The US FDA
has issued the warning Letter to Singapore based
FDA investigators observed specific violations including, but not limited to, the following.
1. 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)).
During aseptic manufacturing of your sterile ophthalmic products (b)(4) (lot (b)(4)) and (b)(4) (lot (b)(4)), you documented numerous leaking containers and other bottle formation defects. To address these defects, you routinely adjusted your (b)(4) ((b)(4)) equipment and resumed production. You subsequently released these lots. Following distribution, you received customer complaints of leaking containers.
In addition, you found numerous critical container-closure defects, including leaking products, during media fills studies. Container integrity is imperative to ensure sterility of ophthalmic drug products. The lack of assurance that your (b)(4) equipment consistently manufactures an integral container-closure system diminishes confidence in the sterility of your marketed products.
Additionally, our inspection found that your firm re-uses (b)(4) as many as (b)(4) times before discarding them. (b)(4) should normally be used once, then discarded after manufacturing a single product lot. Repeated use and re-sterilization can compromise (b)(4) efficacy and physical/chemical stability (e.g., particles, leachables, extractables).
During our inspection, you acknowledged your failure to validate your process prior to distributing drugs. In your response, you committed to develop and execute protocols for process performance qualification and equipment qualification.
In response to this letter, provide the validation protocols and studies that evaluate whether your (b)(4) equipment is reliable. This includes but is not limited to determining whether your process reproducibly yields an integral container-closure system, and whether other process parameters and quality attributes are consistently met.
Also, by definition, a validated process operates in an ongoing state of control. It is essential that your firm improves your process design and control to correct the root causes of your recurring container-closure integrity defects. Without such remediation, successful process performance qualification studies alone are insufficient to demonstrate that your process is truly capable of a continuing state of control. In your response, provide an analysis of the root causes of in-process integrity defects and container-closure defects affecting distributed products. Also provide an update on all CAPA activities that have been undertaken to improve your process.
2. Your firm failed to establish the reliability of the container-closure supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals (21 CFR 211.84(d)(3)).
Your firm uses (b)(4) supplied by (b)(4) in your (b)(4) equipment to manufacture the container-closures for your ophthalmic products. You accepted values reported on the supplier’s certificate of analysis for density and (b)(4) for each incoming lot but did not verify the reliability of the supplier’s results.
Using (b)(4) that does not meet its quality attributes, such as density and (b)(4), may result in container-closure integrity defects that could compromise the sterility of your ophthalmic drug products.
In your response, you committed to sending samples from (b)(4) batch of (b)(4) received to an external laboratory for density testing. You also committed to periodically evaluate your (b)(4) supplier. You did not provide justification for your acceptance criteria for the (b)(4). In addition, you did not provide external laboratory results for density and (b)(4) values, or any supplier evaluations.
In response to this letter, provide justification to demonstrate your (b)(4) specifications are appropriate for the drug products you manufacture. Provide your supplier evaluations and a summary of laboratory test results relating to all of the components, containers, and closures you use to manufacture your sterile drug products.
3. Your firm failed to ensure that your drug products bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).
Your firm failed to conduct stability studies for Buffered Saline and (b)(4) ophthalmic solutions produced in 2014 and 2015. Furthermore, at the time of the inspection, you could not provide raw data to support test results from stability studies you conducted for other products.
Your failure to conduct stability studies and lack of data supporting expiration dates compromises your ability to detect quality problems with marketed ophthalmic products. Without stability data, you cannot assure the quality of your products throughout their labeled shelf lives. In addition, you have received multiple customer complaints of leaking ophthalmic containers, which also calls into question your ability to maintain sterility of your ophthalmic products throughout their labeled expiration dates.
In your response, you commit to conducting stability studies on your Buffered Saline and (b)(4) products. However, you did not provide the raw stability data for other ophthalmic products.
In response to this letter, provide the following:
- raw stability data for all of your ophthalmic products manufactured for the U.S. market within expiry
- antimicrobial effectiveness testing that evaluates whether your products contain a suitable preservative system
- an evaluation of whether your products’ preservative systems remain effective at their expiration dates
Source: FDA
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