Observations cited in a Form 483 need to be reviewed carefully, because they represent — at least in the mind of that investigator — conditions that could make a drug adulterated.
So what are investigators seeing? The number one observation over the last two years has been that responsibilities and procedures applicable to the quality control unit are not in writing or fully followed, said Rebeca Rodriguez, national expert investigator in FDA’s Office of Regulatory Affairs, during a breakfast meeting at the Parenteral Drug Association meeting in Washington, D.C.
Regulatory maturity matters, she stressed, noting that if companies understand the requirements and can explain why they made the decisions they made, the FDA views them more favorably.
Rodriguez said that QC unit deficiencies are more often found in smaller companies, or in those that use more contract agreements. Also, because the purview of the QC unit is so wide, the agency likely would not cite a company for just one observation, but rather look for consistent failures.
Poor Lab Controls
Laboratory controls came in at number two on the list of Form 483 observations, and data integrity issues often are related to lab controls, she said, noting that the increase of foreign inspections is one of the main reasons for the increase in data integrity observations.
Company culture also matters when it comes to inspections outcomes, because the manager’s behavior — even if it’s not acceptable — becomes the norm in a company, she said.
“FDA relies on accurate information to ensure drug quality, and data integrity problems break trust,” said Brooke Higgins, senior policy advisor for CDER’s Office of Compliance, and Office of Manufacturing Quality.
Examples of data integrity issues included lab records not containing complete data, lack of raw data in logbooks, and even discarded data found in trash bins.
Inspectors also have observed a lack of basic lab controls to prevent changes to data, noting audit trails turned off, or user names and passwords being shared.
Another frequent observation related to data integrity is the failure to record activities at the time they are performed. For example, using rough notes to capture original data and backdating production records.
Number three on the list was failure to review unexplained discrepancies thoroughly.
“One of the issues I have observed quite frequently is that it seems like the investigations are conducted to exonerate the product, which could be a natural consequence of the investigation,” said Rodriguez. “But if that is the goal — and it seems to be in most cases — it does limit the ‘thinking-out-of-the-box’ scenario we expect people to have when they are conducting investigations.”
The fourth most common 483 observation was not establishing written procedures to prevent microbiological contamination of sterile drug products.
Similarly, number five was not having written procedures for production and process controls, which is where validation lives.
Rodriguez said the agency is instructing investigators to target processes that are not well designed. She stressed that validation is part of the lifecycle that starts with design.
“We were seeing companies trying to validate by replicating three batches and finding problems. You can’t replicate a process that is not well designed,” she said.
Sometimes issues are tied to lack of management supervision, said Rodriguez, noting that either the ratio of supervisors is inadequate or oftentimes later shifts with temporary employees encounter more problems. Resources are also key, she said, and this is where risk needs to determine resources.
Still, inspectional trends can’t be analyzed as numbers or hard data, Higgins said, because subjectivity and circumstances need to be reviewed first for each case. The FDA will assess each case and then gather more evidence before taking further enforcement action, she said.
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