Data integrity is ‘biggest issue’ for drug, API firms during inspections, FDA official says
Regulatory News | 06 August 2024 |
FDA investigator badges on display at the agency's White Oak campus. (Credit: Ferdous Al-Faruque)
Inspectors at the US Food and Drug Administration (FDA) say lack of data integrity, transparency, record retention, and inadequate controls are some of the most common issues they see during inspections of manufacturers, according to a US Food and Drug Administration (FDA) official who spoke at the Orange County Regulatory Affairs Discussion Group annual conference last week.
“Data integrity is the biggest issue that is identified on the field by the investigators, and we cite them on our warning letters for different reasons that we see,” Yasamin Ameri, a compliance officer with the Center for Drug Evaluation and Research (CDER) Office of Manufacturing Quality (OMQ) at FDA, told attendees.
CDER has issued 60 current good manufacturing practice (CGMP) warning letters as of May 2024, with 21 letters issued to firms in the United States, 7 in China, 7 in India, 2 in Mexico, and 21 in other areas of the world. Most of those warning letters issued related to routine surveillance (40.0%), first surveillance (35.0%), section 704(a)(4) (20.0%), and sample collection and testing (5.0%). CDER is on track to release a similar number of warning letters compared to 2023, and the proportions of evidence types cited in those warning letters are also similar to the previous year, Ameri said.
Nearly all the CGMP warning letters issued so far in 2024 were for over-the-counter (OTC) drugs (88.3%), followed by active pharmaceutical ingredients (APIs) (8.3%), and prescription drugs (3.3%). Ameri noted that the OTC drugs that received warning letters were “spread out all over the world” and not specific to the United States.
Concerning inadequate controls, firms are commonly cited for issues related to aseptic manufacturing, microbial contamination, cleaning and cross-contamination, poor excipient quality and manufacturing controls, facility design and maintenance, and supply chain globalization and contract manufacturing. In particular, out-of-specification (OOS) result investigations “is a huge issue,” Ameri said. A small number of firms receive warning letters because they refuse inspection and fail to respond to record requests, she noted.
For API manufacturers, Ameri said they use International Council for Harmonisation (ICH) guidelines for inspections, which are similar but not identical to 21 CFR. Common issues cited during API manufacturer inspections are similar to what is seen with drug manufacturers and include problems with access controls, controls to prevent omissions, audit trails and change records in computer systems.
Inadequate OOS investigations are also seen during API manufacturing inspections. “OOS results are not adequately investigated and documented,” Ameri said. “Firms don't investigate the OOS to find the root cause of the issues, they just do a surface review of the OOS, and they are not documented according to the written procedures.” Other issues seen are companies that perform inadequate data analyses and the assessments for significant issues, do not properly close out their corrective and preventative actions (CAPAs), and do not perform resampling and retesting based on their written standard operating procedure. Inspectors also see companies with incorrect specifications or specifications that are not scientifically sound, incorrect sampling plans, and incorrect testing procedures, Ameri said.
Another important deviation trend for API manufacturers when the responsibility of quality control unit “is not properly defined or followed.” Firms also have issues with transfer of information when quality or regulatory information received from an API or a manufacturer is not transferred to the users. Ameri said that API manufacturers also run into problems with cleaning validation, lack of procedures for cleaning, inadequate or lack of process validation, and failure to maintain laboratory control records.
Manufacturers of non-application drugs, such as OTCs, can still receive an inspection from the FDA. “We still inspect those firm based on the risk that we have on our system,” Ameri said. “When OMQ become aware of a high-risk dose form of a drug product—something like eye drops, ear drops or nose drops—we can have a target inspection by asking the field officers to collect samples or scheduling them for the expedited inspection.” These companies are still subject to compliance actions like warning letters, import letters, and product recalls, she noted.
“Data integrity is the biggest issue that is identified on the field by the investigators, and we cite them on our warning letters for different reasons that we see,” Yasamin Ameri, a compliance officer with the Center for Drug Evaluation and Research (CDER) Office of Manufacturing Quality (OMQ) at FDA, told attendees.
CDER has issued 60 current good manufacturing practice (CGMP) warning letters as of May 2024, with 21 letters issued to firms in the United States, 7 in China, 7 in India, 2 in Mexico, and 21 in other areas of the world. Most of those warning letters issued related to routine surveillance (40.0%), first surveillance (35.0%), section 704(a)(4) (20.0%), and sample collection and testing (5.0%). CDER is on track to release a similar number of warning letters compared to 2023, and the proportions of evidence types cited in those warning letters are also similar to the previous year, Ameri said.
Nearly all the CGMP warning letters issued so far in 2024 were for over-the-counter (OTC) drugs (88.3%), followed by active pharmaceutical ingredients (APIs) (8.3%), and prescription drugs (3.3%). Ameri noted that the OTC drugs that received warning letters were “spread out all over the world” and not specific to the United States.
Concerning inadequate controls, firms are commonly cited for issues related to aseptic manufacturing, microbial contamination, cleaning and cross-contamination, poor excipient quality and manufacturing controls, facility design and maintenance, and supply chain globalization and contract manufacturing. In particular, out-of-specification (OOS) result investigations “is a huge issue,” Ameri said. A small number of firms receive warning letters because they refuse inspection and fail to respond to record requests, she noted.
For API manufacturers, Ameri said they use International Council for Harmonisation (ICH) guidelines for inspections, which are similar but not identical to 21 CFR. Common issues cited during API manufacturer inspections are similar to what is seen with drug manufacturers and include problems with access controls, controls to prevent omissions, audit trails and change records in computer systems.
Inadequate OOS investigations are also seen during API manufacturing inspections. “OOS results are not adequately investigated and documented,” Ameri said. “Firms don't investigate the OOS to find the root cause of the issues, they just do a surface review of the OOS, and they are not documented according to the written procedures.” Other issues seen are companies that perform inadequate data analyses and the assessments for significant issues, do not properly close out their corrective and preventative actions (CAPAs), and do not perform resampling and retesting based on their written standard operating procedure. Inspectors also see companies with incorrect specifications or specifications that are not scientifically sound, incorrect sampling plans, and incorrect testing procedures, Ameri said.
Another important deviation trend for API manufacturers when the responsibility of quality control unit “is not properly defined or followed.” Firms also have issues with transfer of information when quality or regulatory information received from an API or a manufacturer is not transferred to the users. Ameri said that API manufacturers also run into problems with cleaning validation, lack of procedures for cleaning, inadequate or lack of process validation, and failure to maintain laboratory control records.
Manufacturers of non-application drugs, such as OTCs, can still receive an inspection from the FDA. “We still inspect those firm based on the risk that we have on our system,” Ameri said. “When OMQ become aware of a high-risk dose form of a drug product—something like eye drops, ear drops or nose drops—we can have a target inspection by asking the field officers to collect samples or scheduling them for the expedited inspection.” These companies are still subject to compliance actions like warning letters, import letters, and product recalls, she noted.
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