Provide stability data to support that your product will meet the quality attributes for a period of (b)(4) after containers are opened, as claimed on your product label.

• A retrospective risk assessment of the stability of all batches of your drug product on the U.S. market within expiry. 

• A retrospective, independent review of the impact of all OOS results for all products currently in the U.S. market and within expiry as of the date of this letter.

Inadequate Response

In your response, you stated that you did not intend to respond to each Form FDA 483 observation since you had ceased production for the U.S. market.

Your response is inadequate because it did not provide any detail or evidence of corrective actions to bring your operations into compliance with CGMP. Specifically, your response did not address the effect these violations may have on your OTC drug product within expiry and currently in the U.S. market.

Remediating these CGMP violations will be necessary if you plan to resume drug manufacturing operations for the U.S. market. We acknowledge your commitment to notify this office if you propose to resume U.S. supply. We also acknowledge your commitment to be in "full compliance with all the applicable laws and regulations before proceeding."

Quality Systems Guidance

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.

Process Controls Guidance

Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA's guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

CGMP Consultant Recommended

If you resume drug manufacturing operations for the U.S. market, 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 that the consultant evaluates the completion and efficacy of your corrective 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 that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

FDA placed your firm on Import Alert 66-40 on January 10, 2020.

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

Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at FICOSOTA LTD., Madara Boulevard 48, Shumen, Shumen, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to COMP 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-OMO-Communications@fda.hhs.gov or mail your reply to:

Qin Xu
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51 , Room 4235
10903 New Hampshire A venue
Silver Spring, MD 20993

Please identify your response with FEI 301411 5921.


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

CC: Ms. Miglena I. Bankova
Head of R&D and QC Department
Madara Boulevard 48

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