Warning Letter for Japanese Sterile Manufacturer

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.

 

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug product is adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

 

We reviewed your February 26, 2016, response in detail and acknowledge receipt of your subsequent correspondence.

 

During our inspection, our investigator observed specific violations including, but not limited to, the following.

 

1.      Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

 

During the inspection we noted that your firm did not perform routine personnel monitoring during sterile manufacturing operations prior to your renovations. Although you have drafted a new standard operating procedure, Common Hygiene Standard-015: Monitoring of Adherent Microorganism for the Filling Operator of (b)(4) Drugs Production, this SOP lacks clear instructions. For example, it does not sufficiently address the appropriate response to take when personnel monitoring yields results outside of action and alert limits. In addition, it is unclear if the action and alert limits are supported by an appropriate scientific rationale.

 

Additionally, during the inspection we found that you did not perform routine surface sampling of cleanroom environments. You also lack data on the air quality within your (b)(4). Although we acknowledge your revised SOPs, C011: Measurement Location and its Frequency for Environmental Monitoring and Common Hygiene Standard-014: Manufacturing Facility Surface Sampling (Aseptic Production Area: White Zone), your environmental monitoring frequencies and locations remain deficient.

 

In response to this letter, provide a reassessment and CAPA (Corrective Action and Preventive Action) of your environmental monitoring program to ensure it supports robust environmental control, including but not limited to:

• justifying sampling locations, and associated action and alert limits
• ensuring all locations are sampled at appropriate frequencies, with special emphasis on implementing routine sampling of aseptic processing room surfaces
• defining circumstances under which investigation of an adverse trend or out-of-limit result is triggered, as well as appropriate responses to such occurrences in order to promptly address contamination hazards 

2.      Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

 

You did not perform smoke studies under “at rest” and “dynamic” conditions to evaluate air flow characteristics of your open Restricted Access Barrier System (RABS). You subsequently released the sterile (b)(4) products manufactured on this aseptic processing line without studies to demonstrate unidirectional airflow over the exposed sterile product during processing.

 

Your firm has since renovated your RABS to use a closed design and conducted validation studies. However, your response is deficient in that it does not address your release of (b)(4) products currently on the U.S. market using the original open RABS design.

 

In response to this letter, provide a risk assessment describing process failure modes, full sterility history (e.g., sterility testing, media fills), and all actions taken to evaluate and address the acceptability of (b)(4) produced on the open RABS that were distributed to the U.S. market.

Source: FDA

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