- Delivery Method:
- VIA UPS
Recipient NameMr. Matt Dailey
Recipient TitleCEO & President
- Chemical Services Group, Inc./Royal Chemical Company
8679 South Freeway Drive
Macedonia, OH 44056-1535
- Issuing Office:
- Division of Pharmaceutical Quality Operations I
CMS # 648378
April 5, 2023
Dear Mr. Dailey:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Royal Chemical Company, FEI 2517008, at 1336 Crowe Road, East Stroudsburg, Pennsylvania 18301, from October 31 to November 8, 2022.
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 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 reviewed your November 22, 2022 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
Your firm manufactured over-the-counter (OTC) hand sanitizer drug products1 on equipment also used to manufacture industrial chemicals, including those for cleaning, polymer production, and paint additives. It is unacceptable as a matter of CGMP to manufacture drugs using the same equipment that you use to manufacture these non-pharmaceutical products due to the risk of cross-contamination. Additionally, your drug component and bulk drug product transfer pipes were found open to the outside environment. Your firm lacked procedures to clean the transfer pipes and external storage tanks.
In response to this letter, provide:
- Confirmation whether you will discontinue manufacturing drugs on shared equipment in your facility. If you intend to continue to manufacture both pharmaceutical and non-pharmaceutical products at your facility, provide a plan to show how you will separate the areas in which you will maintain dedicated manufacturing equipment for your pharmaceutical manufacturing and industrial product manufacturing operations.
- A risk assessment for all drugs you have previously produced on equipment shared with industrial products. For each product, assess the risk of potential contamination due to the shared equipment, and provide your plans for addressing the product quality and patient safety risks for any product still in distribution, including potential recalls or market withdrawals.
- For drug product dedicated equipment, a comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment, facility piping, or storage tankers that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product.
- Your corrective action and preventive action (CAPA) plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
- A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
- A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
2. Your firm failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(2)).
Your firm relied on certificates of analysis (COA) from unqualified suppliers for your ethanol for specifications such as purity, strength, and quality. By not adequately analyzing your components for identity, purity, strength, and quality, you failed to ensure your incoming components meet appropriate specifications.
Additionally, during the inspection, you only identified (b)(4) ethanol suppliers and manufacturers in use. However, in response to FDA’s August 31, 2022 request for records and other information pursuant to section 704(a)(4) of the FD&C Act, you identified (b)(4) additional suppliers of ethanol.
Furthermore, separate ethanol lots appear to have been co-mingled in a storage tanker for use in hand sanitizer manufacture. The supplier and ethanol lot number are not recorded in your manufacturing records which only list the ethanol source as “bulk.” The lack of supplier testing verification, co-mingling of component lots, and inadequate batch traceability poses a significant risk to consumers and hinders your ability to adequately respond to any ethanol related investigations and product recalls.
In response to this letter, provide:
- Confirmation that ethanol you use as a drug substance meets, at a minimum, the standards delineated in the USP monograph for ethanol.
- 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.
- Procedures for controlling incoming raw materials including, but not limited to, ensuring that they are not co-mingled. In addition, provide an analysis of storage tanks that held ethanol and bulk hand sanitizer, and whether material from those tanks could have been contaminated via co-mingling or inadequate cleaning.
- A list of all ethanol grades, lots, and manufacturers used from January 2022 to the present.
- An action plan for any hand sanitizer drug product released to the market manufactured with ethanol that does not comply with USP standards. This plan should include a list of batches, volume distributed, manufacture and expiry dates, and test results.
- Controls for maintaining traceability of ethanol lots used in drug product manufacture, including procedures and an updated Master Batch Record.
3. Your firm failed to establish acceptance criteria for the sampling and testing conducted by the quality control unit that are adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release (21 CFR 211.165(d)).
Your firm sampled in process material for the purpose of batch release testing which likewise did not include all appropriate tests to ensure that the finished drug products you manufacture conform to all pre-determined quality attributes appropriate for their intended use. Specifically, batches were (b)(4) removal from the bulk hand sanitizer and your batch release testing did not include known impurities, such as for methanol and benzene.
In response to this letter, provide:
- A list of chemical and microbiological 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, take rapid corrective actions, such as notifying customers and product recalls.
- A comprehensive, independent 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.
4. 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).
Your quality unit (QU) failed to provide adequate oversight of the manufacture of your OTC drug products. For example, your QU failed to ensure the following:
- Written procedures for equipment and facility cleaning, monitoring, and cleaning of your water system, vendor qualification, packaging and labeling operations, process validation, and the release of drug products (21 CFR 211.22(d)).
- Adequate investigation into high colony counts in your (b)(4) system used to generate component (b)(4) water for your drug products. (21 CFR 211.192).
- Validation of manufacturing processes before release of material to the market (21 CFR 100(a)).
The CGMP regulations assign responsibilities to the QU which include approving or rejecting incoming materials, in-process materials, and drug products; ensuring that controls are implemented and completed satisfactorily during manufacturing operations; and reviewing production records and investigating any unexplained discrepancies. You have not demonstrated that you have a QU capable of these responsibilities.
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.
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.
- An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes, and will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
- A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
- A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, you should engage 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 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 any violations and for preventing their recurrence or the occurrence of other violations.
Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.
Failure to address violations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days.2 Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. 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 firstname.lastname@example.org. Your written notification should refer to the Warning Letter, CMS # 648378 and reference: FEI 2517008.
If you have any questions, contact Compliance Officer CAPT Liatte Closs at email@example.com.
Program Division Director
U.S. Food and Drug Administration
OPQO Division I
Mr. Bryan Benner, Director of Quality
Royal Chemical Company
1336 Crowe Rd
E Stroudsburg, PA 18301
Mr. Dave DeBord, COO
Royal Chemical Company
1336 Crowe Rd
E Stroudsburg, PA 18301
1 Due to an increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, the FDA published the Guidance for Industry: Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19) on March 19, 2020, and subsequently updated the guidance several times. The guidance was withdrawn effective December 31, 2021 (86 Fed Reg at 56960). This guidance communicated the agency’s temporary policy that we did not intend to take action against firms for CGMP violations under section 501(a)(2)(B) of the FD&C Act if such firms prepared alcohol-based hand sanitizers for consumer use (or for use as a health care personnel hand rub) during the public health emergency, provided certain circumstances described in the guidance were present. These circumstances included preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. Because Royal Chemical Company hand sanitizer drug products were not consistent with the formulations described in these guidances, they did not fall within any temporary agency policy not to take action against firms manufacturing hand sanitizer products for violations of section 501(a)(2)(B) of the FD&C Act.
2 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.