- Delivery Method:
- VIA UPS
Recipient NameMr. Brian W. Davidson
- Colorful Products Corporation
2550 Azurite Circle
Newbury Park, CA 91320-1201
- Issuing Office:
- Division of Pharmaceutical Quality Operations IV
May 10, 2022
Dear Mr. Davidson:
The U.S. Food and Drug Administration inspected your drug manufacturing facility, Colorful Products Corporation, FEI 2083633, at 2550 Azurite Circle, from November 8 to November 17, 2021.
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 have not received a response from your firm for corrective actions to the observations identified during the inspection in our Form FDA 483.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. 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 CFR211.22).
Your firm manufactures over-the-counter (OTC) topical drug products such as (b)(4) and hand sanitizers1. Your Quality Unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. For example, your QU failed to ensure the following:
- Testing for the identity and strength of the active ingredients was performed and reviewed prior to release for each batch of drug product (21 CFR 211.165(a)).
- Thorough investigations for out-of-specifications (OOS) results, complaints, deviations, and other discrepant results per an adequate written and approved procedure (21 CFR 211.192).
- Appropriate documentation and assessment of production and process control changes (21 CFR 211.100(a)).
- Establishment of an adequate, ongoing stability program (21 CFR 211.166(a)).
- Performance of appropriate annual product reviews (21 CFR 211.180(e)).
- 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/media/71023/download.
In response to this letter, provide the following:
- 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 list of chemical and microbial test methods and specifications used to analyze each lot of your drug product before making a lot disposition decision, and the associated written procedures.
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.
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.
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 comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, 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, corrective action and preventive action (CAPA) effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
- A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedure(s) to ensure changes are justified, reviewed, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.
- A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
o Stability-indicating methods.
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).
o All procedures that describe these and other elements of your remediated stability program.
2. 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 (21 CFR 211.100(a)).
Your firm lacked appropriate process validation for your drug products. For example, you confirmed to our investigator that process validation was not performed for your (b)(4) or hand sanitizer drug products. In addition, you also did not provide documentation or written procedures for performing process validation. You also confirmed that equipment qualification has not been performed on your (b)(4) water (b)(4) or on the equipment (e.g., mixing tanks, filling lines, and packaging lines) used to manufacture your drug products.
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 appropriately and 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 before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure 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/media/71021/download.
In response to this letter, provide the following:
- 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 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 (including analytical methods used by you and contract testing labs), quality of input materials, and reliability of each manufacturing process step and control.
- A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
- A timeline for performing process performance qualification for each of your marketed drug products.
- Your process performance protocols, and written procedures for qualification of equipment and facilities.
- A detailed program for designing, validating, maintaining, controlling, and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.
- Your 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.
3. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements, and you failed to establish written procedures for cleaning and maintenance of equipment (21 CFR 211.67(a) & (b)).
You have not demonstrated that your cleaning practices are adequate to remove contaminants from the shared equipment used to manufacture your OTC drug products and non-drug products. For example, our investigator observed inadequate cleaning and maintenance of your drug manufacturing equipment, specifically:
Lack of Cleaning Validation
You confirmed to our investigator that cleaning validation has not been performed for the equipment (e.g., mixing tanks, hoses, filling lines, and packaging lines) used to manufacture your OTC drug products.
Lack of Equipment Cleaning
Your firm lacks cleaning and maintenance procedures for your equipment used to manufacture your drug products. While you document the cleaning of your filling lines, you confirmed to our investigator that you do not document the cleaning of other equipment used to manufacture your drug products. In addition, you stated to our investigator that documentation of the filling lines’ cleaning only began in August 2021. Further, our investigator noted missing information for the filling lines' cleaning logs including product description, lot numbers, and cleaning and sanitization start and end times.
Lack of (b)(4) Sanitization
Your firm lacks procedures on how to sanitize and maintain your (b)(4). Your firm stated that you began sampling your water system in September 2021. Our review of your water system testing results, collected by our investigator, found total plate count (TPC) results of (b)(4) cfu/mL ((b)(4) cfu/mL). You stated to our investigator that you resanitized the water system and resampled. Our review of the retest results only found the testing for total organic carbon (TOC). Your firm has not provided evidence that your (b)(4) is operating in a state of control. In addition, you could not provide a written investigation, including a description of your resanitization activities, a root cause for the elevated microbial results, or an appropriate CAPA.
Inadequate removal of active ingredients and residues from manufacturing equipment during cleaning can result in cross-contamination of your drug products. Furthermore, inadequate cleaning and sanitization of your (b)(4) water system can result in microbial contamination of your drug products.
In response to this letter, provide the following:
- 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 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.
- 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.
- Your plans regarding the manufacture of both pharmaceutical and nonpharmaceutical products at your facility. If you intend to continue to manufacture both pharmaceutical and non-pharmaceutical products at your facility, provide your plan to separate the areas in which you will maintain dedicated manufacturing equipment for your pharmaceutical manufacturing and industrial product manufacturing operations.
- 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.
- Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
o drugs with higher toxicities
o drugs with higher drug potencies
o drugs of lower solubility in their cleaning solvents
o drugs with characteristics that make them difficult to clean
o swabbing locations for areas that are most difficult to clean
o maximum hold times before cleaning
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
- 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.
- A comprehensive independent assessment of your water system design, control, and maintenance, and corresponding CAPAs.
- A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design or new system consistently produces water adhering to (b)(4) Water, USP monograph specifications and appropriate microbial limits (total counts, objectionable microbes).
- Regarding the latter, ensure that your total microbial count limit for water is appropriate in view of the intended use of the products produced by your firm.
4. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records. (21 CFR 211.68(b)).
Your firm lacked controls to assure the integrity of (b)(4) used in the manufacturing of your drug products. For example, your firm utilized software (i.e., (b)(4)) for the retention of data, including your drug product formulations and the quarantine and release status of drug products. This software is also used to document the completion of manufacturing steps on batch records, including (b)(4) amounts, manufacturing activities, and calculations. You stated to our investigator that this (b)(4) software was not validated and lacked audit trails.
In addition, your firm lacked adequate controls to ensure that actions are attributed to authorized individuals with unique and unshared login credentials. For example, our investigator observed that the login credentials of employee, (b)(4), were used to document the completion of several manufacturing activities on two drug product batch records dated March 17, 2021, and July 19, 2021. However, you stated to our investigator that (b)(4) has not been employed at the company since September 2019. Further, it was observed that login credentials including “(b)(4)” and “(b)(4)” were used to document the completion of several manufacturing activities. You stated to our investigator that these login credentials were shared by multiple employees. Shared login credentials are unacceptable, as this practice prevents the identification of specific individuals accessing a controlled system.
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/97005/download.
We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following:
- A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.
- A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
- A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
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. 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. 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 ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506
Please identify your responses with the unique identifier: CMS 624415.
If you have questions regarding the contents of this letter, please contact Santiago Gallardo Johnson, Acting Compliance Officer via email at, Santiago.GallardoJohnson@fda.hhs.gov or by telephone at 619-941-3760.
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
1 Due to an increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, 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 are present. These circumstances included preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. A review of the formulations of the drug products indicates that such products were not prepared consistent with FDA’s temporary policy set forth in the guidance. Because Colorful Products Corporation 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 drug products for violations of section 505 of the FD&C Act.