Inspections, Compliance, Enforcement, and Criminal Investigations
Sanochemia Pharmazeutika AG 19-Nov-06
Department of Health and Human Services
Public Health Service
Center for Biologics Evaluation and Research
November 19, 2006
Ms. Susanne H. Kolar
Head of Quality Assurance
Sanochemia Pharmazeutika AG
A-2491 Neufeld/Leitha, Austria
Dear Ms. Kolar:
The Food and Drug Administration (FDA) conducted an inspection of Sanochemia Pharmazeutika AG, located at A-2491 Neufeld/Leitha, Austria, between May 9 and May 15, 2006. At the close of the inspection, FDA issued a Form FD 483, Inspectional Observations, that described a number of significant objectionable conditions relating to your facility's compliance with Title 21, Code of Federal Regulations, (21 CFR) Parts 600-680, with the Quality System Regulation in 21 CFR Part 820, and with statutory provisions applicable to the manufacture of in vitro diagnostic devices. Those statutory provisions include Sections 501(h) and 520(f)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and Section 351 of the Public Health Service Act (PHS Act).
Regulatory violations observed during the inspection include, but are not limited to, the following:
1 . Failure to develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications and failure to establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications, including documented instructions, standard operating procedures (SOPs) and methods that define and control the manner of production [21 FR820.70 (a)] and failure to maintain records concurrently with each step in the manufacture and distribution of products [21 CFR 600.12 (a)] in that:
a. Alarms for out-of-temperature specification events of incubators, refrigerators and freezers are audible only in the vicinity of the equipment, and there is no system in place to notify employees of these alarms after hours or over the weekend. Audible alarms due to out-of-limit temperatures are not documented and product impacted by those out-of-limit temperatures is not evaluated. Further, the timeframe to review occurrences of alarm activation, established in your SOP #DG-IN-0010-4D, entitled [redacted] does not allow for timely response to incubator, refrigerator, and freezer alarms.
b. Your records do not show that you follow the instructions on form D-401/4, entitled "Fluorognost HIV-1 Slide Performance Testing," which instructs, [redacted]slides were tested for [redacted] and [redacted] but a test result for only one of the [redacted] slides was documented on December 7, 2005. Even if the one recorded test result does represent the average for the [redacted] tested slides, your failure to record the individual result for each of the [redacted] slides tested violates your process control procedures. Further, your company's Head of Microbial Quality Controlled told investigators that the infection rate documented in the batch record is the average of the [redacted] slides, but there is no documentation to provide assurance of the calculation of this average.
c. On December 2, 2004, 16 Batch Release Assays were performed for Fluorognost Batch# [redacted] test kits, but only one test result is documented.
2. Failure to establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have adverse effect on product quality [21 CFR 820.70 (e)], in that OOS microbial test results for glove and surface samples in the Grade [redacted] Area of the Diagnostic Production Department are not being evaluated for product impact. Reagents in the Fluorogonost it affected by these OOS results include:
a. Positive Serum Control Batch #[redacted]
b. Negative Serum Control Batch #[redacted]
c. FITC Concentrated Conjugate Batch [redacted]
d. Mounting Media and FITC Batch [redacted] and [redacted]
3. Failure to establish and maintain a procedure for submitting Biological Product Deviation Reports (BPDRs) to CBER [21 CFR 600.14].
4. Failure to establish and maintain procedures for implementing corrective and preventive actions by failing to investigate the cause of nonconformities relating to product, processes and the quality system [21 CFR 820.100 (a) (2)] . Investigation # DG-05/0l was initiated August 22, 2005 due to out of specification (OSS) test results for [redacted] and [redacted] of Mounting Media, Lot # [redacted] but did not include investigation of the [redacted] result.
5. Failure to maintain device history records, including the quantity manufactured and the quantity released for distribution [21 CFR 820.184 (b) and (c)], in at you did not reconcile and document the number of Fluorognost batch [redacted] slides manufactured, used for release testing, and/or designated for retention samples.
6. Failure to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit and failure to process complaints in a timely manner [21 CFR 820.198 (a)], in that:
a. Complaints received in 2004 and 2005 were not immediately forwarded to the Quality Assurance Department as is required by your SOP #QA-AD-0002-3E entitled "Complaint Handling." These complaints were not processed until April 26 2006, and they include # N-R-DG-04/02; N-R-DG-04/ 3; N-R-DG 05/01; N-R-DG-05/03; N-R-DG-05/04; N-R-DG-05/05 .
b. Batches associated with complaints, classified as Class 3 Complaints, were not quarantined in the [redacted] system during failure investigation, as is required by your SOP #QA-AD-0002-3E. The Class 3 Complaints include N-R-DG-04/02; N-RDG-05/04; N-R-DG-05/05.
This is a similar deviation to Form FDA 483 item #9 from the June 17-23, 2004 Team Biologics inspection.
7. Failure to evaluate complaints to determine whether the complaint represents an event which is required to be reported to FDA under 21 CFR Part 803, Medical Device Reporting [21 CFR 820.198 (a) (3)] . Your SOP #SC-SI-0009-1E entitled, "Medical Device Reporting (MDR) to FDA," clearly defines expectations of medical device reporting to the FDA; however, it was noted during the inspection that your Quality Assurance Department did not appear familiar with the full range of events that must be reported to FDA. Consequently, there is no assurance that complaints have been evaluated properly to determine the need for Medical Device Reporting.
8. Failure to maintain adequate records of investigations of complaints, in that your records do not include any reply to the complainant [21 CFR 820.198 (e) (8)].
9. Failure to establish and maintain a quality system that is appropriate for the specific medical device(s) designed or manufactured, and that meets the requirements of this part [21 CFR 820.5]. Examples include:
a. No procedure has been established for BPD Reporting.
b. Failure of Quality Assurance to capture deviations in equipment qualification reports.
c. Nonconformities are not investigated at the time of the deviation.
d. Complaints are not processed in a uniform and timely manner.
e. Complaints are not evaluated for Medical Device Reporting.
Additional objectionable conditions from current good manufacturing practice in the manufacture of Fluorognost were observed during the inspection. Specific areas of concern include, but are not limited to:
PRODUCTION AND PROCESS CONTROLS
1. Your SOP # DG-IN-0008-2E, entitled "Preparation and Maintenance of the [redacted] Master and Working Cell Banks," is not being followed. Test requirements specified in the procedure are not requirements on your Form D-451/2, "'Production Protocol and Batch Record Form for Working Seed Bank Cells." These test requirements include: [redacted]
2. Temperature specifications for [redacted] used to store the [redacted] Cells Master and Working Seed Banks have not been established. Further, [redacted] alarms are not routinely calibrated, and there is no system in place for monitoring [redacted] alarms during the weekend.
This is a similar deviation to Form FDA 483 item #4, from the June 17-23, 2004 Team Biologics inspection.
CORRECTIVE AND PREVENTIVE ACTION
3. A vial from [redacted] Cell Working Seed Bank, Lot #[redacted] was used for initiation of a cell culture on January 18, 2005, but was aborted due to failure to meet viability specification of [redacted]. Rather than launching an investigation immediately, the investigation was initiated on April 27, 2006, and the reason for failure was not investigated. This lot remains in inventory, yet there has been no evaluation of the Working Seed Bank or restrictions placed on its use.
This is a similar deviation to Form FDA 483 item #2 from the June 17-23, 2004 Team Biologics inspection.
4. A vial from [redacted] Cell Working Seed Bank, Lot # [redacted] was used for initiation of a cell culture, but was discarded due to low density. This lot remains in inventory, yet there has been no evaluation of the Working Seed Bank or restrictions placed on its use.
This is a similar deviation to Form FDA 483 item #2 from the June 17-23, 2004 Team Biologics inspection.
DEVICE HISTORY RECORD MAINTENANCE
5 . Dates of manufacture of Master Cell Banks (MCBs) and Working Cell Banks(WCBs) are not documented. These MCBs and WCBs include:
a. [redacted] Master Seed Bank lot # [redacted]
b. [redacted] Working Seed Bank lots: [redacted]
c. [redacted] Cells Master Seed Bank lots: [redacted]
d. [redacted] Cells Working Seed Bank lots: [redacted] and [redacted]
e. [redacted] Bank lots: [redacted]
The deviations identified above are not intended to be an all-inclusive list of deficiencies at your establishment. It is your responsibility as management to assure compliance with all requirements of the federal regulations and the standards in your license. While these deviations were documented during the most recent inspection of your facility, we note that similar significant deviations were documented during the inspection of June 17-23, 2004, as noted above. We also note that your firm promised corrective actions in response to the Form FDA 483 issued at the close of the June 2004 inspection, but the recent inspection has shown that adequate and effective corrective actions have not been implemented.
Federal agencies are advised of the issuance of all Warning Letters about drugs and devices so that they may take this information into account when considering the award of contracts.
We acknowledge receipt of your written response dated July 14, 2006, which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection. We have reviewed your response and the accompanying documents. Corrective actions addressed in your response may be referenced in your reply to this letter, as appropriate; however, your July 14, 2006 response did not provide sufficient detail to fully assess the adequacy of many of your corrective actions, as we discuss specifically below. Further, we note that your proposed timeframes for implementation of corrective and preventive actions are exceptionally lengthy, for example, the proposed timeframe for implementation of corrective action for numerous observations is May 31, 2007. We recommend that you reevaluate and shorten these timeframes where possible. Additionally, the modifications and enhancements to your operations, described in your response, should be detailed in the appropriate written SOPs.
We have the following specific comments regarding your response. The items are numbered to correspond to the observations listed on the Form FDA 483.
FDA 483 item #1
Your response neither addressed why failure investigations were not completed nor the implementation of corrective actions. Please provide comments.
FDA 483 item #1.A.1
Your response states that you will implement a new SOP describing procedures in the event of a cooling unit OOS. Please address the lack of alternate power for cooling units and incubators.
FDA 483 item #1.A.2
Your response states that you will retest all [redacted] batches of supernatants against all standard release panels by May 31, 2007. The completion date for this testing appears excessive, and we recommend that you reevaluate your proposed timeframe so that this testing is completed in a more timely manner.
FDA 483 item #1.A.3
Your response states that you will implement a follow-up stability program for the [redacted] batches of supernatant by May 31, 2007. The completion date for implementation of a stability program appears excessive, and we recommend that you reevaluate your proposed timeframe so that this program is initiated in a more timely manner.
FDA 483 item #1.A.4
Your response states that a new freezer which will only be used for back-up has been acquired and is in the process of being qualified. You also state that the logbook which documents the stored supernatants will be updated. You indicate at "Every single batch will be documented including the number of vials, the amount per vial, and the storage place. The amount per vial will correspond to the amount which is needed for the production of one batch so that there will be no left over and the vial is totally used up." You failed to address the claim that the referenced product was no exposed to the cited temperature deviation. Please provide documentation of alternate storage of Supernatant lot # [redacted]
FDA 483 item #1.B.1
Your response states that you will report investigation #N-I-DG-05/02 in the 2005 Annual Product Review. Please clarify whether you are planning to submit a revised Annual Report and provide the time frame within which you will make this submission. Additionally, your response did not address your failure initiating a timely investigation. Please provide details of the steps you will take to prevent reoccurrence of such.
FDA 483 item #1.B.3
Your response states that the [redacted] Cell Working Seed Bank, lot [redacted], will be evaluated retrospectively and the evaluation attached as an annex to the investigation, and that parameters of the cell culture will be checked again by May 31, 2007. The completion date for this evaluation appears excessive. We recommend that you reevaluate your proposed timeframe such that this evaluation is completed in a timely manner.
FDA 483 item #2.A
Your response states that a batch clearing will be performed for the cell banks and supernatant, and that for remaining batches, testing according to the relevant SOPs or production procedures will be performed. Your response further states that historical data will be compiled and documented when possible; old batches will be kept for research purposes and stored separately; and documentation of the storage will be logged by May31, 2007. The completion date for this corrective action appears excessive, and we recommend that you reevaluate your proposed timeframe such that this action is completed in a more timely manner.
FDA483 item #2.B
Your response states that you will perform [redacted] as required by your SOP #DG-IN-0008-2E entitled "Preparation and Maintenance of the [redacted] Master and Working Cell Banks’ by May 31, 2007. You also state that in the future the new cell batches will be checked according your updated SOP. Please provide details regarding updates to your SOP and to Form D-451/2. Additionally, please address not having performed a [redacted] test on this lot, [redacted] testing, as required by your SOP. The completion date of May 31, 2007 for this corrective action appears excessive, and we recommend that you reevaluate your proposed timeframe such that this action is completed in a more timely manner.
FDA483 item #2.C
Your response states that you will characterize [redacted] Cells, according to SOP DG-IN-0011, and that lots # [redacted] will be checked retrospectively in accordance with your SOP #DG-IN-0011 entitled "Preparation and Maintenance of the [redacted] Master and Working Cell Banks" by May 31, 2007. The completion date for this corrective action appears excessive, and we recommend that you reevaluate your proposed timeframe such that this action is completed in a more timely manner.
FDA 483 item #2.D
Your response states that the temperature specifications for the [redacted] Cells Master Seed Bank and the [redacted] Cell Working Seed Bank will be defined and set in correlation with the weight of [redacted] in the [redacted] so that there can be proof that the upper limit for the storage specifications will be met, at which the weight of the [redacted] would not be exceeded by May 31, 2007. The completion date for this corrective action appears excessive, and we recommend that you reevaluate your proposed timeframe such that this action is completed in a more timely manner. Further, you failed to address the specific issues in that you did not address alarms being audible only in the manufacturing area, and your inability to monitor alarms over the weekend. Additionally, you neither addressed the means by which you will determine when alarms are generated nor the means of determining the internal temperatures of the cell banks upon identification of an alarm. Also, you failed to address routine calibration of alarms. Please provide specific details of corrective actions that you will take to address these matters.
FDA 483 item #3
Your response states that a reply to the complainant will be attached to the complaint files. Please clarify whether you intend to revise your SOP accordingly. Also your response states that you retroactively documented complaints of 2004 and 2005 will be listed, described, and attached to the Annual Product Reviews of 2004 and 2005. Please clarify whether you intend to submit amended Annual Product Reviews to CBER.
FDA 483 item #4.A
Your response states that Production Protocol D-451 will be updated and forwarded to FDA with your 2006 Annual Product Review. However, you failed to address the lack of authorized approval for the changes that you made, and you failed to explain how you plan to prevent such omissions in the future.
FDA 483 item#4.C
Your response states that SOP DG-IN-0008, entitled "Preparation and Maintenance of the [redacted] Master and Working Cell Banks" and the Production Protocol, D-451 will be adapted to each other. Please describe the changes you make.
FDA 483 item#5.A
Your response states that production protocols will be adapted. Please provide specific details regarding how you intend to modify your protocols.
FDA 483 item #5.B
Your response states that in the future, release testing of batches will be performed, checked, and signed by two technicians and the Qualified Person (QP). Please indicate whether this requirement will be included in the appropriate SOP. If so, please provide a copy of your revised SOP.
FDA 483 item#5.C
Your response states that the batch number of the [redacted] test kits will be documented retrospectively, and the QP will check and sign the tests retrospectively. Please indicate whether this requirement will be included in the appropriate SOP.
FDA 483 item #5.E
Your response states that in the future, stability testing will be performed, checked, and signed by two technicians and the QP. Please clarify whether this requirement will be specified in an SOP.
FDA 483 item #5.F
Your response states that alarm log books will be utilized, which will include documentation of the occurrence of an alarm and the kind and duration of the alarm. According to your response, the impact of the duration of the alarm on concerned goods must be evaluated and documented. You also state that if the alarm exceeds the duration limit, an action must be performed to avoid damage to the goods, and that this action must be documented. You also state that a system will be implemented to handle alarms on weekends and holidays. You state that an [redacted] and [redacted] have been approved and the selected system has been ordered. The completion date of May 31, 2007 for this corrective action appears excessive, and we recommend that you reevaluate your proposed timeframe such that this action is completed in a more timely manner. Please explain what you mean by [redacted] and [redacted]. Please explain if the alarm notification system is to be utilized on weekends and holidays only, or if it is to also to be used after hours during the work week.
FDA 483 item #6
Your response states that all monitoring data will be attached to the production protocols and in the future, there will be a specific description of the product impact in the case of a deviation. Please provide a copy of your updated SOP.
FDA 483 item #7.A
Your response states that your Quality Assurance Unit will implement a system for periodic retrieval of complaints in the different departments to avoid complaints not being handled and documented in the appropriate timeframe according to the SOP, "Complaint Handling QA-AD-0002." Please provide your rationale for performing your review every three months as opposed to a more frequent review.
Please notify this office in writing, within 15 days of receipt of this letter, of any steps you have taken or will take to correct the noted violations and to prevent their recurrence. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Failure to promptly correct these deviations may result in regulatory action without her notice. Such actions include license suspension and/or revocation.
Your reply should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, 1401 Rockville Pike, Suite 200N, HFM-600, Rockville, MD 20852-1448. Please contact Ms. Maria Anderson in the Division of Case Management at (301) 827-6201 to discuss any questions regarding this letter.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research