Warning Letter: Pliva

On April 28, the US Food and Drug Administration's Center for DrugEvaluation and Research (Rockville, MD, www.fda.gov/cder)issued a Warning Letter (www.fda.gov/cder/warn/2006/320-06-02.pdf)to Pliva Hrvatska d.o.o., a subsidiary of  Pliva d.d. (Zagreb,Croatia,  www.pliva.com).The six-page letter, which FDA posted on May 5, refers to a variety ofshortcomings noted during inspections conducted Jan. 23 through Feb. 8,2006, as well as in August 2002:

• Maintenance of facilities used to manufacture injectabledrugs (21 CFR 211.58),including water dripping from a light fixture in a Class C injectableproduction area and torn flexible piping.

• Cleaning and maintenance ofequipment (21 CFR211.67.a), including failure to demonstrate the effectiveness ofdisinfectants used and equipment observed in-use with alarm lights lit.

• Instrument calibration(21 CFR 211.160.b.4),including failure to calibrate equipment used in sterilization.

• Justification of deviationsfrom written specifications (21 CFR 211.160.a), specificallyinconsistencies in standards used to evaluate cleaning swabs andsolvent tests.

• Establishing scientificallysound and appropriate test procedures for identity, strength, quality,and purity (21 CFR211.160.b), including errors in hold-time studies and microbiologicaltests.

• Adhering to test procedures(21 CFR 211.160.a).

• Laboratory record keeping(21 CFR 211.194.a).

• Investigation of unexplaineddiscrepancies in tests of batches or components (21 CFR 211.192), including delays ofup to several months in studying a two-hour process stoppage, use of anincorrect program in testing, and an equipment failure.
  

In a May 8 statement, Pliva said that it was "addressing this issuevery seriously and is in the process of implementing a correctiveaction plan, which was submitted to the FDA in April and which, exceptas stated in the warning letter, has been accepted by the FDA."

According to the statement, Pliva does not expect any disruption indelivery of finished dosage forms and active pharmaceutical ingredientsto Pliva Inc. (its US subsidiary) or other customers. Though thecompany does anticipate that FDA will not approve any of Pliva'spending abbreviated new drug applications (ANDA) until the issues areresolved, the company "does not currently expect this to have anymaterial impact on the Company's financial outlook for 2006."