- Delivery Method:
- VIA Electronic Mail
- Issuing Office:
- Office of Pharmaceutical Quality Operations, Division II
Case #: 623475
Dear Mr. Gonzalez Camp:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Agropharma Laboratories, Inc., FEI 3000203462, at Carr 701 Km 0.4, Playa Salinas Industrial Park, Salinas, Puerto Rico, from October 21 to November 3, 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 reviewed your December 6, 2021, response to our Form FDA 483 in detail. Although you mentioned that you engaged the services of a consultant to help you complete a detailed evaluation of the observations and provide responses, you did not provide specific information or evidence of corrective actions to the observations identified during the inspection on our Form FDA 483.
During our inspection, our investigators 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 CFR 211.22).
Your firm manufactures over-the-counter antiseptics indicated for open wounds, as well as hand sanitizers1 labeled for use by healthcare personnel. Your Quality Unit (QU) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure the following:
- Adequate testing of your incoming components for identity, purity, strength, and other appropriate quality attributes (21 CFR 211.84(d)(1) and (2)).
- Adequate testing and appropriate specifications for your finished drug products (21 CFR 211.165(a)).
- Adequate procedures describing process validation, investigations, deviations, equipment cleaning, and change management (21 CFR 211.22(d)).
- Adherence to your ongoing stability program (21 CFR 211.166(a)).
- Performance of annual product reviews (21 CFR 211.180(e)).
Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help in 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 that your QU is given the authority and resources to function effectively. 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 drug products.
2. Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition (21 CFR 211.56(a)).
Drug manufacturing areas at your facility were in disrepair. For example, our investigator observed facility damage such as broken walls in the production area, filth, and pooling water in close proximity to open manufacturing equipment.
In response to this letter, provide 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.
3. Your firm failed to establish 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 has not established that your processes used to manufacture drug products are validated. Additionally, your firm uses water from your water system as a component to manufacture your drug products; however, you have not established that the water system is adequately designed, controlled, maintained, and monitored to ensure that it consistently produced water suitable for its intended use.
Your firm lacks a process validation program. 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 ensure 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 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/media/71021/download.
In response to this letter, provide the following:
- 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 appropriate process performance qualification for each of your marketed drug products.
- Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
- Provide a detailed program for designing, validating, maintaining, controlling and monitoring each of our 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. A comprehensive, independent assessment of your water system design, control, and maintenance.
- 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 consistently produces water adhering to Purified Water, USP monograph specifications and appropriate microbial limits.
- 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.
- A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
Drug Production Ceased
We acknowledge your commitment to cease production of drugs at this facility. However, your firm continues to be registered as a manufacturer. In response to this letter, clarify whether you intend to resume manufacturing any drugs at this facility or another in the future.
If you plan to resume manufacturing drugs, ensure that adequate corrective actions are in place and notify this office to schedule a meeting before resuming your operations.
Based upon the nature of the violations we identified at your firm, if your firm intends to resume manufacturing drugs for the U.S. market, 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.
Repeat Violations and Observations at Facility
In a previous Untitled Letter (11-SJN-UTL-02) dated October 13, 2010, and in subsequent inspections, FDA cited similar CGMP violations and observations. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
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 these violations 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.
Your written notification should refer to case # 623475.
Please electronically submit your reply, on company letterhead, to Dayna I. Martinez, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to firstname.lastname@example.org and email@example.com
If you have questions regarding the contents of this letter, you may contact Dayna I. Martinez via phone at (787) 729-8608 or email at firstname.lastname@example.org
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
Cc: Ms. Marianela Maldonado
Agropharma Laboratories, Inc.
P.O. Box 1150
Salinas, Puerto Rico 00751-1150
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 Agropharma’s 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.