Inspections, Compliance, Enforcement, and Criminal Investigations

Pure Source LLC 2/20/19

 

  

Black HHS-Blue FDA Logo

 

 

 
Office of Pharmaceutical Quality Operations, Division 2
4040 N. Central Expressway, Suite 300
Dallas, Texas 75204 

 

February 20, 2019
 
Case # 555240
 
Warning Letter
 
VIA UPS Overnight
           
Joel J. Meyerson, Owner
Pure Source LLC
9750 NW 17th Street
Doral, Florida 33172-2753
 
Mr. Meyerson:
 
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Pure Source LLC (FEI 3002754162) at 9750 NW 17th St., Doral, Florida from February 8 to March 1, 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).
 
This inspection also revealed that your firm manufactures and distributes misbranded drugs labeled as homeopathic under section 503(b)(4) of the FD&C Act, 21 U.S.C. 353(b)(4). We reviewed your March 19, 2018, response in detail.
 
During our inspection, our investigators 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).
 
Your quality unit did not initiate an out-of-specification (OOS) investigation for a raw material with excessive microbial growth. In addition, you did not conduct a thorough investigation for drug products with failing assay results.
 
Microbiological results
 
For example, you used a (b)(4) raw material lot with a too-numerous-to-count result for total aerobic microbial count. Your specification is less than (b)(4) colony forming units per gram. You use (b)(4) as a raw material in your Continuously (b)(4) acne treatment, an over-the-counter (OTC) drug product that you contract manufacture for a customer.
 
You failed to thoroughly investigate the excessive microbial contamination of (b)(4). You distributed finished product made with the highly contaminated raw material.
 
You released the failed lot of (b)(4) raw material, which was used in the manufacture of the finished drug product ((b)(4) acne treatment batch (b)(4)) and failed to provide adequate corrective actions and preventive actions (CAPA). You did not identify the microorganisms to determine whether any were potentially pathogenic and failed to evaluate the consumer hazard posed by this microbial contamination. Further, you decided that this ingredient batch did not need to conform to a microbial specification because it is from a natural mineral source. Your firm’s quality unit approved this deviation report (180106), despite the minimal investigation and unacceptable justification.
 
Notably, you also told our investigator that you informed the product owner about the failing result and the owner insisted on using the failing (b)(4) ingredient. Insistence from a customer does not relieve you from your obligation to follow CGMP regulations.
 
See FDA’s guidance document, Contract Manufacturing Arrangements for Drugs: Quality Agreements, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf
 
OOS assay results
 
In addition, your quality unit released the following OOS drug products for distribution without conducting a thorough investigation.
  • Avobenzone sunscreen drug product Lot C06Z9, which had a failing assay result of 0.85% (specification: (b)(4)%).
  • Bulk in-process material (b)(4) Pain Relief Gel Lot (b)(4) had a failing assay result of 2.47% w/w (specification: (b)(4)).
In your response, you stated that you are revising your Investigation of OOS Test Results procedure to define the responsibility of the quality control and quality assurance unit during investigations. You also have opened a retrospective investigation for (b)(4) and are working to identify the microbial colonies.
 
We were unable to evaluate the adequacy of your responses because it lacked sufficient relevant information for FDA to evaluate the root cause of the microbial contamination of (b)(4), or whether you conducted a thorough investigation. When an investigation lacks conclusive evidence of laboratory error, a thorough investigation would turn to potential manufacturing causes. We were not able to evaluate your interim OOS procedure or timelines for completion of your retroactive laboratory investigation because you did not provide them.
 
In response to this letter, provide:[1]
  • a retrospective, independent review of all invalidated OOS (raw material, in-process and finished testing) results obtained for products currently within expiry. Assess whether the scientific justification and evidence for each invalidated OOS result was conclusive. For investigations that conclusively establish laboratory root cause, determine effectiveness of the corrective action, and ensure that other laboratory methods vulnerable to the same root cause are identified for remediation. For any OOS results with inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, raw materials, process capability, deviation history, batch failure history). Provide a corrective action plan that identifies manufacturing root causes and specifies meaningful improvements;
  • detailed final investigations, with root causes analysis of the source(s) of contamination for all chemical and microbiological tests that yielded an OOS result since January 2015;
  • a retrospective review of all lots within expiry to determine whether your firm released other lots not conforming to established raw material and finished product specifications;
  • a comprehensive, independent assessment of your overall system for investigations of deviations, atypical events, complaints, out-of-specification results, and failures. In addition, you should also include a plan addressing, at a minimum, improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also, include your process for evaluating CAPA effectiveness; and,
  • your plans for addressing product quality and patient safety risk for all drug products manufactured with OOS raw materials currently in distribution, including potential recalls or market withdrawals.
 
For more information about handling failing, out-of-specification, 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.
 
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 failed to adequately validate the test methods you use with your (b)(4) microanalyzer to analyze the microbiological properties of your deionized water, raw materials, and finished drug products. You attempted to validate your test methods, but you failed to evaluate:
  • whether your media can promote microbial growth;
  • your ability to detect specific microorganisms;
  • your system’s limits and accuracy;
  • your method’s suitability to detect microorganisms in a sample; and,
  • your method’s reproducibility.
In your response, you stated that you are scheduling a revalidation of your (b)(4) test methods used to conduct microbiological testing, and that you are developing procedures to evaluate growth promotion. You also stated that you have opened a CAPA plan to address your test method deficiencies and are communicating with a microbiology consulting firm to review your revised procedures.
 
We were unable to evaluate the adequacy of your response because it is not clear whether you continue to use the (b)(4) microanalyzer without assuring that it is suitable for its intended use. You also did not commit to use interim methods (e.g., USP methods) to test your drug products while you are conducting method validation studies for your alternate methods. In addition, you did not provide details of your CAPA plan for our evaluation. Your response did not address the potential risks to the quality of your drug products due to inadequate method validation. In addition, you did not provide timelines for completion of your CAPA or the professional qualifications of the consultants you intend to hire.
 
In response to this letter, provide:
  • a comprehensive evaluation of the test methods you use with your (b)(4) microanalyzer to determine method suitability and adequacy. You should correct any deficiencies identified in these methods before you initiate revalidation;
  • a study that determines whether your microbiological test methods are equivalent to the USP method. Include all findings and deviations encountered in assessing whether your revised method is equivalent or superior to the USP compendial method;
  • your protocols and timelines for your revalidation. Also, include your final method validation report;
  • your finished product microbiological specifications and their justification;
  • your commitment to test all drug products you manufacture using a valid test method (e.g., USP method) until your system has been qualified. These USP methods should include USP <61> Microbiological Enumeration of Nonsterile Products: Enumeration tests, and USP <62> Microbiological Enumeration of Nonsterile Products: Tests for Specified Organisms; and,
  • a commitment to use a valid test method (e.g., USP method) to test all retain samples for all drugs released to the U.S. market within expiry.
3.  Your firm failed to establish adequate 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, and to follow all of its written production and process control procedures (21 CFR 211.100 (a) and (b)).
 
Our inspection indicated that your water quality is not suitable for its intended use. Your firm also lacked water system validation and did not demonstrate that it can consistently produce water that is suitable for pharmaceutical use.
 
Pharmaceutical Grade Water
 
You routinely use “deionized water” for drug manufacturing and equipment cleaning. The use of deionized water for pharmaceutical manufacturing does not assure that the drugs produced will have the quality and purity they purport or are represented to possess. You lack sufficient chemical testing for this water system, including total organic carbon. You also infrequently performed microbial monitoring of this system. In addition, your acceptance limits for chemical and microbial quality were inadequate.
 
Water System Design, Control, Maintenance, and Validation
 
Our findings indicate that your water system is not designed to consistently produce high purity water for use in drug products, in part because the procedures for the water system do not adequately address the control and maintenance of the water system. Your firm also failed to perform water system validation studies. You only had a brief vendor operational qualification report regarding an obsolete version of your water system.
 
Water is a major ingredient in many of your drug products, which include aqueous-based dosage forms. It is essential that you employ a water system that is robustly designed, and that you effectively control, maintain, and monitor the system to ensure it consistently produces water suitable for pharmaceutical use. (See also, e.g., 21 CFR 211.113 and 211.160(b)).
 
In your response, you stated that you will requalify your deionized water system and revise your monitoring and testing program to cover total organic carbon and coliform bacteria. You also stated that you are trending pH and resistivity in order to set limits for your water system.  We were unable to evaluate the adequacy of your response because you did not address how you will assure that the water you use in drug manufacturing will meet appropriate microbial standards. You did not submit details of your protocols or timelines of your water system validation for our evaluation. We also note that you 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.
 
In response to this letter provide:
  • a comprehensive evaluation of the water system design, including a thorough CAPA plan to install 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 100 CFU/ml would be appropriate for products produced by your firm;
  • a commitment to increase the frequency of your microbial testing to an appropriate timeframe (e.g., at least daily); and,
  • a detailed risk assessment addressing potential effects of water system deficiencies on the quality of all aqueous-based drug product lots currently on the market within expiry.
Manufacturing Process Validation
 
You validated your manufacturing process for (b)(4) Acne Wash OTC drug product for batches up to (b)(4). However, in 2016 you released nine batches each weighing (b)(4), which exceeded the size for your validated process. Furthermore, you did not follow your process validation procedure, which requires you to validate major changes in your process.
 
In your response, you stated that in March 2017 you completed a retrospective validation for batch sizes of (b)(4). You also stated that you are working with your product owners to develop standardized order sizes.  However, because you failed to provide your process performance qualification protocol, details of your overall program for assuring maintenance of the validated process, and a timeline for completion, we could not evaluate the adequacy of your response.
 
Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed to assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies determine whether an initial state of control has been established. Successful process qualification studies are necessary prior to commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure that you maintain a stable manufacturing operation throughout the product lifecycle.
 
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/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf
 
Misbranded Homeopathic Drugs
 
FDA reviewed the product labels of (b)(4), and (b)(4) obtained during the FDA inspection of your facility. Your firm’s products, (b)(4), and (b)(4), are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and/or because they are intended to affect the structure or any function of the body. Examples of claims that establish the intended uses for (b)(4), and (b)(4) include, but may not be limited to, the following:
 
(b)(4)
 
Because of their toxicity or other potential for harmful effect, or the method of their use, or the collateral measures necessary to their use, (b)(4), and (b)(4) are not safe for use except under the supervision of a practitioner licensed by law to administer such drugs. Therefore, these products are subject to section 503(b)(1) of the FD&C Act, 21 U.S.C. 353(b)(1), and 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.”[2] It is prohibited to introduce or deliver for introduction into interstate commerce a misbranded drug under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
 
In addition, (b)(4), and (b)(4), are not currently listed with FDA. Under section 510 of the FD&C Act, as amended, and Part 207 of FDA's regulations, all drugs manufactured, prepared, propagated, compounded, or processed for commercial distribution, as defined by 21 CFR 207.1, must be listed by the registrant. See section 510(j)(1) of the FD&C Act, 21 U.S.C. 360(j)(1); see also 21 CFR 207.41.Failure to properly list a drug product as required by section 510(j) of the Act misbrands the product (see section 502(o) of the FD&C Act, 21 U.S.C. 352(o)) and is a prohibited act under section 301(p) of the FD&C Act, 21 U.S.C. 331(p). Introduction or delivery for introduction into interstate commerce of a misbranded drug is also a prohibited act under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
 
We recognize that (b)(4), and (b)(4) are represented as being homeopathic drugs with active ingredients measured in homeopathic strengths. Under section 201(g)(1) of the FD&C Act, 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 our Compliance Policy Guide, 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.
 
Responsibilities As A Contractor
 
Your firm acts as a contract manufacturer for drug products. Your failure to comply with CGMP may significantly affect the quality, safety, and efficacy of the drugs you manufacture for your clients. It is essential that you understand your responsibility to operate in full compliance with CGMP, and to immediately inform your customers (e.g., owners, sponsors) of production problems or quality issues that may pose a patient hazard. Your customer also remains responsible for oversight of contract manufacturers to ensure its products are being made in compliance with CGMP. 
 
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. We also recommend that the qualified third party perform a comprehensive audit of your entire operation for CGMP compliance, including the quality assurance system, materials system, facility and equipment system, laboratory system, production system, and packaging and labeling system. Your CAPA should then be evaluated by the third party to help ensure systemic remediation before you pursue resolution of your firm’s compliance status.
 
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 for 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.
 
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
 
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 believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
 
Your written notification should refer to the Warning Letter Number above (Case #555240). Please electronically submit your signed reply on your firm’s letterhead to CDR John W. Diehl, M.S., Director, Compliance Branch, at john.diehl@fda.hhs.gov and orapharm2_responses@fda.hhs.gov.
 
If you have questions regarding the contents of this letter, please contact Mr. Mark Rivero, Compliance Officer, at (504) 846-6103 or mark.rivero@fda.hhs.gov.
 
Sincerely,
/S/ 
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division II
 
 
 
CC:
 
Renee Alsobrook, Chief
Department of Business and Professional Regulation
Division of Drugs, Devices and Cosmetics
Compliance and Enforcement
2601 Blair Stone Road
Tallahassee, Florida 32399-1047
 


[1] These corrective actions are also required to address your firm’s failure to follow its own written production and process control procedures (21 CFR 211.100(b)) (see third violation below).
[2] FDA’s Compliance Policy Guide, Conditions Under Which Homeopathic Drugs May be Marketed (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 FDA 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.”

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