- Delivery Method:
- VIA UPS
- Reference #:
Recipient NameMr. Suresh Chilakalpudi
- Essnd Global
Office 14B, Plot No. 89A/B Industrial Estate
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
10903 New Hampshire Avenue
Silver Spring, MD 20993
February 14, 2020
Warning Letter 320-20-25
Dear Mr. Chilakalpudi:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Essnd Global, FEI 3014466792, at C-176 Maharashtra Industrial Development Corp. (MDIC), Sinnare, Nashik, Maharashtra, India, from September 9 to September 13, 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 have not received a response from your firm regarding corrective actions to the observations identified during the inspection.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to perform, 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, and for each batch of drug product required to be free of objectionable microorganisms, appropriate laboratory testing, as necessary (21 CFR 211.165(a) and (b)).
Your firm contract manufactures an over-the-counter (b)(4) drug product. You released your drug product without adequate testing, including identity and strength testing of the active ingredient. In addition, you released your drug product without appropriate testing for total aerobic microbial count and objectionable microorganisms. Testing is essential to ensure that the drug product you manufacture meets established specifications for the chemical and microbial attributes they purport to possess.
In response to this letter, provide the following:
• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.
• 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.
• 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.
• The method to be used for assay testing of your active ingredients.
• Your timeline for implementation of finished product assay testing of your active ingredients.
2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. 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)).
Inadequate Component Testing
Your firm failed to adequately test incoming components, including the active ingredient (b)(4), for their identity, purity, strength, and other appropriate quality attributes. Furthermore, you informed our investigator that your clients can send the raw materials, the labeling, and packaging materials without the Certificates of Analysis (COA) to your facility. Identity testing is required for each component lot used in drug product manufacturing, and you can only rely on a COA for other component attributes by validating the supplier's test results at appropriate intervals.
In response to this letter, provide the following:
• 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 SOP that describes this COA validation program.
• 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.
Inadequate (b)(4) System Monitoring
Your firm failed to routinely monitor your (b)(4) system for all required quality attributes. (b)(4) from this system is used as a component in your drug product. Your firm lacked microbiological testing of your (b)(4). Without routine (b)(4) monitoring, you cannot ensure that your (b)(4) meets minimum microbiological standards suitable for the manufacture of your drug product.
In response to this letter, provide following:
• A procedure for your (b)(4) system monitoring that specifies routine microbial testing of (b)(4) to ensure its acceptability for use in each batch of drug products produced by your firm.
• The current action/alert limits for total counts and objectionable organisms used for your (b)(4) system. Ensure that the total count limits for your (b)(4) are appropriately stringent in view of the intended use of each of the antiseptic drug product produced by your firm.
• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets (b)(4), USP monograph specifications and appropriate microbial limits.
• A summary of your program for qualifying and overseeing contract facilities that test your raw materials, (b)(4), or the drug products you manufacture.
3. Failure to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed. (21 CFR 211.22(a) and (d)).
Your firm lacks an adequate quality unit (QU). You informed our investigator that you had not fully established your QU. In addition, you lacked adequate written procedures for numerous quality functions. For example, you could not provide procedures for stability studies, out-of-specification investigations, product release, and deviation investigations. An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality.
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/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.
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:
• 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.
• A 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 identity, strength, quality, and purity of all products.
Responsibilities as a Contractor
Drugs must be manufactured in conformance with COMP. 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 and your customer, (b)(4), have an agreement regarding your manufacture of drug products destined for the United States. 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/media/86193/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 if your firm intends to resume manufacturing drugs for the U.S. market. 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 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 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 31, 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 Essnd Global, C- 176 Maharashtra Industrial Development Corp. (MDlC), Sinnare, Nashik, Maharashtra, India, 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 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-OMO-Communications@fda.hhs.gov or mail your reply to:
Daniel W. Brisker
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 3014466792.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research