TWO STRIKES AND YOU’RE OUT — GULF PHARMA REMAINS UNDER FDA IMPORT ALERT.
Gulf Pharmaceutical Industries was audited between September 25 and October 3, 2011. During this inspection, the FDA found significant violations related to aseptic processing. Several of these violations were a repetition of violations observed during a previous audit in December 2004. In addition, the FDA noted that until such time as their manufacturing practices (Gulf Pharma) are verified to comply with CGMPs, the firm will remain under FDA Import Alert, and FDA will continue to refuse admission of all articles manufactured at Gulf Pharmaceutical Industries located at Airport Road, United Arab Emirates into the United States.
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 include validation of the sterilization process [21 C.F.R. § 211.113(b)].
a) You failed to perform unidirectional airflow pattern studies (i.e. smoke studies) for the ampoule filling line used for the production of (b)(4) Lot (b)(4), distributed to the U.S. on July 13, 2010.
This is a repeat observation from the December 2004 inspection at this facility. Our current inspection found that your firm failed to perform smoke studies for the ampoule filling line. Your firm was previously cited in 2004 for a failure to conduct smoke studies for your vial filling line.
Your response of October 28, 2011, is inadequate because you failed to describe the specific steps that you are taking to ensure adequate oversight by the quality unit over critical aseptic operations such as unidirectional airflow pattern studies.
Smoke studies are a requirement within Aseptic Processing Areas (APA) and have been identified as required within the FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing (cGMP) September 2004. The lack of possessing these data after having seven years to complete them does not bode well with the FDA. Any repeat Observations, even one, can be grounds for a Warning Letter. The extent of these Observations suggests that any product manufactured in such a facility is at risk of non-sterility.
b) The unidirectional airflow studies performed for the vial filling line are inadequate in that the studies do not show unidirectional airflow.
These unidirectional airflow studies showed turbulent airflow in the following areas: above the (b)(4) just prior to entry into the filling (b)(4), over the stopper (b)(4) adjacent to the filling (b)(4), and over the (b)(4) tray filled with partially-stoppered vials during the automatic loading of vials into the (b)(4). We are concerned that your quality unit failed to identify these instances of turbulent airflow.
Although you state in your response that (b)(4) will perform complete smoke pattern studies for the ampoule filling line and the vial filling line, you have not proposed the implementation of additional actions or controls needed while you complete smoke studies and demonstrate that these areas are suitable for aseptic manufacturing of sterile drug products. In addition, you failed to provide your risk assessment for all sterile products within expiry that were manufactured under these unacceptable conditions.
Failing to provide a risk assessment for sterile products that were manufactured within the expiration date under unacceptable conditions can be a difficult, if not impossible task. Continuing to produce products while awaiting the completion of smoke studies can create situations within manufacturing that are indefensible. While a Company desires to produce under all costs, producing product that may ultimately need to be destroyed because a lack of cGMP can become a very costly proposition.
d) Your firm demonstrated poor aseptic technique in gowning and production during the manufacture of (b)(4) Injection Lot (b)(4) on Sept 28, 2011.
During gowning and production operations, investigators observed poor aseptic practices, including, but not limited to, excessive touching of the outside of hood and gown during gowning, exposing aseptic processing equipment and equipment parts in the Class 1000 area prior to introduction into the Class 100 area, disrupting airflow with hands and forearms over the stopper bowl while transferring (b)(4) stoppers, and excessive and repeated touching of parts of the filling machine and (b)(4) barriers.
Your response references corrective actions through training employees, equipment purchase, and procedural improvements. However, your response fails to specifically address the observed deficiencies in aseptic operations and the impact to the sterility of (b)(4) Injection Lot (b)(4) and other products.
Poor personnel aseptic practices can only be remedied through sufficient training and retraining to assure that the personnel understand the consequences of their actions. However, if the personnel still do not understand the microbiological consequences of their actions following repeated training, questions by regulators will arise regarding how various manufactured lots can be sold without questioning the product’s sterility.
e) The revalidation of the (b)(4) sterilization cycles for machine parts is deficient in that the exact placements of the biological indicators (BIs) and (b)(4) are not documented and consequently can not be confirmed as the worst case locations.
Your response indicates that BI locations are now identified in SOP QAS 296 and that retraining has occurred. However, SOP QAS 296, provided in your response, indicates that BIs are not attached with the (b)(4) in several locations including, but not limited to, (b)(4) of the (b)(4), within the (b)(4) attached to the (b)(4), and (b)(4) through the (b)(4) with (b)(4) and (b)(4). Your response is inadequate because it fails to include your rationale for not routinely placing BIs next to the (b)(4) in the areas you have designated as most difficult to sterilize.
Biological Indicators (BI) should only be located in their respective positions after the autoclave has been temperature mapped with thermocouples. Thermocouples used as part of developing a load pattern are essential for determining the “cold” spots within the autoclave. Placing the BI within the “cold spots” after locating them through the use of thermocouples will provide for the Sterility Assurance Level of 10-6 that is required to confirm sterility.