Creepy, crawly compliance: The FDA’s recent Warning Letters for insects and pests

With Halloween upon us, AgencyIQ wanted to take the opportunity to add some levity to our normal coverage by examining recent violations of current Good Manufacturing Practice (cGMP) regulations involving creepy-crawly things like spiders, insects and other vermin.

In recent years, many manufacturers of drugs, animal drugs and dietary supplements have been warned for insufficient pest control procedures and received something rather frightening from the FDA: Warning Letters citing their violation of federal law. We decided to do a deep dive through our Warning Letter database to find notable examples of when companies’ manufacturing operations had unwanted visitors, earning companies a scare from the FDA.

Regulatory Background

• Maintaining good manufacturing practices at a production, packaging or distribution facility for pharmaceutical and biotechnology products requires a production area to be free of contaminants, including bugs and vermin. Under 21 CFR 211.56, pharmaceutical and biopharmaceutical companies are required to ensure four things:
• First, that “Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a clean and sanitary condition. Any such building shall be free of infestation by rodents, birds, insects, and other vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.
• Second, “There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.”
• Third, “There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling materials, or drug products and shall be followed. Rodenticides, insecticides, and fungicides shall not be used unless registered and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).”
• And fourth, “Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.”
• In other words, companies need to keep their facilities clean (including of all pests), have a plan in place to maintain cleanliness, training and procedures for staff, and ensure that such cleaning is applicable to all persons within a facility (and not just full-time staff). There are similar requirements for manufacturers of dietary supplements, medicated feeds for animals, and drug wholesalers.
• While most companies find it relatively easy to remain compliant, FDA Warning Letters do indicate that not all facilities are so successful in their efforts – even at remediating known issues. “We acknowledge your response,” the FDA wrote to Optimum Bioenergy International, a manufacturer of dietary supplements, in a December 2017 Warning Letter. “However, we find your response to be inadequate in that you only provided photos of rodent traps and failed to provide actual written procedures for cleaning and pest control.” The FDA said the company would need to develop written pest control procedures for the interior of the facility or maintain records to demonstrate that the company monitored for pests.
• Companies also need to make sure that their efforts extend beyond the facility itself. The same Warning Letter indicated that the company should take care to maintain “roads, yards and parking lots so that they do not constitute a source of contamination.” For example, an overgrown yard can create “a harborage area which can attract pests.”

In the spirit of Halloween and 21 CFR 211.56, we wanted to find examples of creepy-crawly problems from FDA Warning Letters.

• New Vitalis Pharmacy: “The FDA investigators noted that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA. For example, […] Vermin were observed in an area immediately adjacent to the firm’s production area.” (Source)
• Advanced Cosmetic Research Laboratories: “Multiple bug zappers were observed in close proximity to filling/packaging lines. Insects killed by the zappers could fall into open equipment and finished product packaging.” (Source)
• Marck Biosciences Ltd.: “The investigators noted numerous dead insects in the “Sample Pass Through” Room, located approximately (b)(4) from the Sterile Filling Line #(b)(4) of the small volume parenterals facility. In addition, dead and decaying frogs were found next to the product exit dock. Your response states that these pest infestation issues would be corrected. It also includes a commitment to remove the manufacturing waste near the entrance to the facility and to fill in the swamp-like perimeter that appeared to be serving as a harborage for vermin.” (Source)
• Unimark Remedies Limited: “Among other observations, our investigator found that the walls of your manufacturing area had open holes that could permit ingress of insects, birds, lizards, rodents, or other animals to the manufacturing space. During the inspection, the investigator observed dirt and birds in the manufacturing area as well as a lizard in the controlled (b)(4) processing area.” (Source)
• HomeChoice Partners, Inc.: “Vermin was observed in an area immediately adjacent to your production area. Two live insects were observed inside the ante room beyond the line of demarcation. The technician stepped on one of the insects while wearing full gowning garb and continued to mop the ante room. Shortly thereafter, and prior to completion of mopping, a live spider was observed crawling near the negative pressure room. Vermin is a source of microbial contamination. Therefore, your products intended to be sterile were produced in an environment that may not provide adequate protection against the risk of contamination.” (Source)
• Les Produits Chimiques B.G.R., Inc.: “In addition, your quality unit did not ensure the cleanliness of buildings and facilities used to manufacture API. You lacked sufficient controls to prevent the presence of pests in your packaging material storage area. At least twice, our inspector observed insects and spider webs in and on plastic-wrapped stacked containers used for packaging API.” (Source)
• Medoz Pharmacy of Polk Inc: “Your firm’s cleanroom, anteroom, and non-sterile suite contained vermin including numerous dead ants, living spiders, and a dead cockroach. In addition, a colony of dead ants was observed on (b)(4) bag containing sterile stoppers located in the unclassified area.” (Source)
• Pan Drugs Limited: “Our investigators also observed gaps and holes in the walls of your facility around piping and air ducts. These gaps and holes were open to the surrounding environment and allowed pests to enter your facility. During the inspection, we observed a lizard exiting one of the holes, and evidence of other pest activity. For example, our investigators observed what appeared to be rodent droppings within three feet of (b)(4) bags purported to hold (b)(4) drug product.” (Source)
• Optimum Bioenergy International Corp.: “You failed to establish and follow written procedures for cleaning the physical plant and for pest control, as required by 21 CFR 111.16. Specifically, your firm does not have written pest control procedures for the interior of the facility or maintain records to show monitoring for pests are performed. In addition, we observed several gaps approximately ½ inch wide around the perimeter of the roll-up door, a live spider in the blending room and two dead insects in the tablet room. In addition, your firm does not have written procedures for the maintenance, cleaning and sanitation of the facility.” (Source)
• Auro Pharmacies, Inc.: “The FDA investigators observed vermin in your production areas. Specifically, ants were observed on the floor in your pre-gown room where non-sterile hairnets and masks are donned prior to entering the ISO 8 classified gowning room. In addition, an ant was observed on the outer surface of an FDA investigator’s sterile hood cover in the ISO 8 classified gowning room after he exited the ISO 7 classified aseptic production room. Vermin are a source of microbial contamination. Therefore, your products intended to be sterile were produced in an environment that may not provide adequate protection against the risk of contamination.” (Source)
• Rapid Equine Solutions, LLC: “Approximately three insects in the laboratory room as operators were preparing vials for the (b)(4). Two were located on the viewing window of the sterile production room and a third was observed to be within the nonsterile anteroom. FDA also observed a roll of flying insect tape hanging from the ceiling next to the sink in the laboratory room. Vermin (e.g., insects) are unacceptable in a production environment for both sterile and non-sterile drugs and can contribute to contamination in drug products.” (Source)
• Xinxiang Tuoxin Biochemical Co. Ltd: “Our investigator also observed gaps around windows and doors, and holes in ceilings directly above open (b)(4). Flying insects that were observed in clean rooms and on product transfer (b)(4) may have entered through these gaps and holes.” (Source)
• Malladi Drugs & Pharmaceuticals Ltd.: “Parts of your facility in which API production is conducted are open to the outdoors. Our investigator observed vermin, such as birds and insects, in the facility near open equipment used for drug manufacturing. Their presence puts your drugs at risk of contamination. You failed to take adequate precautions to prevent the risk of contamination while producing drugs using open equipment.” (Source)
• Cheng Fong Chemical Co., Ltd.: “For example, our investigator observed filth, insects, wet layers of (b)(4) unidentified material on the floors, and foul odors in the cold rooms used to store raw materials and intermediates used in the manufacture of your finished API. Firm officials noted that the rooms had never been cleaned.” (Source)
• Baoying County Fukang Medical Appliance Co., Ltd.: “Our investigator documented copious amounts of unknown black, mold-like material on the floor and walls of warehouse #2. In addition, our investigator observed standing water on the floor and live insects at the entrance of the same warehouse. This warehouse is a storage area for (b)(4) used in the production of your firm’s (b)(4). The poor conditions in your facility could compromise the quality of the products you manufacture.” (Source)

To contact the author of this piece, please email Alec Gaffney ( [email protected]).

This piece originally ran in October 2020. We have since updated it with additional examples of compliance issues affecting companies.