Write it Down, Investigate, and Control

Of the variety of FDA warning letters sent to bio/pharmaceutical manufacturing and distribution companies at the end of 2022, a good amount seemed to be targeted at those companies trying to market unadulterated COVID-19 treatments. But the agency did have some feedback for bio/pharma manufacturers producing legitimate medicines.

As expected, quality assurance and control were the top issues FDA pointed out to companies. Investigating deviations through corrective actions and preventive actions (CAPA), establishing robust quality control units (QU), and having written procedures in place were mentioned in a variety of warning letters sent to drug manufacturers in 2022.

The following are some notable comments from FDA.

CAPA, CAPA, CAPA

In a warning letter (1) regarding an inspection done in March and April of 2022 at a Phoenix, Ariz. facility, the agency reproached the company for not thoroughly investigating batch discrepancies, failures, and out-of-specification results.

“You failed to effectively implement corrective actions and preventive actions (CAPA) and return your aseptic processing line and manufacturing operations to a state of control. Multiple media fill failures occurred between April and October 2021, when simulating aseptic processing operations on the filling line used for your drug product Abraxane (a sterile (b)(4) drug),” the letter stated.

According to FDA, the company did not adequately perform an evaluation and remediation of the loss of control of aseptic operations and released batches that may have been impacted by the batch failures. “Your investigations into the following media fill failures were inadequate in that they lacked sufficient rigor in determining root causes and scope of impact after the media fills revealed serious non-sterility risks in your aseptic process operations,” the letter stated.

After the agency’s inspection and findings, the company took steps that included a Field Alert Report, batch rejections, and suspension of operations. However, FDA stated these actions were not sufficient. “However, you continued to observe contaminated units in subsequent media fills. The recurring incidents of contaminated units in media fills are an indicator of an adverse trend in your aseptic filling line. You did not provide a comprehensive assessment of contamination risk factors in your aseptic processing operations that support robust and holistic remediations to your aseptic processing operation design. Systemic remediations are essential to address a pattern of recurring contamination events and ensure sustainable control of your aseptic processing operations,” the letter stated.

In response, the company was required to provide FDA with a comprehensive risk assessment of contamination hazards in its aseptic facility and processes. The company must also provide a remediation plan and a CAPA plan to implement routines, operations, and management. An evaluation of the company’s aseptic processing operations was also required by the agency.

Write it down

Following good manufacturing practices (GMPs) helps produce a quality product that is effective and safe. Having written standard operating procedures (SOPs) is a staple of GMPs. These written procedures not only ensure that employees know the required steps to perform manufacturing operations, they also assure FDA that a company’s processes and methods are sound and efficient.

In a warning letter dated Sept. 27, 2022 (2), FDA inspectors found a company in India had not established adequate written procedures for equipment cleaning and for monitoring control of processing steps that may cause variability in quality characteristics. This lack of written procedures resulted in the agency asking the company to provide an independent, retrospective assessment of effectiveness of their cleaning processes to evaluate the possibility of cross-contamination. A CAPA plan and improvements in the company’s cleaning validation program were also required. The agency also asked for a procedure for a risked-based review of all of the company’s products.

A China facility also received notification from FDA that they lacked written procedures for equipment cleaning (3). “You manufacture drug products using the same equipment that you use to manufacture non-drug industrial products such as (b)(4) and (b)(4). Inadequate removal of residues from manufacturing equipment during cleaning can lead to contamination of drug products subsequently manufactured on the non-dedicated equipment … In your response, you provided a document outlining your procedures for cleaning and disinfecting manufacturing equipment. It is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture industrial products due to the risk of cross-contamination,” FDA stated in the letter.

In addition to a risk assessment of the products manufactured on the shared equipment, the agency requested a summary of updated SOPs that showed an appropriate validation and verification program for cleaning procedures.

Control quality

The creation of an adequate quality control unit has been something FDA has continually mentioned in warning letters to drug manufacturing companies. In October 2022, a Mexico facility (4) was given an FDA warning letter that pointed out the company’s quality control unit did not ensure the products manufactured met CGMP compliance or established specifications.

The letter stated the quality unit did not provide adequate oversight and did not have adequate procedures for handling vendor qualification, batch release, reserve samples, investigations, complaints, and training. The QU also did not properly test incoming components or adhere to a stability program.

In another FDA warning letter (5), a China facility failed to fully investigate API impurities in associated batches. “Though you identified at least four lots that failed your (b)(4) impurity specification, you did not extend your investigation to all lots manufactured prior to August 2018 after you identified (b)(4) had a higher risk of forming,” FDA stated in the letter. The firm also did not establish an impurity profile for identified and unidentified potential impurities. “Your firm failed to perform a systematic evaluation of the manufacturing process of (b)(4) API and have robust procedures to identify the potential formation of (b)(4) impurity,” the agency stated.

Computer and systems controls were mentioned in an FDA warning letter to a German facility (6), where the company did not have appropriate controls ensuring changes to master production and control records were limited to authorized personnel. “You failed to have adequate controls in place for your Fourier Transform Infrared Spectrometer (FTIR) system. For example, you did not establish unique usernames and passwords for each analyst. In addition, the audit trail function was disabled even though this Fourier Transform Infrared Spectrometer is routinely used for raw material and finished product testing … Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture,” the agency stated.

Conclusion

The issues included herein have been seen in a variety of FDA warning letters this year and in the past. It is apparent that the agency is still focused on ensuring that manufacturers are following GMPs and taking product quality seriously.

References

1. FDA. Warning Letter to Abraxis Bioscience LLC. FDA.gov. Oct. 31, 2022.
2. FDA. Warning Letter to Lupin Limited. FDA.gov. Sept. 27, 2022.
3. FDA. Warning Letter to Beijing Xinggu Lvsan Technology Co., Ltd. Formerly known as Beijing Lvsan Technology Co.,Ltd. FDA.gov. Oct. 5, 2022.
4. FDA. Warning Letter to Eksa Mills S.A. de C.V. FDA.gov. Oct. 5, 2022.
5. FDA. Warning Letter to Zhejiang Tianyu Pharmaceutical Co.. Ltd. FDA.gov. Aug. 17, 2022.
6. FDA. Warning Letter to System Kosmetik Produktionsgesellschaft fur kosmetische GmbH. FDA.gov. Sept. 9, 2022.

About the author

Susan Haigney is managing editor of Pharmaceutical Technology.

Article details

Pharmaceutical Technology
Vol. 47, No. 1
January 2023
Page: 38–39

Citation

When referring to this article, please cite it as S. Haigney. Write it Down,
Investigate, and Control. Pharmaceutical Technology 2023 47 (1).