The US Food and Drug Administration (FDA) on Tuesday released a warning letter sent in November 2017 to German pharmaceutical company Bayer AG after an inspection of its Leverkusen-based site uncovered inadequate equipment cleaning practices and questions about the site’s quality control unit.
An FDA inspector observed a residue on some of exterior surfaces in one manufacturing area and following its inspection, Bayer tested for cross-contamination and recalled several lots of an unspecified drug.
“In three different rooms, our investigator observed white residues in and around the [redacted] of three [redacted]identified as ‘clean,’” the warning letter says, calling on the firm to provide, among other responses, a comprehensive plan to assess cleaning procedures, practices and validations for each piece of manufacturing equipment used to manufacture more than one product.
In addition, the warning letter notes that Bayer’s investigations into product quality complaints are inadequate and that the site’s quality control unit did not sufficiently oversee the adequacy of procedures at the facility to assure drug product quality.
“For example, when you investigated two complaints of leaking [redacted] containing [redacted] batch [redacted], you did not determine a root cause for the container-closure defect,” the letter says.
FDA investigators also observed “discarded forms used to document and set inspection parameters for your automated tablet visual inspection machinery. These parameters are used to accept or reject tablets. In your response, you noted that you documented and approved final set-up parameters, ‘but historically the calculations generated in support of those parameters have not been preserved.’ You indicate that programming the visual inspection machine to detect defects may not be a CGMP activity. We note that the parameters of this machinery are used to discriminate between acceptable and unacceptable tablets. Accordingly, entering reliable settings into machine programming is part of CGMP.”
Bayer told Focus in a statement: "Since the initial routine inspection in January 2017, Bayer has continued to implement remediation activities in a timely manner. Relevant regulatory authorities have been kept informed. Bayer is fully committed to diligently addressing the FDA observations and to continue the corresponding implementation of necessary corrective actions. Comprehensive reports on the progress of these corrective actions have been shared with the agency. We have no evidence that patient safety was or is at risk; release and distribution of products from Supply Center Leverkusen continues.
"Due to the ongoing remediation and also modernization measures at the site, we expect temporary supply limitations affecting our mature product portfolio. The business impact will be reflected in our upcoming 2018 guidance on February 28," the company said.
Other Warning Letters
Also on Tuesday, FDA released warning letters sent to over-the-counter (OTC) drugmakers, including China-based Guangzhou Baiyunshan Pharmaceutical Holdings Co. and Jiangmen Nowadays Daily Goods Co., as well as Korea-based Cosmecca Korea Co.
For Cosmecca, FDA’s investigator reviewed batch records for five OTC products for which the company could not provide analytical data to support their release. For Guangzhou, FDA said it was unable to identify the manufacturer of one of its raw material batches on site and lacked “sufficient systems to properly qualify raw materials.”
FDA also warned Jiangmen Nowadays Daily for, among other violations, failing to adequately test products for conformance to specifications, including identity and strength.
FDA’s Center for Devices and Radiological Health also warned Kleinostheim, Germany-based Curasan, which manufactures dental products.
Bayer Pharma AG 11/14/17
Cosmecca Korea Co., Ltd. 2/2/18
Guangzhou Baiyunshan Pharmaceutical Co., Ltd. 11/1/17
Jiangmen Nowadays Daily Goods Co., Ltd. 9/12/17
Curasan AG, Frankfurt Facility 8/23/17
Editor's note: Article updated with Bayer comment.