INDIAN MANUFACTURING FACILITIES CONTINUE TO RECEIVE FDA REGULATORY ACTIONS

HOSPIRA’S  IRUNGATTUKOTTAI FACILITY RECEIVES WARNING LETTER (052813)

Recently Ranbaxy settled a $500 million lawsuit with the Dept. of Justice for selling improperly manufactured and tested drugs (see previous Blogs).  More recently, Maharashtra-based Wockhardt received an Import ban (see previous Blogs to learn of what other Indian based companies have received Import bans).

In this particular case, Hospira Healthcare India Pvt., Ltd located in Irungattukottai, Sriperumburdur, India received a Warning Letter (052813) — even after the Company submitted their initial response and a secondary response on January 29, 2013.  While Hospira received only two major Observations within this Warning Letter, I have chosen to focus on 21 CFR 21l.113(b) as noted below.

Violations included 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)).

a.  Surfaces are not always sanitized prior to use….the investigator observed an operator bringing the out-feed vial transfer belt from outside the primary HEPA area and re-attaching it to the line without sanitizing the belt.  This was observed four times during the inspection.  Your management instructed the operators to cull out the implicated vials only after the investigator brought this to your management’s attention.

b.  Aseptic manufacturing interventions are not performed in a manner to protect sterile drug products from contamination…the investigator observed at least two instances in which operators performed interventions requiring them to reach over unstoppered vials.  In both cases, the exposed vials were not removed and line clearance was not performed.  We are concerned because these types of interventions can contaminate open vials and can affect the unidirectional airflow used to protect the sterile equipment, surfaces, and products.

COMMENT:

The above Observations represent basic issues that are covered in “Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, September 2004”.  Whenever an Investigator performing a Regulatory Audit becomes a Company’s Quality Assurance Unit and must bring an Observation to management’s attention, it significantly will affect the outcome of the audit.

c.  No dynamic airflow studies (e.g., smoke studies) have been performed to demonstrate unidirectional airflow and to determine risk to product sterility for certain routine aseptic interventions, including removal of jammed stoppers within the hopper, reloading rubber stoppers, and removal of jammed vials in the automatic weight checker.  Your firm’s response states that these interventions have now been simulated, but you provided no documentation or evidence of these simulations.  In response to this letter provide a copy of the video/DVD containing the dynamic airflow studies (e.g., smoke studies) performed to demonstrate unidirectional airflow during these interventions.

COMMENT:

The above Guidance for Industry within Section IV-A discusses the use of dynamic airflow studies in detail to include “Proper design and control prevents turbulence and stagnant air in the critical area.  Once relevant parameters are established, it is crucial that airflow patterns be evaluated for turbulence or eddy currents that can act as a channel or reservoir for air contaminants (e.g., from an adjoining lower classified area).  In situ air pattern analysis should be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions.  The studies should be well documented with written conclusions, and include evaluation of the impact of aseptic manipulations (e.g., interventions) and equipment design.  Videotape or other recording mechanisms have been found to be useful aides in assessing airflow initially as well as facilitating evaluation of subsequent equipment configuration changes.”  Again, the lack of the Hospira Indian facility to follow this Guidance which has been available since 2004 suggests issues within the Quality Assurance Unit.

d.  Your media fill batch records do not describe the rationale for not incubating vials following media fills.  For example, your firm rejected 272 vials during the media fill batch BMF001/12 for penicillin liquid conducted in May 2012, while having no documentation for the specific reasons why the vials were rejected.  Your management told the investigator that the vials rejected are most likely non-integral, but had no documentation to support this  position.  Media fill reconciliation documentation should include a full description of units rejected from a batch and accounting for the rejection of each.

COMMENT:

Section IX, A-8 from the above Guidance also discusses this issue in detail wherein “When a firm performs a final product inspection of units immediately following the media fill run, all integral units should proceed to incubation.  Units found to have defects not related to integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected.  Erroneously rejected units should be returned promptly for incubation with the media fill lot.

After incubation is underway, any unit found to be damaged should be included in the data for the media fill run, because the units can be representative of drug product released to the market.  Any decision to exclude such incubated units (i.e., non-integral) from the final run tally should be fully justified and the deviation explained in the media fill report.  If a correlation emerges between difficult to detect damage and microbial contamination, a thorough investigation should be conducted to determine its cause (see Section VI.B).”

In the above Observation “management told the investigator that the vials rejected are most likely non-integral, but had no documentation to support this.”  All filled units should have accountability.

e.  Gloves used during manufacture of sterile products are used without adequate assurance of their sterility.  For example, during the inspection, the investigator evaluated the 18 inch gloves used during aseptic processing and found significant damage to the integrity of a large percentage of the boxes as well as the individual packaging for the gloves.  The investigator also noticed that one of the boxes containing individually packaged sterile gloves was incorrectly labeled as “non-sterile surgical gloves.”  Your quality management informed the investigator that these gloves are not sterilized prior to use in the aseptic manufacturing suites.  We are concerned that your environmental excursion investigations or other quality oversight did not uncover the potential for use of gloves whose sterility was compromised.

COMMENT:

Again, as before, a Company does not want an Investigator to become the Quality Assurance Unit for their organization.  Any damage to the primary sterile glove package violates the integrity of the container and potentially renders the container “non-sterile”.  Mis-labeling of gloves, e.g. sterile vs. non-sterile, questions the vendor who supplied the gloves as well as the vendor’s source.  The Investigator should not be identifying these issues for a Company.

“We are concerned that similar violations were found during a recent inspection February 12 through March 1, 2013 conducted at your Rocky Mount Hospira facility located in North Carolina, USA.  Please provide a current global corrective action plan for your facilities (US and foreign sites).  Include a comprehensive training module on aseptic process techniques for all employees involve in aseptic process operations and how you plan to measure the effectiveness of any training being provided.”

COMMENT:

When a facility such as Hospira has as many plants as they do involved in FDA inspections and Form FDA 483s, the request for a “current Global corrective action plan” and a “comprehensive training module on aseptic process techniques” should not come as a surprise.  Hospira has most likely become very proactive within this area and have a “Master List” that identifies issues not on the FDA’s hit list, but on their own which continually circulates Corrective Actions.