An Italian pharmaceutical firm, Corden Pharma Latina S.p.A, Italy, was inspected from May 21-29, 2015. As a result of this audit the FDA issued a Warning Letter on May 20, 2016. The Warning Letter summarized cGMP violations for finished pharmaceuticals, 21 CFR parts 210 and 211 as well as significant deviations from cGMP for active pharmaceutical ingredients (API). Because the methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to cGMP, the drugs are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
The FDA observed specific violations and deviations including the following:
“Finished product violations
- Your firm failed to have facilities used in the manufacture, process, packaging and holding of drug products of appropriate construction to facilitate cleaning, maintenance, and proper operations. (21 CFR 211.42(a))
We observed (b)(4) floor tiles (approximately (b)(4) by (b)(4)) in your sterile (b)(4) manufacturing area. Black grime and filth were visible in the tile (b)(4) throughout the aseptic area, including in the direct vicinity of the manufacturing equipment. Furthermore, cracked and inadequately repaired floor tiles created more gaps to hold filth.
In your response, you stated that you repaired cracked floor tiles and damaged seals in the (b)(4) room and under the (b)(4), and replaced the flooring in the area of the aseptic filling machine.
Your response is inadequate. Floors should be (b)(4) where sterile products are manufactured. Smooth, hard surfaces that are easy to clean prevent accumulation of filth and discourage microbiological growth. There is no assurance that the repairs you made to the floors and the new tiles installed are adequate and appropriate for an aseptic processing facility. Specifically, there is no assurance that the repaired/replaced tile floors can ever be sufficiently cleaned and disinfected.
In your response to this letter, provide:
- A plan and timeline to replace the floors, including underneath heavy equipment, with a (b)(4)floor that is easy to clean and sanitize, without cracks and crevices. Send your plan and timeline before you install the new floors. Include your remediation actions for contaminants found under the tile floor. The remediation plan should include details regarding use of cleaners, sporicidal agents, and moisture removal.
- Your plan to requalify the facility after construction, including environmental qualification and media fill strategy.
- Photographic evidence after you complete the floor replacement to demonstrate that your facility meets CGMP requirements.”
It appears that the Client misunderstood what the FDA expected in terms of flooring. Having tiled floors initially and then attempting to repair them is contrary to what the FDA states within their Aseptic Processing Guidance (September 2004, Click Here). Not only did the flooring need replacement, but the subflooring needed to be completely dry. (See my Blog on Sanofi-Pasteur, Toronto, Canada Click Here) for a similar situation. The FDA, with the issuance of the Warning Letter, understands that the Client is “clueless” in that terms of 211.42(a) and requested that their Client forward their plan to requalify the facility following construction as well as a plan and timeline before the Client performs any remediation work on the building.
- “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. (21 CFR 211.67(a))
Your cleaning procedure includes spraying (b)(4) of water throughout the aseptic area. As a result, stagnant water collects underneath the aseptic filling machine. Stagnant water is a potential source of microbiological contamination, including biofilms and other filth.
According to your response, you are using a “(b)(4)-Mop” after cleaning to remove pools of water under the filling machine, and evaluating alternative disinfecting agents that will not require removal with water as a (b)(4)step. You did not demonstrate that the “(b)(4)-Mop” and new disinfectants are adequate for cleaning and sanitizing the floor.
After you have remediated your facility in line with the items above, update your cleaning procedures to ensure no stagnant water remains, and review all your cleaning practices to ensure they do not increase the risk to the product for microbial or particulate contamination.”
According to USP<1072> any sanitizer/disinfectant that is used within a classified environment should demonstrate the destruction of bacteria, yeast and mold on all surfaces to which the sanitizer/disinfectant are exposed. All sanitizers/disinfectants should be purchased as sterile or sterilized in-house. Further, all mops/buckets and any other materials used in the application of the sanitizer/disinfectants should be sterilized prior to use. Any sanitizer/disinfectant that is not consumed on the day of preparation should be tested and documented for shelf-life in a report that the various regulatory agencies may view. In addition, no stagnant water should be present.
- Your test procedures are not scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity.
Your environmental monitoring data is not reliable. On May 27, 2015, our investigators observed 61 damaged (b)(4) plates during plate reading. Examples of damage included discolored (b)(4), desiccated (b)(4) shrinking away from the edge of microbial plates, and (b)(4) that had completely detached and fallen onto the (b)(4) when(b)(4) during incubation. (b)(4) that is desiccated, cracked, or damaged fundamentally compromises microbial growth promotion and accurate enumeration, and may result in the underestimation of microbiological counts and false negatives.
In your response, you evaluated each type of plate damage and concluded that the effects of plate damage are negligible, because microbiological growth on such (b)(4) is possible. This response is inadequate; use of deficient media fundamentally compromises the validity of your microbiological test results. Furthermore, you did not commit to stop using damaged plates for microbiological tests.
In your response to this letter, provide:
- An accelerated timeline for completing retroactive microbiological testing of all potentially-compromised batches via an independent laboratory, and a commitment to respond promptly with all OOS results.
- Your review of all microbiological test methods to ensure that they are suitable for their intended use.”
USP<61> and <62>, USP<1117> and USP<1227>, and Guidance for Industry, Aseptic Processing (September 2004), all discuss damage to include discolored, desiccated, shrinking away from the edge of microbial plates, and plates so dry that the media has fallen upon the lid during incubation. Any media containing plate that is desiccated, cracked, or otherwise damaged fundamentally compromises microbial growth promotion and accurate enumeration, and may result in the underestimation of microbiological counts and false negatives. These results all suggest that the laboratory technicians are not following their SOPs and are allowing the plates containing the microorganisms to unduly age prior to attempting to count the test results.
“5. The buildings and facilities used in the manufacture of your API are not designed and constructed to limit exposure to objectionable microbiological contaminants.
The floor of the sterile API aseptic processing area has multiple drains. In International Standards Organization Class 5 (ISO 5/Grade A) areas for aseptic filling, drains should not be used because of microbiological contamination risks.
In your response, there is insufficient scientific rationale for drains in the floor of your sterile API filling suite.
In response to this letter, provide your plan for removing drains from sterile API manufacturing areas.”
Drains should not be present in ISO Class 5/Grade A facilities. Drains within a classified environment represent a significant microbiological contamination risk. Even when sterilants are applied to a drain, microbial contamination reoccurs within a day.
FDA’s Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice guidance document may help you ensure that all aseptically-filled drug products meet standards for drugs purported to be sterile. Download from (Click Here)”