Departmentof Health and Human Services PublicHealth Service Rockville, MD 20857
Warning Letter
WL: 320-02-01
November 21, 2002
Mr. Alexander B. Bell
Vice President Technical Operations
Mayne Pharma Pty., Ltd.
1-23 Lexia Place
Mulgrave North, Melbourne, VIC 3170
Australia
Dear Mr. Bell,
This letter is in response to an inspection of your pharmaceutical manufacturingfacility in Melbourne, Australia, by the United States Food and Drug Administration(FDA) on, April 8-16, 2002. This inspection revealed significant deviationsTom U.S. Current. Good Manufacturing Practices (CGMP) Regulations (Title 21CFR, Parts 210 and 211) in the manufacture of sterile drug products. At thecompletion of this inspection, you were issued a 46-item Inspectional Observations(FDA-483) form. These CGMP deviations cause your drug products to be adulteratedwithin the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and CosmeticAct.
Our review also included your May 21, 2002, August 22, 2002 and October 11,2002 written response letters to the FDA-483 observations. We acknowledge thecommitments to correct the deficiencies; however, the response lacks sufficientdetails, explanations, and documentation to address the deviations observedduring the April 2002 inspection.
In addition, we have the following concerns that include, but are not limited to:
1. In the last two years there were 11 product sterility failures involvingthe organism [redacted]. The investigations into these routine results foundno assignable cause or the sterility failures. Some of the failures involved[redacted] sterilized products that included [redacted]. There were no correctiveactions identified in these investigations and the batches were released onthe basis of the survivor test. [21 CFR 211.192]
The production department conducted no investigations, although the productionsystem could not be ruled out as the potential cause of the product contamination.The response stated that no probable cause was identified in four investigations,i.e., no conclusive evidence that the failure was due to either laboratory orproduction error therefore corrective action could not be documented. In threeinvestigations the most probable cause for the sterility positives was deemedto be laboratory error. Further, you acknowledged at a minimum retraining ofboth production and laboratory staff should have taken place, as a correctiveaction. The response also indicated that extended review of trends for sterilityfailures was not undertaken, but will be considered as a corrective action inany future investigations.
In not addressing probable causes and not initiating corrective actions thefirm failed to identify the cause of the contamination and neglected to insurethat this type of problem would not recur. Furthermore, the drug products thatwere released failed to meet their established standards or specifications andhad no assurance to be free of objectionable microorganisms.
In the three investigations for which the sterility positives were deemed tobe laboratory errors, the investigations failed to identify the type of errorsor relate them to laboratory errors. In these three cases, the firm identifiedthe sterility positives as laboratory errors only because the product was [redacted]sterilized. The firm failed to implement any corrective actions to insure thatthe laboratory errors would not occur in the future.
2. The test methods used for sterility testing are inadequate. [21 CFR 2 11.165]There is a lack of data to demonstrate that the methods are capable of recoveringlow levels of organisms that would be found in a typical non-sterile drug product.The study summaries and raw data lacked any counts for the inoculated controlsand samples, and there is insufficient data to interpret whether the productinhibits growth of organisms. The reproducibility of the method was not demonstrated.For example, only one result following a negative recovery was used to validatethe [redacted] Method.
It was also noted that you have not completed [redacted]
Validation for 7 of 15 products with [redacted]
In the August 22, 2002 response, it states that the methodology complies withthe requirements of USP Sterility Test [redacted] Validation for [redacted].It clarified that the counts used to initially inoculate the test and controlsamples are quantified, but you don?t explain how the procedure is done. Italso states that an update to the validation requirement such that three validationtests will be performed in order to comply with the requirements of Validationof [redacted] from Pharmacopeial Articles [redacted].
Further, the response included a commitment to repeating the Validation for [redacted] testing three times for any new formulations/presentations. The validation will be performed twice on existing products the next time the batches are manufactured. As to the products requiring [redacted] inclusion in the validations, this will be scheduled for the next production batches being produced.
Until this validation is completed, the sterility test methods used are inadequatein that there is no documentation, which demonstrates the accuracy and repeatabilityfor [redacted] from Pharmacopeial Articles. Also there is no assurances thatthe sterility positive &Its identified as errors were accurate assessmentsbecause of the inadequacy of the test methods.
3. written procedures designed to prevent microbiological contamination ofsterile drug products were inadequate and resulted in: [21 CFR 211.113]
- inadequate monitoring of differential air pressures between clean rooms
- inadequate support of changes for the movement of walls and HVAC modifications made to the [redacted] facility
- inadequate controls and procedures for gowning
- inadequate validation of the sterilization process in no microbiological qualification or determination of the resistance of the biological indicator challenge system was performed for [redacted]
The responses and commitments made by the firm to correct these deficienciesin item #3 appear adequate. However, this raises concerns about the QualityControl Unit. We remind you of their responsibilities in reviewing and approvingail procedures related to production, quality control, and quality assuranceto assure the procedures are adequate for their intended use.
The CGMP deviations identified above or on the FDA-483 issued to your firmare not to be considered an all-inclusive list of the deficiencies at your facility.FDA inspections are audits, which are not intended to determine all deviationsfrom CGMPs that exist at a firm. If you wish to continue to ship your productsto the United States, it is the responsibility of your firm to assure compliancewith all U.S. standards for Current Good Manufacturing Practices.
Failure to correct these deficiencies may result in FDA denying entry of articlesmanufactured by your firm into the United States. The articles could be subjectto refusal of admission pursuant to Section 801(a)(3) of the Act in that themethods and controls used in their manufacture do not appear to conform to CurrentGood Manufacturing Practices within the meaning of Section 501(a)(2)(b) of theAct.
Please respond to this letter within 30 days and provide documentation regardingcorrections of the above deviations. Your response should include data collectedin your corrections to the deficiencies cited as well as copies of proceduresnot already included.
Please identify your response with CFN 9610999. Until FDA can confirm compliancewith CGMP?s and correction to the most recent inspection deficiencies, thisoffice will recommend disapproval of any new applications listing your firmas the manufacturer of sterile drug products.
Please contact Anthony A. Charity, Compliance Officer, at the address and telephonenumbers shown below, if you have any questions, written response or concernsregarding these decisions:
U.S. Food & Drug Administration
CDER HFD-322
7520 Standish Place
Rockville, MD 20855-2737
Tel: (301) 827-0062; FAX (301) 594-1033
To schedule a re-inspection of your facility, after corrections have been completedand your firm is in compliance with CGMP requirements, send your request to:International Operations Branch, HFC-132, 5600 Fisher?s Lane, Rockville, MD,20857. You can also contact that office by telephone at (301) 827-5655 or byfax at (301) 443-6919.
Sincerely,
/s/
Joseph C. Famulare
Director
Division of Manufacturing and Product Quality
Center for Drug Evaluation and Research
Departmentof Health and Human Services