Specific violations observed during the inspection include, but are not limited, to the following:

1. Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. Such procedures shall include validation of all aseptic and sterilization processes [21 C.F.R. § 211.113(b)].
For example:

a. Your in situ air pattern analysis (smoke studies) does not demonstrate unidirectional airflow and sweeping action over and away from the critical processing areas under dynamic conditions.

Your response indicates that dynamic smoke studies for the (b)(4) filling area would be completed by the end of November, 2011. However, your response is inadequate because you failed to include a detailed interim plan describing additional steps taken in an effort to ensure that these areas were suitable for aseptic manufacturing of sterile drug products. Please provide a summary of the complete smoke studies (i.e., copy of video) conducted to evaluate whether the (b)(4) filling area is suitable for aseptic manufacturing of sterile drug products, and your firm’s risk assessment of the product released to the market prior to your completion of the smoke studies.


Smoke study profiles are becoming a significant target of FDA inspections.  They have especially become notable with foreign inspections.  Included within the FDA’s comments has been the question of how a firm determines its risk assessment of all products released to the marketplace prior to a satisfactory evaluation of the risk and the development of an interim plan to assure all of the areas (ISO Class 5) are acceptable for use.  Including such responses in the initial response to the Form FDA 483 can assist in eliminating the follow-up Warning Letter.

b. Your firm demonstrates poor aseptic practices during the filling of sterile (b)(4) products including, but not limited to:

• An operator performing critical aseptic operations with exposed skin at the forehead, posing an unreasonable risk of the product becoming contaminated.
• Operators moving very quickly in the aseptic area, which may create unacceptable turbulence in the area, and disrupt the unidirectional airflow.
• Operators leaning halfway in and out of the class 100 area while performing interventions over opened bottles.

Your firm’s response indicates that the operators are trained in aseptic practices. However, it fails to specifically address the observed deficiencies in the aseptic area during the inspection and the potential impact of these practices on drug products already distributed.


Training of operators in aseptic practices is only part of what management needs to assure.  The other area that needs to be assured is that the operators practice what they have learned.  The supervisors and managers must assure that the taught practices are being practiced each and every day.  It is not the FDA’s role to assure this when they visit a site.  Further, the FDA continues to ask the question when a poor practice is observed “what is the potential impact of these practices on drug products already distributed?”  In responses to FDA 483s, this must always be considered as part of any response.  Please visit my other Blogs for similar issues as well as the FDA’s Guidance for Industry which discusses Aseptic Processing Best Practices from September 2004.

2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].

For example, during the aseptic filling of (b)(4) Solution lot (b)(4), the batch record documented two dropper-plugging problems. The filling operation was stopped for 10 and 30 minutes, respectively, before this problem was rectified. There was no investigation or documentation of line clearance to remove potentially compromised bottles.

Your response indicates that the firm created a standard operating procedure (SOP) entitled, “Handling of Interventions During (b)(4) Filling,” which includes appropriate investigation requirements for interventions due to manufacturing problems, and defining a method to segregate bottles potentially impacted during interventions. Your response is inadequate because you failed to include a risk assessment for the (b)(4) Solution lots already distributed prior to the implementation of this procedure.


Too many firms believe that by writing an SOP they will satisfy regulatory requirements.  A Risk Assessment must be conducted on all lots in distribution as well as any produced, but not distributed within the facility.  Can the entire lot meet the requirements or is a Recall required because no one knows what occurred to the product (what was the intervention; was it cleared from the line) during the stoppage.

3. Batch production and control records do not include complete information related to the production and control of each batch produced [21 C.F.R. § 211.188(b)].

b. Your firm failed to document in the batch record that the sterilization cycle for (b)(4) Solution, lot (b)(4) was aborted due to a failure to reach the (b)(4) set point temperature during production. 

This lot was ultimately rejected for confirmed out-of-specification (OOS) assays for (b)(4) of 56.6% (limit (b)(4)%-(b)(4)%) and (b)(4) of 55.5% (limit (b)(4)%-(b)(4)%). However, our inspection also noted multiple fundamental CGMP recordkeeping deviations. The sterilization cycle deviation was not documented in batch records or your firm’s incident logs. Your firm also lacked any documentation, such as a printout, of the (b)(4) time and temperatures for the aborted load. 

Your response indicates that (b)(4) failure events will now be handled through an incident reporting system to ensure appropriate documentation, traceability and controls. Your response is inadequate because it does not provide any specific details concerning the new incident reporting system. Please provide a copy of the new procedure for the incident reporting system. 

Our inspection revealed several basic deficiencies in your firm’s documentation of manufacturing operations and deviations. We urge you to perform a comprehensive evaluation and global remediation of your facility’s documentation systems, including both manufacturing and laboratory operations.


If an organization advises a regulatory agency that a new system is to be established, the organization must provide SOPs, procedures, documentation of training, etc of the pertinent information to assure the Agency that every area of concern is documented and that the personnel are trained.  Do not attempt to train the personnel until the documentation is in place.  Various organizations have received both 483s and Warning Letters because training was performed prior to the issuance of documents. 


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