Inspections, Compliance, Enforcement, and Criminal Investigations
Xttrium Laboratories, Inc. 5/20/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
May 20, 2009
RETURN RECEIPT REQUESTED
Mr. Kevin S. Creevy
President and Chairman
Xttrium Laboratories, Inc.
415 W. Pershing Road
Chicago, IL 60609
Dear Mr. Creevy:
During an inspection of your firm located in Chicago, Illinois, from July 2 to August 27, 2008, and October 27 to December 31,2008, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Chlorhexidine Gluconate (CHG) solutions in various concentrations to be used as antimicrobial skin cleansers (such as 2% and 4% CHG Solutions for uses in surgical settings) and oral rinses. In addition, your firm manufactures 20% CHG Solution, an in-process material, used in your drug products and also sold to other firms for further manufacturing.
The inspections revealed that these drugs are adulterated within the meaning of section 501 (a)(2)(B) of the Federal Food, Drug, and Cosmetic 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 are not in conformance with the current Good Manufacturing Practice (CGMP) regulations, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211.
The inspections also revealed that these drugs are adulterated within the meaning of section 501(a)(I) of the Act [21 U.S.C. § 351(a)(1)] in that they consist in whole or in part of any filthy, putrid, or decomposed substance. They are also adulterated under section 501 (a)(2)(A) of the Act [21 U.S.C. § 351(a)(2)(A)], in that they have been prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or whereby they may have been rendered injurious to health.
We acknowledge your written response, dated January 23, 2009, addressing our investigators' observations that were presented to you on the Form FDA 483, List of Inspectional Observations. The violations we observed, along with comments regarding your responses, include, but are not limited to, the following:
INSANITARY CONDITIONS AND PRESENCE OF FILTH
1. FDA's laboratory analyses have found that your product is contaminated with objectionable microorganisms. FDA Sample 470459 was collected on July 11, 2008, at Xttrium from retention samples of 2% CHG Topical Solution, Lot 804-2022-062, manufactured for and shipped to (b) (4). The FDA laboratory found that two of four sub-samples collected were positive for Burkholderia cepacia, water-borne contaminant that is a significant opportunistic pathogen. Please note that B. cepacia can cause serious infections in patients, and that those with certain health problems such as immature or weakened immune systems, or chronic disease, are most susceptible. Your analysis of these same samples confirmed the presence of B. cepacia.
2. We also note fourteen cases in which 320z. bottles were rejected on-line on August 10, 2007, during the packaging of Lot 708-1061-326, 4% CHG Solution, because the bottles contained insects. In addition, on January 18, 2008, Xttrium received Customer Complaint 2008006 of an insect found inside a bottle by a nurse when she opened the bottle in the operating room (Lot 710-1021-306, 2% CHG Solution).
1. Failure to thoroughly review any unexplained discrepancy 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. Failure to extend investigations to other batches of drug product that may have been associated with the specific failure or discrepancy. Failure to include conclusions and follow up in written records of the investigation as required by 21 CFR § 211.192. For example:
a. Investigations into Out-of-Specification (OOS) microbial results for finished drug product are not adequate. From May 2008 to August 2008, your firm tested 10 lots of finished drug product (e.g. 2% CHG Solution, 4% CHG Solution, and 0.12% CHG Oral Rinse) which did not meet established microbial limits. Upon retesting of these OOS lots, three also tested positive for Pseudomonas aeruginosa. Despite this objectionable microbial contamination in ten lots, nine were released on the basis of in-specification tests of retain samples. Prior to the release of eight of these nine lots, investigations were opened and the root cause for the OOS results was either documented as "not determined" or "possible sampling/laboratory error." The OOS results were invalidated without any evidence that ascribed the microbial contamination to laboratory error.
You provided a draft QA Standard Operating Procedure (SOP) (b) (4) "Investigating Microbial Out-of-Specification Results," that states if a laboratory "QNRA determine whether the initial OOS results are valid or invalid" based on duplicate testing of retain samples by two different microbial technicians at either the same laboratory or different laboratories. Your procedure is inadequate in that it does not ensure that an OOS result is invalidated only when microbial growth is clearly and conclusively ascribed to laboratory error. Because your investigations were inadequate and inconclusive regarding the origin(s) of the contamination, please provide your scientific justification for allowing these nine lots to remain on the market.
b. Investigations into Out-of-Limits (OOL) microbial results for purified water are not adequate. Daily water samples did not meet established microbial limits on numerous occasions during 2007 and 2008. On most days when a water sample tested OOL, a retain water sample was also tested and in most instances an investigation was initiated that concluded the root cause of the OOL result was either the possible development of biofilm in the production hose or sampling error. OOL results were invalidated without any evidence and strong scientific rationale that ascribed the microbial contamination to laboratory error.
Your response states retain samples are not utilized to invalidate results or release product but are utilized to gather more data on the water system, and that QA SOP (b)(4) was revised to include the steps for handling purified water OOL results. However, this SOP is inadequate because it indicates that OOL water results can be invalidated based on duplicate finished product testing that meets established microbial limits. Your procedure is inadequate in that it does not ensure that an OOL result is invalidated when microbial growth is clearly and conclusively ascribed to laboratory error. Because your investigations were inadequate and inconclusive regarding the origin(s) of the contamination, please provide your scientific justification for allowing lots manufactured with water that did not meet established microbial limits to remain on the market.
c. Customer complaint 2008033 was received April 22, 2008, regarding the presence of an orange precipitate at the bottom of 15 drums of 20% CHG Solution, Lot 708-100-330. The customer sent a sample from the drums to your firm for analysis; however, the sample was filtered upon receipt in your QC laboratory and only the liquid portion was analyzed to demonstrate whether the product met all specifications. The precipitate was not analyzed or identified as part of investigation #804-024 that concluded the root cause was "most likely outside contamination in the 20% CHG."
You provided a draft QA SOP (b)(4), "Incident Investigations," that now states that any issue resulting in particulate or foreign matter contamination must be identified as part of the investigation and include the steps to be taken when the particulate cannot be identified. Your response is inadequate because it does not address your rationale for filtering the sample or failing to analyze the precipitate in April 2008. Please provide the results of the analysis of the precipitate that has since been conducted and indicate if your firm's investigation has changed its identification of the root cause as a result of this analysis.
d. Lots 710-100-337 and 710-100-350 of 20% CHG Solution were rejected due to appearance failures related to cloudiness and formation of white precipitate. Investigation (b)(4), dated January 31, 2008, concluded that the root cause of these appearance failures were incomplete dissolution of the Chlorhexidine (CH) Base, a raw material used to manufacture the 20% CHG Solution, due to the inferior quality of the CH Base. However, the investigation did not extend to any other lots (including but not limited to lots 710-100-338 through 710-100-349) of 20% CHG Solution that were manufactured during this time and may have been affected. Significantly, we note that Customer Complaints 2008016 and 2008018 were subsequently received in February 2008, and 2008032 in April 2008, with each reporting a cloudy appearance and precipitates in distributed Lot 710-100-338.
Your response states that the cause of the 20% CHG Solution cloudiness has been confirmed as unincorporated CH Base and that you were able to identify the specific lots of CH Base that caused the solution cloudiness through analytical results of the finished product. In addition, your firm conducted chemical analysis of Lot 710-100-338 to determine if all results were within specification. Please provide the "follow up investigations" initiated in response to the noted customer complaints for Lot 710-100-338. In addition, please explain why the investigation was not extended to other potentially affected lots.
e. Fourteen cases of320z. bottles, receiving #707-106918, were rejected online on August 10, 2007, during the packaging of Lot 708-1061-326, 4% CHG Solution, because the bottles contained insects. Investigation #801-005 was not conducted until Customer Complaint 2008006 (Lot 710-1021-306, 2% CHG Solution) was received January 18,2008. In this complaint, a nurse found an insect inside a bottle (receiving #708-107166) when she opened it in the operating room. In addition, investigation #801-005 did not extend to other lots such as Lot 708-1021-292,2% CHG Solution, that was made with the same shipment of bottles, receiving #707-106918, found contaminated with insects.
Your response states Lot 708-1021-292 was inadvertently missed during your investigation, and QA SOP 23-6 now outlines the process of inspecting raw materials and components from the batch in question to determine if the raw material or component is still in stock or utilized for the manufacture of other batches. In addition, you now purchase bottles from a different vendor. However, your response does not address the investigation conducted into the potential contamination of Lot 708-1021-292 or the preventive actions implemented by your firm during incoming acceptance activities (e.g. sampling, testing, examination) to ensure contaminated bottles are rejected upon receipt at your facility.
2. Failure to establish and follow written procedures designed to prevent objectionable microorganisms in drug products not required to be sterile as required by 21 CFR § 211.113(a). QC SOP (b)(4) "U.S.P. Purified Water Testing," dated December 12, 2007, states that if the Total Plate Count (TPC) of an initial water sample indicates the presence of a microbe, then the retain water sample must be tested. Products made with water from that day would be quarantined until this further testing was conducted and results indicated the absence of any pathogens. Your firm's practice is to allow the satisfactory results of a test of a retain water sample to suffice for release of product batch(es) manufactured with contaminated water from quarantine. This practice is unacceptable because a negative re-test alone is not enough evidence to release a batch from quarantine. For example:
a. The TPC for the initial and retain water samples, collected May 29, 2007, was (b)(4) CFU/100mL and (b)(4) CFU/100mL, respectively. The water was used to manufacture Lot 705-2000-476, 0.12% CHG Oral Rinse, and Lot 705-1021-272, 2% CHG, released on June 5, 2007 and June 11,2007, respectively. However, identification testing was not conducted to indicate the presence or absence of an objectionable organism.
Your response states that both lots of product underwent microbial analysis prior to final batch release. In addition, your proposed practice for handling water results that are OOL for microbial limits is to perform testing on product manufactured with "suspect water" prior to release. QA SOP No. (b)(4) "Investigating Microbial Out-of-Specification Results," Draft, was revised accordingly.
b. The TPC for the initial water sample, collected June 2, 2008, was 100mL. The water was used to manufacture Lot 806-1021-369, 2% CHG, Lot 806-2001502, Peridex 0.12% CHG Oral Rinse, and Lot 806-2108-046, Mouth Refresh II Solution. These lots were released for distribution between June 10, 2008 and June 11, 2008. However, the retain result of (b)(4) CFU/100mL was not received from the contract testing laboratory until June 13, 2008, nor was identification testing conducted to indicate the presence or absence of an objectionable organism.
Your response indicates that retain sample testing is not required to provide disposition of the batch manufactured with the tested water, and that retain sample results are utilized to gather more data on the water system in order to properly evaluate the system. In addition, your response states that finished product is released if it meets microbial specifications.
c. The TPC for the initial water sample collected on August 27, 2008, was (b)(4) CFU/100mL. The culture was gram-stained and the results indicated a gram positive culture. However, identification testing was not conducted to indicate the presence or absence of an objectionable organism. The water was used to manufacture Lot 808-200-136, Perox-A-Mint, and Lot 808-2000-748, 0.12% CHG Oral Rinse.
Your response indicates that the revised QC SOP (b)(4) "USP, Purified Water Testing," Draft, better clarifies the specific steps required upon receipt of a microbial count.
Your responses are inadequate. The detection of product contamination by your firm, as well as FDA's finding in our laboratory testing, is consistent with 2007 and 2008 purified water system data that indicates that the system failed to meet your established microbial limits on several occasions. The low quality water was then used as a primary component during the manufacturing of various CHG solutions. These finished products were released for distribution based on finished product testing that did not detect microbial contamination, despite the purified water test results that indicated the presence of microbial contamination.
While failing test results for water samples were not appropriately investigated or resolved, your firm nonetheless indicates that you released and will continue to release products on the basis of finished product microbial testing. Be advised that finished product testing, regardless if it is performed in duplicate, is not a substitute for adequate CGMP controls. In addition, you failed to include the CGMP controls you plan to implement to prevent future recurrence of microbial contamination in your purified water system such as reevaluation (and revalidation) of your USP Purified Water System to ensure it can reliably and consistently produce water of acceptable microbiological quality. A revalidation of your water system should demonstrate whether the preventive actions (e.g. quarterly sanitization and flushing of the production hose with hot water (b)(4)) implemented by your firm are adequate to remove biofilm and stop the proliferation of microbes. Finally, you did not address any further testing conducted to determine the presence or absence of objectionable organisms in the daily purified water samples cited above.
3. Failure to perform reviews of investigations conducted under § 211.192 for each drug product to evaluate, at least annually, the quality standards of each product to determine the need for changes in drug product specifications or manufacturing or control procedures as required by 21 CFR § 211.180(e)(2). From January 2008 to August 2008, six investigations were initiated as a result of microbial contamination in at least eleven lots of bulk product and ten lots of finished drug product. In 2007, two investigations were initiated as a result of microbial contamination in two finished drug product lots. Although the number of finished product lots testing OOS for microbial limits notably increased from 2007 until 2008, your firm failed to review the related investigations to determine whether changes needed to be implemented to ensure finished products conform to appropriate standards of quality.
Your response indicates that all finished products will be tested for microbial limits and specifications have been revised to add (b)(4) to your list of pathogenic organisms. Your response also states additional finished product samples (e.g. beginning, middle, and end) are analyzed and QA SOP (b)(4) now describes how investigations should be conducted of water results that are OOL for microbial limits. However, your response is inadequate because it does not include any provisions for other areas where corrective and preventive actions are needed (e.g. enhancements to design or maintenance of your water system or manufacturing process; monitoring the water system more frequently).
4. Failure to establish scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity as required by 21 CFR § 211.160(b). For example,
a. Your firm uses an in-line conductivity meter on the USP Purified Water System that should not be used for pharmaceutical purposes, as per the conductivity meter's operating manual. As indicated in the operating manual and USP General Chapter <645> Water Conductivity, the type of temperature compensating algorithm used by this conductivity meter may not be accurate because it automatically corrects the actual reading and displays the theoretical value at the nominal temperature of 25°C. In addition, the firm has not established a written procedure that describes water conductivity testing.
Your response states conductivity readings will now be taken from the TOC Analyzer (which does not compensate for the water temperature) while simultaneously recording the actual water temperature. This conductivity reading will be compared against the chart in USP<645> that lists the required conductivity reading based on water temperature. Although QC SOP (b)(4) has also been revised to include the steps for monitoring and documenting the water conductivity, page 6 of this SOP still solely has the conductivity specification of (b)(4) In addition, your response does not address the investigation conducted to determine the actual water quality and possible impact in the quality of the drug product manufactured with that water. At the time of inspection, the Director of Regulatory Affairs and Quality Assurance stated an investigation would be initiated.
b. Your firm does not shake samples of20% CHG Solution prior to performing the appearance test. Investigation #712-077 determined that 20% CHG Solution samples should be shaken and poured in order to determine if there is cloudiness or precipitate at the bottom of the sample container; however your firm is not shaking the sample.
You indicated that QC SOP (b)(4), "Raw Material, In-Process, and Finished Product Testing," dated January 19,2009, has been revised to require that samples (b)(4) to performing the appearance test. However, QC SOP (b)(4) "Identification Tests for 20% CHG Solution," which specifically describes the appearance test, has not been revised. In addition, your response does not address how you will ensure that the corrective actions identified during failure investigations are implemented and monitored to ensure that they are effective.
5. Failure to establish and follow written procedures describing the handling of all written and oral complaints regarding a drug product, and failure to include the findings and follow-up of investigations conducted under § 211.92 in written records when investigating a drug complaint, as required by 21 CFR § 211.198(a) and (b)(2). For example:
a. At the time of inspection, it was brought to your firm's attention that Customer Complaint 2008028, received on April 3, 2008, of two premature infants that experienced an adverse reaction after being "prepped with 2% CHG," (Lot 7061021-278), had not been investigated. Although the completed product complaint record, QA007A, indicated an investigation was required, the investigation was not conducted until October 31, 2008 (six months after receipt of the complaint).
Your response states "QA SOP (b)(4) does identify the regulatory path of how to submit the adverse reaction through FDA Form 3500A, but does not identify the steps to be taken internally to investigate the incident." QA SOP (b)(4), "Product Complaint Handling Procedure," Draft, has been revised to include the investigational steps to be taken when an adverse reaction is received. In addition, your response states that the complaint is considered a non-serious, expected adverse reaction and would be reported in your periodic report to the agency in February 2009. Your response is inadequate because you have not addressed your review of prior product complaint records to determine if other adverse reactions were reported that may require investigations.
b. Customer Complaint 2007028, received on May 8, 2007, details findings of a foreign matter (described as a paint chip) in an unknown lot of2% CHG Solution. QA007A indicated "an investigation should be started after knowing the lot number or receiving the product." However, the product complaint record does not include the findings of the investigation (if any) or the follow-up.
Your response indicates that this complaint was "transferred from being managed in the Product Complaint file" and is now "managed in the Incident Investigation file." Your response is inadequate because you have not addressed the findings and follow-up of the investigation conducted into this complaint, nor how investigations are handled for product complaints when a lot number is not provided.
We note that many of the revised procedures attached to your response are not implemented because these procedures have no effective dates. The CGMP regulations require that procedures be approved by your Quality Control Unit. We acknowledge your commitment to develop a written procedure describing the actions to be performed prior to the initiation of manufacturing when your water system, or any other piece of equipment, is not used over an extended period of time. addition, you indicated that you may hire a consultant(s). Please note that based upon the inspectional findings, including but not limited to, deficient procedures, inadequate investigations, and invalidating test results without appropriate scientific justification, we strongly agree that it would be valuable for your firm to engage a consultant to assess your facility, procedures, processes, systems, and sources of microbial contamination.
Regarding your firm's CHG products, FDA considers these products for use in surgical settings to present a higher risk than general topical drug products in light of the microbiological contamination discussed above. We recommend that the final formulation of these products be produced as sterile to avoid introducing exogenous microorganisms.
In addition, we suggest that you revise PROD SOP (b)(4) "Production Personnel Responsibilities," Draft, to include detailed instructions for the calibration of analytical balances and performing daily balance checks. Your procedure for performing daily balance checks should address how many significant figures to include in documented weights and the acceptable ranges (b)(4). (See Form FDA 483 - Observation 3D). QA SOP (b)(4) should be revised to include a timeframe for initiating a complaint investigation, and to require the scope of your review of prior product complaints be based on sound rationale rather than an arbitrary timeframe such as (b)(4) months. (See Form FDA 483 - Observation 4A and 4B).
You should take prompt action to correct the violations cited in this letter. Failure to promptly
correct these violations may result in legal action without further notice, including, without
limitation, seizure and injunction. Other federal agencies may take this Warning Letter into
account when considering the award of contracts. Additionally, FDA may withhold approval of
requests for export certificates, or approval of pending new drug applications listing your facility as
a manufacturer until the above violations are corrected. A reinspection may be necessary.
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 the noted violations. Include an explanation of each step taken to prevent recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. Additionally, your response should state if you no longer manufacture or distribute any drug product(s) manufactured at your facility, and provide the date(s) and reason(s) you ceased production.
Your response should be sent to: Lorelei Jarrell, Compliance Officer, Food and Drug Administration, 550 W. Jackson Blvd., 15th floor, Chicago, IL 60661. If you have any questions about the content of this letter, please contact Ms. Jarrell at 312-596-4216.
Scott J. MacIntire