Inspections, Compliance, Enforcement, and Criminal Investigations
Pierre Fabre Medicament Production 3/26/10
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Silver Spring MD 20993|
VIA FEDERAL EXPRESS MAIL WL: 320-10-02
March 26, 2010
Mr. Jean-Paul Ithier
Plant Deputy Director
Pierre Fabre Medicament Production - Aquitaine Pharm International 2
50 Chem de Mazerolles
Idron, 64320, France
Dear Mr. Ithier:
During our September 1 through September 8, 2009 inspection of your pharmaceutical manufacturing facility, Pierre Fabre Medicament Production - Aquitaine Pharm International 2 located at 50 Chem de Mazerolles, Idron, 64320, France, investigators from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We have reviewed your firm’s response of September 29, 2009, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1) Failure to thoroughly investigate unexplained discrepancies (including a percentage of theoretical yield exceeding the maximum or minimum percentage established in the master production and control records) or the failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed. [21 C.F.R. § 211.192]. For example,
a) Aloxi (Palonosetron HCl) injection batches (b)(4) failed to meet the yield limits; no root cause was identified.
In particular, batches (b)(4) failed to meet yield limits of (b)(4)%– (b)(4)%. Validation batches (b)(4) reported yield out-of-limit (OOL) values of (b)(4)%, (b)(4)%, and (b)(4)%, respectively. You indicated that the result obtained for batch (b)(4) was due to a high particle per volume content documented during manufacturing and product visual inspection of the vials. However, the root cause for the increased number of particles in the product remains unclear. There is also no information regarding the overall impact of the problem in the quality of the product, or the corrective actions implemented to prevent recurrence of the problem. You identified the defect but were unable to determine the root cause. In addition, you failed to assess the product yield OOL values documented for batches (b)(4).
Because your firm was unable to determine the root cause of the yield OOL values in the first validation batch ((b)(4)), you could not implement corrective and preventive actions for the subsequent batches. Consequently, the second and third validation batches ((b)(4)) and ((b)(4)) also reported yield OOL values.
b) Out-of-limit results obtained during the in-process fill weight examination for validation batches (b)(4) were not investigated.
Specifically, you reported 31 in-process fill weight OOL results for validation batch (b)(4), while reporting 11 and 3 OOL results for batches (b)(4), respectively. In addition, the batch record does not contain any evidence that you evaluated the in-process results to determine the impact of the out-of-limit fill weight results in product quality.
During our review of data pertaining to the validation of batch (b)(4), we noted the use of two different in-process fill weight specifications. On December 17, 2008, the fill weight record reflects that the specification for fill weight was (b)(4)g – (b)(4)g, but on December 18, 2008, the specification used was (b)(4)g – (b)(4)g. The investigator noticed that for batch (b)(4), you reported a total of 31 OOL results in the fill weight, but failed to conduct an investigation. In your response to this letter, please clarify which limits are correct, the scientific rationale for using two different limits, and the resulting impact on the product filled using the incorrect limit.
c) During the filling of validation batches (b)(4), you obtained OOL results for the non-viable particle (NVP) count of 0.5 μm and 5.0 μm particles,
but did not adequately investigate these results.
In batch (b)(4), the monitoring data for non-viable particles reported a maximum value of 10,319 particles. This result was obtained in a critical area—class 100 (ISO 5)—where the recommended limit for 0.5 μm particles is 3250/m3 particles.2 You failed to investigate these NVP excursions and determine the impact on product quality or its possible relation to the higher particulate content observed in batch (b)(4). During the inspection, your firm provided the investigator a copy of procedure 15.89.01/1 “NVP Monitoring.” This procedure was made effective on June 18, 2009, approximately seven months after you manufactured the validation batches.
d) A self-check test of validation batches (b)(4) reported 19 and 6 trays, respectively, with critical defects (particles) during your routine visual inspection evaluation. No investigation was conducted.
The intent of the self-check test is to challenge the operator effectiveness in the visual inspection process. You conducted a 100% visual inspection after inspecting the batches twice in the Brevetti automatic visual machine. Your investigation report number 6237 indicates that batches (b)(4) were 100% re-inspected, however, you failed to document such re-inspection. You also failed to evaluate the impact of the particle content on the quality of batches (b)(4).
Your procedure for the visual inspections of filled vials is inadequate in that it fails to demonstrate adequate control (detection) of critical defects (particles) in vials. We are concerned that you found vials with critical defects (particles) after two Brevetti automatic inspections and a 100% visual inspection conducted by your manufacturing operators. We are also concerned with your OOL yield, the number of particles per volume in your product, and the effectiveness of your visual inspections. Your QCU failed to ensure that manufacturing deviations documented in the validation studies were investigated in a timely manner. Your response states that you implemented corrective actions and that you will manufacture a mock batch to demonstrate validation of the Aloxin manufacturing process. We disagree that performing validation studies of an additional batch is sufficient to show that the process is validated. Provide us the root cause analysis of this deviation and any implemented corrective
actions, and address our aforementioned concerns.
2) Your firm has not established and followed written procedures that describe the in-process controls, tests, or examinations to be conducted on appropriate samples of in-process materials to monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product [21 C.F.R. § 211.110(a)].
For example, as referenced in violation number 1 of this letter, your process validation, which consists of compounding, vial washing/depyrogenation, filling, capping, sterilization, and visual inspection for Aloxi (Palonosetron HCI) injection resulted in a high vial rejection rate. Additionally, a lack of NVP monitoring with OOL results was reported, as well as fill weight discrepancies. This is all an indication of deficient process controls in a non-validated manufacturing process.
We are concerned that you have not conducted a thorough investigation involving all three Aloxi (Palonosetron HCI) validation batches. Your response indicates that the batches met the 100% visual inspection, chemical-physical specification, and microbial controls, and you concluded that the product possesses the necessary quality attributes to be released. We disagree with this conclusion because quality must be built into the product throughout the manufacturing process. Testing alone is not sufficient to demonstrate that the process is validated, particularly when discrepancies such as the ones described above were observed. It appears that your process is not capable of consistently producing acceptable quality products, in light of your firm’s numerous OOL results.
We acknowledge your response dated September 29, 2009, which states that after you review the results from the mock batch, you will make a decision on market release of the three validation batches. We are concerned with your decision to release the Aloxi (Palonosetron HCI) product validation batches based on the mock batch results. Your validation studies demonstrated the lack of reproducibility and failure to consistently manufacture Aloxi (Palonosetron HCI) in compliance with CGMP. We recommend that you conduct a thorough evaluation of your initial Aloxi (Palonosetron HCI) validation studies and execute a second process validation study to ensure validation of the manufacturing process.
3) Your firm fails to follow written production and process control procedures during the execution of production and process control functions [21 C.F.R. § 211.100 (b)].
For example, procedure 03.24.07/8 “Manual Visual Inspection of Anti-Cancer Products in Idron Sites” for visual inspection of product vials states that the inspection be conducted in (b)(4) minute intervals, with (b)(4) minutes for an eye-resting break. This procedure also states that each individual vial be inspected for (b)(4) seconds ((b)(4) seconds against a black background and (b)(4) seconds against a white background). During the review of the marketed product (b)(4), the investigator observed that none of the (b)(4) mg injection batches met the elapsed time requirement. Specifically, batch record 100464 indicated that (b)(4) vials were inspected in a period of 8 hours and 45 minutes. On April 23, 2008, (b)(4) vials were inspected in the same time interval (8 hours and 45 minutes). Based on procedure requirements of (b)(4) seconds per vial, (b)(4) vials would have taken a minimum of 12 hours, while (b)(4) vials would have taken approximately 17 hours. The calculation does not take into account the eye-resting break mentioned in your procedure 03.24.07/8. We are concerned with the operator’s practice and how the results are reported. Your QCU failed to ensure that the visual inspection elapsed time is in accordance with your approved procedure.
Your written response indicated that you plan to train operators in procedure 03.24.07/8 “Manual Visual Inspection of Anti-Cancer Products in Idron Sites.” However, your response fails to indicate whether you conducted an investigation to address the discrepancies. Please provide evidence that you have addressed the visual inspection discrepancies in the elapsed time taken by the operator.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, this office will recommend withholding approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, failure to correct these violations may result in FDA denying entry of articles manufactured at Pierre Fabre Medicament Production - Aquitaine Pharm International 2, 50 Chem de Mazerolles, Idron, 64320, France into the United States. The articles could be subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)], in that, the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Please identify your response with FEI #3004136115.
If you have questions or concerns regarding this letter, contact Rafael Arroyo, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51
10903 New Hampshire Ave.
Silver Spring, MD 20993
Tel: (301) 796-3671
Fax: (301) 847-8741
Teddi Lopez on behalf of Richard Friedman
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
1Your record documented additional excursions in non-viable particles
2See Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice