PHARMACEUTICAL COMPANY JELFA SA (POLAND) RECEIVES WARNING LETTER (7/14/11) PART II

JELFA SA FAILS TO FOLLOW FDA’S ASEPTIC PROCESSING GUIDANCE FOR INDUSTRY (SEPTEMBER 2004)  

2.  Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)]. For example, 

a. During the aseptic filling of two injection batches on filling line (b)(4), where (b)(4) injection for the U.S. is filled, employees were observed following poor aseptic techniques.  Specifically, movements inside the class A area were not slow and deliberate; operators and an engineer were observed with exposed facial skin during the filling operation; and a forcep was observed in a class B (ISO 6) area and was then used to remove fallen ampoules from the aseptic processing line in the class A (ISO 5) area. 

COMMENT 

Appropriate written procedures to prevent microbiological contamination should be in place and followed.  FDA’s Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing, CGMP (September 2004) specifically addresses the issues of slow and deliberate movement by personnel within an ISO Class 5 environment, proper gowning to eliminate any showing of “skin” and the movement of sterile forceps between an ISO Class 6 and 5 environment. 

b. Employees who perform critical duties in your aseptic filling line (b)(4) did not participate in an (b)(4) line qualification (process simulation) during 2010, 2009, and 2008. 

COMMENT 

Employees who participate in product fills in an aseptic processing environment should participate in the media fills when the aseptic process is being qualified and then on at least one media fill per year (see Aseptic Processing Guidelines, September 2004).  Not having personnel participate in these media  fills (Process Simulations) demonstrates a lack of understanding of FDA’s Guidance. 

c. The tubing ends used to connect the solution tanks to the filling line (b)(4) are not protected prior to sterilization to reduce the potential of contamination after sterilization, and prior to the aseptic connection. 

COMMENT 

A lack of sterile technique is demonstrated by the above Observation.  Connections such as those noted above should be protected. Tubing “welders” are available to assist in providing sterile connections. 

d. The disinfectant efficacy studies have not been completed for three of the (b)(4) disinfectants used to sanitize surfaces in the sterility testing suite and production aseptic core filling line (b)(4). 

COMMENT 

Disinfectant Efficacy Studies should be considered as a fundamental requirement during the development of  Qualifications of  disinfectants on various surfaces with both ATCC and in-house isolates. These disinfectants should be used on each of the surfaces the disinfectants will potentially contract within the sterility testing suite. 

Your response indicates corrective action through training employees, equipment purchase, and procedural improvements. However, your response fails to specifically address the observed deficiencies and whether the products already distributed have been evaluated.  

COMMENT 

An organization cannot operate within a “silo” when the FDA provides an Observation.  Product that has been released, exists in-house and released or in-process should be considered when an Observation impacting all product occurs. 

3.  The quality control unit does not adequately exercise its responsibilities to approve procedures or specifications that may impact the identity, strength, quality, and purity of the drug product [21 C.F.R. §211.22(c)]. For example, 

There was inadequate oversight of the media fill process conducted for batch #(b)(4).  Furthermore, the “responsibility” section of procedure JZ-V/JK-053, Validation of Aseptic Manufacturing and Filling Process Using the PST (media fill), makes no mention of the quality control unit having an active role in the oversight of media fill studies. 

COMMENT 

The Quality Control Unit (QCU), whether it be Quality Assurance or Quality Control, should play an active role and have representative(s) present during any media fill as observers or actively involved in the sampling of gloves, changing of airborne viable plates and settling plates as well as monitoring the non-viable airborne particulates. 

Your response indicates that procedural corrections will be implemented.   Please provide more information in your response regarding how the quality control unit’s role has evolved including describing its function relating to observation and approval of media fills (e.g., recent March 2011 media fills). 

We note that the CGMP violations listed in this letter include similar violations to those cited in the previous inspection in February 2008, and in our letter to you dated July 17, 2008. For example, 1) unqualified operators involved in aseptic filling operations (no media fill participation), 2) inadequate environmental monitoring practices, 3) failure to adequately conduct disinfectant efficacy studies, and 4) inadequate quality control unit oversight. 

COMMENT 

The FDA takes a very dim view when they find that previous CGMP violations are similar to current violations (See H&P Industries, Ranbaxy India, and Deltex Pharmaceuticals as additional examples).  Repeat violators often will find themselves receiving Warning Letters (as with this Warning Letter) or worse to include seizures, import bans and Consent Decrees. 

We remind you that it is your responsibility to implement sustainable corrective actions to ensure that you firm’s drug manufacturing operations are in compliance with the applicable requirements, including the CGMP regulations. FDA expects Pharmaceutical Company Jelfa SA to undertake a comprehensive assessment of the manufacturing operations to ensure that drug products conform to FDA requirements. 

We are particularly concerned with your firm’s failure to implement a robust Quality System. Repeat citations from prior inspections indicate that your quality control unit is not exercising its responsibilities, and may not have the appropriate authority to carry out its responsibilities. Due to continuing CGMP issues at your firm, we recommend you engage a third party consultant having appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems to ensure that your drug products consistently meet standards for identity, strength, quality, and purity. 

COMMENT 

The FDA can make recommendations as noted in the previous paragraph regarding the “engaging of a third party consultant having appropriate CGMP expertise”.  However, the company may follow their own prerogative — even if puts them at significant cGMP risk to include an import ban.   

In addition to the items listed above, this inspection identified other worrisome deficiencies. These deficiencies include, but are not limited, to:  inadequate vendor qualification of your API suppliers and inadequate smoke study results for aseptic filling line (b)(4).