January 22, WARNING LETTER CHI-03-09

Transcription

1 DEPARTMENT OF HEALTH & HUMAN S RVICES Food and Drug Administratio n Chicago District 550 West Jackson Blvd., 15th Floor Chicago, Illinois Telephone : CERTIFIED MAIL RETURN RECEIPT REQUESTED Mr. Vincent W. Foglia, CEO Sage Products, Inc Three Oaks Road Cary, IL Dear Mr. Foglia : January 22, WARNING LETTER CHI During an inspection of your firm located in Cary, Illinois, from June 2 to July 10, 2008, investigators from the United States Food and Drug Administration (FDA) determined that your firm manufactures various oral rinse products and skin cloths. Under Section 201 (g)(1)(13) of the Act [21 U. S.C. 321(g)(1)(B)], these products are defined as drugs because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. The inspection revealed that these drugs are 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 are not in conformity with the current Good Manufacturing Practice (cgmp) requirements found under Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. This inspection also determined that your firm manufactures suction tip catheters. Under Section 201(h) of the Act, [21 U.S.C. 321(h)], this product is a device because it is intended for use in the diagnosis of dise ase or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the s tructure or function of the body. This inspection revealed that this device is adulterated within the meaning of Section 501(h) of the Act [21 U.S.C. 351(h)], in that the methods used in, or the facilities or controls used for, its manufacture, packing, storage, or installation are not in conformity with the current Good Manufacturing Practice (cgmp) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.

2 Page 2 We received a response from Sean Haley, Vice President of Regulatory Affairs and Quality Assurance, dated August 7, 2008, and a response from Mitch Keck, Manager of Quality Assurance, dated October 23, 2008, concerning our investigators' observations noted on the Form FDA 483, List of Inspectional Observations, that was issued to you. We address these responses below, in relation to each of the noted violations. These violations include, but are not limited to, the following : 1. Failure to establish scientifically sound and appropriate specifications designed to assure that components and drug products conform to appropriate standards of identity, strength, quality and purity as required by 21 CFR (b). For example: a) The specification of "TAC " for the Microbial Limits test fo r 2% Chlorhexidine Gluconate (CHG) Cloths is not an appropriate specification for the product because this product is approved for use in surgical settings as a preoperative skin preparation. Specifically, this product is indicated for the preparation of skin prior to surgery. Your responses state that your firm has re-established the TAC limit to the "USP limit for cutaneous drug dosage forms (maximum acceptable count of 200 cfu/ml and maximum acceptable count of 20 cfu/ml for combined yeast and mol d count)." However, you provide no additional information to support the conclusion that this specification is adequate for these products, given that they are approved for use in surgical settings and given the incidences of microbiological contamination discussed below. b) Your "specified list of indicating microorganisms" used for bulk 2% CHG solution and the drug product 2% CHG Cloths are incomplete and not appropriate because Burkholderia cepacia is not included as one of the specified microorganisms on this list. This list contains those organisms that should not be present in your products. Specifically, your firm conducted recalls in June 2006 for Comfort Shield Cloths and in July 2008 for 2% CHG Cloths that were contaminated with Burkholderia cepacia. Your firm failed to include Burkholderia cepacia as a specified organism for which your microbiology laboratory tests prior to release. Your responses state "We are not necessarily concerned with a low concentration of a non-indicating Gram negative organism unless it demonstrates a tolerance to the product's preservatives." We disagree that your products' antimicrobia l activity can be considered a substitute for adequate cgmp controls at your firm. Further, your responses stated that you "have now added B. cepacia to the specified list of indicating organisms for both 2% CHG and Comfort Shield products." However, your responses failed to include any additional cgmp

3 Page 3 controls you plan to implement to prevent future occurrences of microbial contamination (i.e., verification of supplier's certificate of analysis; equipment cleaning; water system sanitation). In light of the significant problems you encountered with the bulk CHG solution (including the aforementioned recalls), as well as the significant and recurring cgmp observations documented during the current inspection, we are concerned about your lack of cgmp controls and your conclusions regarding your products' specifications and microbial testing. These deviations indicate an insufficient level of assurance that your products conform to appropriate standards of quality and safety. Please provide your rationale for the distribution of products that were not recalled, but implicated during the recent microbial contamination incident and manufactured under deficient cgmp conditions. This is a repeat observation from the September 2006 inspection. 2. Failure to establish and follow procedures designed to prevent objectionable microorganisms in drug products not required to be sterile as required by 21 CFR 211,113(a). For example : a) Environmental monitoring test results documented findings of Gram-negative rods, but the specific microorganisms were not further identified in order to determine whether the recovered species were objectionable organisms. Specifically, Gram-negative rods were found in equipment-surface samples on Comfort Bath Line I (CBL 1) on March 28, 2008 and April 18, 2008, and from Comfort Bath Line 2 (CBL 2) on February 28, However, your firm failed to speciate these microorganisms, as required by SOP , "Environmental Monitoring Program," Section Comfort Shield products are manufactured on CBLs 1 and 2. Your responses indicate that you will "re-institute the identification of Gram negative rod shaped bacteria encountered from environmental collection sites." However, your responses lack a commitment to retrain or evaluate the microbiological technicians who failed to conduct this important identification testing and the supervisor that oversees the Quality Control laboratory. b) Environmental monitoring had not been implemented for Comfo rt Bath Line 3 (CBL 3), although this newly operational manufacturing line had been used for approximately three months as of the time of the 2008 inspection. The CBL 3 is the line where 2% CHG Cloths are manufactured. Your responses state "Environmental monitoring is not required for non-sterile types of products we produce." We believe that, given the incidences of microbiological contamination discussed above, it is critical that your drug products that are approved for use in surgical settings (2% CHG Cloths) and that are marketed for uses that may involve a breach in the body's natural barrier to microbial invasion (Comfort Shield products) be manufactured under sufficient controls to ensure an environment suitable for these

4 Page 4 products. If contaminated, these products could pose a significant health risk, especially if used in certain sensitive populations, such as immunocompromised patients. We acknowledge your commitments to expand your environmental monitoring locations by September 30, However, your responses do not indicate the extent of sampling or describe whether equipment surfaces that come in direct contact with drug products or components will be monitored. This is a repeat observation from the September 2006 inspection. 3. Failure to follow procedures for evaluating at least annually, quality standards of each drug product to determine the need for changes in specifications or manufacturing or control procedures as required by 21 CFR (e). For example : a) The 2007 annual product review has not been completed for commercial drugs produced in calendar year b) The 2006 annual product review is neither issue-specific nor sufficiently detailed. For example, records of returned drug products could not be properly reviewed because the reasons for product returns and number of return units for different products were not included. Your response notes that your firm revised the SOP for annual product review and the 2007 annual product review was to be completed by August 31, As this is a repeat observation from the January 2006, April 2004, and December 2003 inspections, your response failed to provide an effective corrective action(s). For example, responsible personnel should have been retrained to ensure that annual reviews will be conducted as required. 4. Failure to investigate the cause of nonconformities relating to product, processes, and the quality system, as required by 21 CFR (a)(2). For example, for the Suction Oral Swabs for your suction tip catheters, the pull port in-process test was not re-evaluated after detecting a high rate of failure to meet this specification from finished product sampling. Your responses state that the Corrective and Preventive Action (CAPA) SOP was updated to assess whether the corrective action would impact the validated machine settings and/or the sampling plan in place. We have reviewed your responses and have concluded that they are inadequate because they fail to address the actual investigations of nonconformities. 5. Failure to review and evaluate the process and perform revalidation when changes or process deviations occur, as required by 21 CFR (c). For example, the change to the lower process parameter on the ultrasonic welder for the Yankhauer production line for your suction tip catheters was not revalidated before it was implemented.

5 Page 5 Your responses state the ultrasonic welder was revalidated and the applicable SOP updated. We have reviewed your responses and have concluded that they are inadequate because the actual results and text of the SOP were not provided with the responses. 6. Failure to document corrective and preventive action activities, including investigations of causes of nonconformities, as required by 21 CFR (b). For example, there is incomplete documentation of an investigation into whether the ultrasonic weld horn caused defects in the Yankhauer production line for your suction tip catheters. Your responses state that SOP Deviations, Justifications & Rationale Letters has been updated. We have reviewed your responses and have concluded that they are inadequate because the text of the changes was not provided. Therefore, we are unable to determine whether the changes adequately address this deviation. 7. Failure to analyze appropriate sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems, as required by 21 CFR (a)(1). For example, CAPA investigations for Yankauer suction handles with similar product problems do not contain the same sort code identifiers. Your responses state that SOP , CAPA procedure has been updated. We have reviewed your responses and have concluded that they are inadequate because the text of the changes was not provided. Therefore, we are unable to determine that the changes adequately address this deviation. 8. Failure to submit relevant information on identified quality problems, as well as corrective and preventive actions, for management review, as required by 21 CFR (a)(7). For example, data submitted for the annual management review, held on 12/18/07, do not include information on identified quality problems and corrective actions. Your responses state that SOP , Management Review Process has been updated. We have reviewed your responses and have concluded that they are inadequate because the text of the changes was not provided. Therefore, we are unable to determine that the changes adequately address this deviation. Regarding your firm's 2% CHG Cloths 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 sterile to avoid introducing exogenous microorganisms. You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are

6 Page 6 advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations hav e been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected. Please notify this office in writing within 15 working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Your response should be sent to : Lorelei Jarrell, Compliance Officer, Food and Drug Administration, 550 W. Jackson Blvd., 15`h floor, Chicago, IL If you have any questions about the content of this letter, please contact Ms. Jarrell at Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance. Sincerely, Scott J. Maclntire District Director