HEMOFARM A.D., VRSAC, SERBIA, RECEIVES WARNING LETTER (6/20/12) FOR ASEPTIC PROCESSING ISSUES

EXAMINE HOW THE REVISED USP<1116> RELATES TO THESE OBSERVATIONS

FIRM IS PLACED UNDER FDA IMPORT ALERT

Hemofarm A.D., Vrsac, Serbia recently received a four Observation Warning Letter for unreliable environmental (to include microbiological) monitoring data.  Several of the CGMP violations listed in their letter include similar violations to those cited in the May 2007 inspection.  The FDA requires that Hemofarm A.D. undertake a comprehensive and global assessment of their manufacturing operations to ensure that the drug products manufactured conform to FDA requirements.

In addition, Hemofarm A.D. was placed under a FDA Import Alert and the FDA will continue to refuse admission of all articles manufactured at their location until the firm’s manufacturing practices are verified to comply with CGMP’s.

FDA advised that Hemofarm’s inability to detect microbial contamination during aseptic processing constitutes a serious concern re: the environment.

1. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that (b)(4) drug product conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].

For example, your environmental monitoring data is not reliable. This is a serious deviation, as your ability to detect microbial contamination in the manufacturing environment during aseptic processing is fundamentally compromised. This information is critical to monitor the acceptability of the environment that the sterile drug and its container-closure components are exposed to during processing, and assure that these conditions consistently safeguard product sterility.

For example, several Observations involved desiccated media wherein:

a)   Over half of the plates documented on November 15, 2011 (155 of a total of 247) were dry and would not reliably support microbial growth,

b)  Plates observed on November 14, 2011 in the environmental incubator were desiccated and the results were described as “dried media”, but not the counts from the plates,

c)  Environmental monitoring data for January 2009 through October 2011 contained documentation of only two Action Limit excursions in the Grade A Manufacturing areas.  During the FDA visit on November 14, 2011, nine plates collected as part of the environmental monitoring program from the Grade A manufacturing were found inside the microbiology laboratory incubator with visible growth.

d) Diagrams of locations for surface samples are inadequately identified.

e)  Insufficient active viable and non-viable airborne samples were not collected from the critical area during manufacturing,

f)   Insufficient agar was present within contact plates (not providing a convex surface)  and, thereby, providing the possibility that the contact surface may not contact the media surface,

g) Melted agar lacks the control to assure that it is adequately cooled prior to being used for “pour” plates.  A “hand touch” is inadequate because the study method was not described.

COMMENT

The various components of Observation 1 describe fundamental laboratory issues that all Quality Control personnel should be aware.  USP<1117> Microbiological Best Laboratory Practices describes the fundamentals that individuals should be aware of when working within a facility where microbial analyses are performed.

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

For example, your firm utilized inadequate aseptic processing techniques during the water runs (Water Lots C100790 and C100811) conducted during the inspection. For example:

a)  Operator leaning over the top of (b)(4) containing filled opened sterile vials – thereby blocking the unidirectional airflow over the vials,

b)  Comprising of the connection’s sterility of the filling line by exposing the (b)(4) to the Grade B area during this aseptic connection,

c)  Transfer of uncovered (b)(4) between two separate Grade A areas while moving in between the two through a Grade B area,

d)  Wetting out of an operator’s gown from water spray and failure to change out the gown until FDA investigator’s intervention. 

COMMENT 

As within Observation 1 above, the issues observed and commented on by the FDA investigator are basic issues that all personnel working within an Aseptic Processing Area (APA) should be aware.  Also, with the issuance of the revised USP <1116>Microbiological Control and Monitoring of Aseptic Processing Environments, one should be able to follow this Guidance and minimize issues such as these observed by the FDA.

3.  Failure of a batch or any of its components to meet its specification whether or not the batch has already been distributed [21 C.F.R. § 211.192].

COMMENT 

The use of 21 C.F.R. § 211.192 is often cited by the FDA in a multitude of ways and its use with microbiological issues appears to be more of an exception than of a rule.  Often it pertains to other issues to include in-coming components, downstream processing, Active Pharmaceutical Ingredients (API), and final product — rather than this.

a)  Failure to conduct adequate investigations of three media fill failures in the aseptic filling line used to produce sterile products.

b)  Release of batches before the last successful media fill had been performed, and the impact of the contamination hazards revealed by these media fill failures on commercial batches.

c)   Inadequate investigations were conducted and not extended to other areas of the aseptic operation as part of the media fill evaluation wherein deficient design or control of rooms, equipment, or the Water for Injection system may have cause the introduction of Burkholderia cepacia.

4. Firm failed to have adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].

a)  Firm failed to have a procedure or process in place to evaluate the changes at your facility that might impact the quality of your product.

b)  The FDA investigators documented that the Quality Assurance did not evaluate the change to the (b)(4), later implicated in the media fill failure of Media Fill Lot (b)(4).

c)  Your response indicated that your firm is revising the Critical Material Management procedure to require Quality Assurance approval for all changes.

d)  Your response, however, failed to adequately describe the new procedures for review and approval of any changes to your production and process controls by Quality Assurance.

e)  In your response to this letter please provide a retrospective review of all the changes that occurred to your processes implemented without Quality Assurance approval since the initial validation, and the impact of these changes on the batches that remain within expiry and released for distribution to the U.S. market.

COMMENT 

The possession of adequate written procedures is essential for any manufacturing operation.  Hemofarm did not describe and provide the new procedures for review and approval of any changes to the production and process controls by Quality Assurance.  Thus, the FDA is requesting a retrospective review of all changes that occurred to the processes implemented without Quality Assurance approval since the initial validation, and the impact of these changes on the batches that remain within expiry and released for distribution to the U.S. market.