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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Analytical Control Systems, Inc 5/8/14

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Detroit District
300 River Place
Suite 5900
Detroit, Ml 48207
Telephone: 313-393-81 00
FAX: 313-393-8139 

 

WARNING LETTER
2014-DET-09
 
May 8, 2014
 
VIA UPS
 
Dr. Dean P. Bonderman, President
Analytical Control Systems, Inc.
9058 Technology Drive
Fishers, Indiana 46038-4511 
 
Dear Dr. Bonderman:
 
During an inspection of your firm located in Fishers, Indianaon October 29, 2013 through December 3, 2013, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Glucose 6 Phosphate Dehydrogenase (G-6-PDH) Depressed and Normal, Angiotensin Converting Enzyme (ACE), Galactose-1-Phosphate Uridyltransferase (Gal-1-PUT), NAFSC Variant Hemoglobin, Lyophilized ACS Hemoglobin Electrophoresis, Angiotensin Converting Enzyme, Lyophilized AFSC Hemoglobin Electrophoresis, Slide Platelet Aggregation Test (SPAT) Positive Controls, and the ACE Calibrator devices. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.
 
This inspection revealed that these devices are 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, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. We received a response from Dr. Dean P. Bonderman, President dated December 18, 2013 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm. We address this response below, in relation to each of the noted violations.  These violations include, but are not limited to, the following:
 
1.    Failure to validate, with a high degree of assurance and approve according to established procedures, a manufacturing process that cannot be fully verified by subsequent inspection and testing, to ensure the process will continue to meet specifications as required by 21 CFR 820.75(a).
 
For example: your firm’s (b)(4) analyzer, utilized to perform production and quality control activities for all product lines, has not been validated.
 
The adequacy of your firm’s response cannot be determined at this time. Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
2.    Failure to establish and maintain procedures for implementing corrective and preventive action as required by 21CFR 820.100(a)(1) – (a)(4).
 
a.    For example, your firm’s Quality Assurance Program procedure, GP-1, revised 09/27/2010, fails to include requirements for: analyzing processes, work operations, concessions, quality records, service records, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product or other quality problems; the utilization of appropriate statistical methodology where necessary to detect recurring quality problems; investigating the cause of nonconformities relating to product, processes, and the quality system; identifying the actions needed to correct and prevent recurrence of nonconforming product and other quality problems; and verifying or validating the corrective and preventive action to ensure it is effective and does not adversely affect the finished device.
 
b.    In addition, subsequent to the receipt of the following complaints and nonconformances, your firm has failed to investigate the cause of the nonconformity, identify actions needed to correct and prevent recurrence of the nonconformity and verify or validate the corrective and preventive action to ensure the action is effective and does not adversely affect the finished device:
 
i.    Complaints dated 07/19/2010 and 03/23/2012 relating to "pellet backmelt," that according to documentation included with the complaints "ruins consistent assay values" and is thought to “result from the loss of vacuum and/or damage to the glass vials”.
ii.    A complaint dated 06/06/2013 alleged that the instructions for use did not contain the temperature to be used when performing assays for G-6- PDH that resulted in a recall by your firm.
iii.    The FDA Investigator discovered six (6) boxes containing nonconforming G-6-PDH and ACE Controls being held for destruction by your firm.
 
The adequacy of your firm’s response cannot be determined at this time. Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
3.    Failure to establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria, and is not released into distribution until the activities required in the DMR are completed, the associated data and documentation is reviewed, the release is authorized by the signature of a designated individual, and the authorization is dated, as required by 21 CFR 820.80(d).
 
For example, despite the fact that lot 1-75-23 of G-6-PDH Deficient Control did not meet established specifications during final quality control testing, your firm released the device for distribution. The Device History Record (DHR) for G-6-PDH Deficient Control Lot# 1-75-23 indicated that the specifications for Total Hgb were 11.0-13.0 G/D L, but your firm's quality control testing indicated that the mean value for Total Hgb was 13.5 G/DL.
 
Additionally, the DHRs were incomplete and/or did not demonstrate the following distributed devices were manufactured in accordance with the Device Master Record (DMR) before release:
 
a.    The DHR for G-6-PDH Deficient Control (Product #Lot# 1-75-23) did not include documentation of the enzyme activity of the hemoglobin pool that was used, the acceptability of that enzyme activity, and the sources and quantities of additives used in the preparation stages of the hemoglobin. The DHR for G-6-PDH Normal Control Lot# 1-75-24 did not include the finished quantity available for shipping, the number of samples used for quality control testing, the number of retain samples, lot shrinkage, a signature and date for the lot history review and the lot disposition.
 
b.    The DHR for Hemoglobin AC Bulk Powder (Product HC-105, Lot# 1-74-32) did not include a value for the amount of 2,3 DPG added as a preservative.
 
c.    The DHR for Lyophilized ACS Hemoglobin Electrophoresis Control (Product#HC-103, Lot# 1-76-8) did not include the signature of the Director of Quality Control. This signature indicates the DHR has been reviewed and is approved for distribution.
 
d.    The DHR for ACE, Calibrator and Controls (Product E-1, Lot #120611) did not include the signature of the Director of Quality Control.  This signature indicates that the DHR has been reviewed and is approved for distribution.
 
e.    The DHR for G-6-PDH Deficient Control (Product HC-108DE, Lot# 1-79-19) states the specification for "G-6-PDH@ 37°C" is "0.5 - 1.0 IU/L/Ghb PROC.345".  However, the value recorded on your Certificate of Analysis was 0.9±0.2 and out of (10) samples analyzed on your laboratory worksheet, values of 1.2 and 1.1 IU/L/Ghb were each documented once.
 
 
Additionally, your firm released the following device despite failing to establish criteria for finished device acceptance criteria. The DHR for SPAT Positive Control Lot #1-78-23 did not include the functional acceptance criteria for the lot or the results of the testing.
 
The adequacy of your firm’s response cannot be determined at this time. Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
4.    Failure to ensure device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution, as required by 21 CFR 820.130.
  
For example:
a.    Despite receiving complaints regarding "backmelt" due to loss of vacuum on the vials, your firm ships your devices in bulk by placing one hundred twenty glass vials into a single zip-lock bag. This bag is then placed in a box that is filled with packing peanuts and shipped via next day air.
 
b.    The labels and instructions for use for all of your products state to store products at 2-8°C (35.6-46.4°F) however, you ship your finished products to customers at ambient temperature via next day air.
 
The adequacy of your firm’s response cannot be determined at this time.  Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
5.    Failure to establish and maintain procedures to control product that does not conform to specified requirements as required by 21 CFR 820.90(a).
 
For example, your firm's Review of Internal Rejection procedure, GP-16 Revised 09/27/2010, does not include provisions for identification, segregation, evaluation, and disposition of nonconforming product. Additionally, the following devices were released for distribution despite failing to conform to specified requirements:
 
a.    The DHR for G-6-PDH Deficient Control (Product #Lot# 1-75-23) did not include the enzyme activity of the hemoglobin pool utilized, the acceptability of the enzyme activity, and the sources and quantities of additives used in the preparation stages of the hemoglobin.  Additionally, the DHR indicated that the Total Hgb for this lot was outside the specification range of 11-13, as the actual value was 13.5.
 
b.    The DHR for G-6-PDH Deficient Control (Product HC-108DE, Lot# 1-79-19) states the specification for "G-6-PDH@ 37°C" is "0.5- 1.0 IU/L/Ghb PROC.345".  However, the value recorded on your Certificate of Analysis was 0.9±0.2 and out of (10) samples analyzed on your laboratory worksheet, values of 1.2 and 1.1 IU/L/Ghb were each documented once.
 
The adequacy of your firm’s response cannot be determined at this time. Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
6.   Failure to establish and maintain written sampling plans based on valid statistical rationale and are adequate for their intended use as required by 21 CFR 820.250(b).
 
For example:
a.    For a total yield of (b)(4) vials of Lyophilized AFSC Hemoglobin Electrophoresis Control (product #HC-102, Lot# 1-74-12) 10 samples were selected for testing.
 
b.    For a total yield of (b)(4) vials of G-6-PDH Deficient Control (Product #HC-108DE, Lot# 1-79-19) 10 samples were selected for testing.
 
c.     For  a total yield of (b)(4) vials of ACE, Calibrator and Controls (Product #E-1, Lot 120611) the number tested could not be determined due to discrepancies within the DHR.
 
The adequacy of your firm’s response cannot be determined at this time. Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
7.  Failure to establish and maintain procedures for changes to a specification, method, process or procedure and to verify or validate, according to 21 CFR 820.75, the change before implementation, as required by 21 CFR 820.70(b).
 
For example, your firm made changes to production procedures found within the Manufacturing Record and Product Specifications for the SPAT Positive Control, Product Code CR-123, without verifying or validating them.  For example: Within the DHR for SPAT Positive Control, Lot #I-78-23, changes were made to the preparation step to include the use of different amounts of platelet packs, (b)(4) and (b)(4), in addition to a dispense volume of (b)(4) ml instead of the (b)(4) ml. specified within the DHR.
 
These changes were not made in accordance with your firm’s procedures.  Section I.A of your firm’s Change of Procedure, GP-15, revised 09/27/2010, states "All changes must be documented on form RF-11 Change of Procedure Form."  Section II states "(b)(4).”  Additionally, section II.A of your firm's Preparation of Manufacturing Protocols procedure, GP-8, revised 09/27/2010, states "(b)(4)" Section II.B. states "(b)(4)"  And lastly, section IV.A states "(b)(4)."
 
The adequacy of your firm’s response cannot be determined at this time. Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
8.    Failure to establish and maintain procedures to control all documents, as required by 21 CFR 820.40. Documents are not always approved in accordance with 21 CFR 820.40(a) and changes to documents are not all reviewed and approved in accordance with 21 CFR 820.40(b). For example, incomplete procedures have been reviewed and approved by your firm’s management and changes to procedures have been reviewed and approved by an individual that has not been specifically designated for this task.
 
The adequacy of your firm’s response cannot be determined at this. Your firm did not include documentation or evidence of the corrections, corrective actions or consideration of systemic corrective actions in the response to FDA.
 
9.    Failure to establish and maintain procedures for the identification, documentation, validation, or where appropriate verification, review and approval of design changes before implementation, as required by 21 CFR 820.30(i).  For example, in January 2012, your firm changed the Total hemoglobin content from a range of 11.0-13.0 G/DL to 12.5-13.5 G/DL and the G-6-PDH at 37° C from 0-2.0 IU/L/Ghgb to .5-1.0 IU/L/Ghgb for G-6-PDH
Deficient Controls and these changes were made without validation or verification prior to implementation.
 
The adequacy of your firm’s response cannot be determined at this time. Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
The inspection also revealed that the Glucose 6 Phosphate Dehydrogenase (Normal, Intermediate and Depressed) Controls, is adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 351(f)(1)(B), because your firm does not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. § 360e(a), or an approved application for an investigational device exemption under section 520(g) of the Act, 21 U.S.C. § 360j(g). The device is also misbranded under section 502(o) the Act, 21 U.S.C. § 352(o), because your firm did not notify the agency of its intent to introduce the device into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. § 360(k). For a device requiring premarket approval, the notification required by section 510(k) is deemed satisfied when a PMA is pending before the agency. [21 CFR 807.81(b)] The kind of information that your firm needs to submit in order to obtain approval or clearance for the device is described on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/default.htm. The FDA will evaluate the information that your firm submits and decide whether the product may be legally marketed.
 
Additionally your firm’s devices including: Glucose 6 Phosphate Dehydrogenase (G-6-PDH) Depressed and Normal, Angiotensin Converting Enzyme (ACE), Galactose-1-Phosphate Uridyltransferase (Gal-1-PUT), NAFSC Variant Hemoglobin, Lyophilized ACS Hemoglobin Electrophoresis, Angiotensin Converting Enzyme, Lyophilized AFSC Hemoglobin Electrophoresis, Slide Platelet Aggregation Test (SPAT) Positive Controls, and the ACE Calibrator devices are misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 803 - Medical Device Reporting.  Significant violations include, but are not limited to, the following: Failure to adequately develop, maintain, and implement written MDR procedures, as required by 21 CFR 803.17.  For example, your firm has not established MDR procedures. 
 
The adequacy of your firm’s response cannot be determined at this time. Your firm did not include documentation or evidence of the corrections, corrective actions, or consideration of systemic corrective actions in the response to FDA.
 
The inspection also revealed that your firm’s Glucose-6-Phosphate Dehydrogenase (G-6-PDH) devices are misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 806 – Medical Devices; Reports of Corrections and Removals. Significant violations include, but are not limited to, the following:
 
Failure to submit a written Report of Correction or Removal initiated to remedy a violation of the act caused by the device which may present a risk to health, as required by 21 CFR Part 806.10(a)(2).  For example: Your firm received a complaint record dated 5/23/2013 alleging that Lot #I-78-2 was not meeting specifications and were getting results of 2.1 IU/L/gHgb when run at 30°C.  Your firm requested the customer return their product for a new Lot of product. After the product and labeling was returned, you determined that the labeling was missing the temperature value in the instructions for use.  A complaint record dated 6/6/2013 stated that they “added to the package insert the Assay Temp and place copies in the Lot folders.”  Your firm notified the affected user facility, Quest laboratories, of the missing temperature value, but did not notify the FDA of your correction.
 
Your firm’s response dated December 18, 2013 it is not adequate. Your firm stated, “The product has already had its insert corrected. As the product is an instrument control and not used to directly test the patient, the chance of patient harm is extremely unlikely and, in our estimation, not a reportable event. We will be updating our complaint form and complaint procedure to include inquiries about patient risk, and an evaluation to determine if the FDA requires notification.”  However, your firm did not provide evidence in your response that you met the requirements of 21 CFR Part 806.20. Your firm’s actions should have been reported to FDA as required by 21 CFR Part 806.10(a)(2.) 
  
Your firm 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 FDA without further notice.  These actions include, but are not limited to, seizure, injunction, and civil money penalties.  Also, federal agencies may be advised of the issuance of 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 violations are reasonably related will not be approved until the violations have 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 fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again.  Include documentation of the corrections and/or corrective actions (which must address systemic problems) that your firm has taken.  If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities.  If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed. Your firm’s response should be comprehensive and address all violations included in this Warning Letter. Additionally, please provide appropriate documentation supporting premarket clearance of the products below based on the current intended use of the product as outlined in the current marketing and advertising of the product:
 
NAFSC Variant Hemoglobin Control
Lyophilized ACS Hemoglobin Electrophoresis Control
Lyophilized AFSC Hemoglobin Electrophoresis Control
 
Your firm’s response should be sent to: Food and Drug Administration-Detroit District Office 300 River Place, Suite 5900 Detroit, MI 48207. Refer to CMS#417234 when replying.If you have any questions about the contents of this letter, please contact: CDR Kimberly Martin at (317) 226-6500 ext. 116.
 
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility.  It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA.  The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems.  Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance. 
 
 
Sincerely yours, 
/S/ 
Art O. Czabaniuk
Acting District Director
Detroit District Office