On February 25, 2025, the U.S. Food and Drug Administration (FDA) issued a Warning Letter (320-25-47) to Linghai ZhanWang Biotechnology Co., Ltd. following a review of records submitted in response to an FDA request under section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
The FDA identified significant violations of Current Good Manufacturing Practice (CGMP) regulations at the company’s facility in Linghai, Jinzhou, Liaoning, China. Due to these violations, the FDA classified the firm’s drug products as adulterated under section 501(a)(2)(B) of the FD&C Act and placed them on Import Alert 66-40, prohibiting their entry into the United States.
Key Non-Conformances Identified
Some of the key non-conformances cited in the warning letter include:
Non-Conformance 1: Failure to Test Raw Material Components for Identity and Purity
Regulatory Citation: 21 CFR 211.84(d)(1) and 211.84(d)(2)
Findings
- The firm did not perform identity and impurity testing for raw materials used in OTC antimicrobial wipes.
- No methanol testing was conducted for ethanol, despite its known toxicity risks.
- No diethylene glycol (DEG) and ethylene glycol (EG) testing was conducted for glycerin and other excipients at high risk for contamination.
Non-Conformance 2: Inadequate Stability Testing Program
Regulatory Citation: 21 CFR 211.166(a)
Findings
- Stability testing was performed under accelerated aging conditions without scientific justification.
- No long-term stability studies were conducted to confirm whether the expiration date on the label is valid.
RELATED ARTICLE: Stability Storage Conditions in Pharma Industry
Non-Conformance 3: Deficient Quality Control Unit (QU)
Regulatory Citation: 21 CFR 211.22(a)
Findings
- The Quality Unit (QU) did not effectively approve or reject materials, packaging, or finished drug products.
- The QU failed to exercise oversight, leading to other CGMP violations.
CAPA Plan Recommendations
To address these violations, Linghai ZhanWang Biotechnology Co., Ltd must implement a Corrective and Preventive Action (CAPA) Plan to ensure compliance with CGMP regulations.
Failure to Test Raw Material Components for Identity and Purity
Regulatory Citation: 21 CFR 211.84(d)(1) and 211.84(d)(2)
Root Cause Analysis (RCA)
- Reliance on supplier CoAs without verification: The company assumed that supplier-provided Certificates of Analysis (CoAs) were sufficient without conducting in-house confirmatory testing.
- Lack of risk assessment procedures: The firm did not assess the risks of toxic impurities, such as methanol, DEG, and EG, in raw materials.
- Inadequate laboratory resources: The company did not have proper equipment (e.g., gas chromatography for impurity testing).
- Weak Quality Unit oversight: The QU failed to enforce raw material testing requirements.
SEE ALSO: Residual Solvents testing in GMP
Corrective and Preventive Actions (CAPA)
- Implement a raw material testing program requiring identity and impurity testing before use.
- Acquire laboratory instruments (e.g., gas chromatographs) for in-house methanol, DEG, and EG testing.
- Mandate supplier qualification audits to ensure raw material purity.
- Train QU personnel on CGMP standards for material testing and oversight.
Inadequate Stability Testing Program
Regulatory Citation: 21 CFR 211.166(a)
Root Cause Analysis (RCA)
- Misunderstanding of regulatory requirements: The firm incorrectly relied on accelerated aging without real-time stability data.
- Lack of written procedures for stability studies: There were no documented protocols to ensure scientifically valid stability testing.
- Inadequate infrastructure: The company did not have a dedicated stability chamber with controlled conditions.
Corrective and Preventive Actions (CAPA)
- Develop a stability study protocol based on ICH Q1A(R2) guidelines.
- Conduct long-term and accelerated stability testing under validated conditions.
- Invest in stability chambers with controlled storage conditions.
- Train personnel on stability testing principles and regulatory requirements.
Deficient Quality Control Unit (QU)
Regulatory Citation: 21 CFR 211.22(a)
Root Cause Analysis (RCA)
- Lack of independent authority: The QU was not empowered to enforce CGMP compliance.
- Inadequate CGMP training: QU personnel did not fully understand their regulatory responsibilities.
- Absence of internal audits: The firm had no routine audit system to ensure CGMP compliance.
- Failure to document review procedures: The QU’s approval processes were not well-defined.
Corrective and Preventive Actions (CAPA)
- Strengthen QU authority by defining its independent decision-making power.
- Hire or train personnel with CGMP expertise and quality assurance experience.
- Implement an internal audit program to identify compliance gaps proactively.
- Establish documented procedures for QU approval of materials and products.
Timeline for Implementation
Immediate Actions (0-3 Months)
- Suspend production until a raw material testing program is in place.
- Train QU personnel on CGMP responsibilities and quality oversight.
- Procure laboratory equipment for in-house impurity testing.
Short-Term Actions (3-6 Months)
- Initiate real-time stability studies on existing products.
- Develop and implement supplier qualification procedures.
- Establish QU review protocols for material and product approvals.
Long-Term Actions (6-12 Months)
- Complete full CGMP compliance validation and submit results to the FDA.
- Conduct an internal CGMP audit to verify corrective action effectiveness.
- Provide a compliance report to FDA demonstrating full adherence to CGMP.
Conclusion
The FDA’s Warning Letter identifies serious CGMP violations at Linghai ZhanWang Biotechnology Co., Ltd. The company must urgently correct deficiencies in raw material testing, stability studies, and QU oversight.
Until compliance is restored, all drug products from this facility remain on Import Alert 66-40, blocking their entry into the U.S. market. The company has 15 working days to submit a detailed CAPA plan to FDA.
Failure to fully address these violations may lead to further regulatory actions, including continued import bans and potential legal consequences.
