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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Biomedica Diagnostics Inc 10/17/11

  

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

Public Health Service
Food and Drug Administration
 10903 New Hampshire Avenue
Document Mail Center
WO 66 - Room 609
Silver Spring, MD 20993-00002 

 

 WARNING LETTER
  
October 17, 2011
 
VIA UNITED PARCEL SERVICE
 
Dr. Abdullah Kirumira
President and CEO
BioMedica Diagnostics, Inc.
94 Wentworth Road
P.O. Box 1030
Windsor, NS BON 2T0
Canada
 
Dear Dr. Kirumira:
 
During an inspection of your firm located in Windsor, Canada on May 30, 2011, through June 02, 2011, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures plasma, coagulation control products.  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 are intended to affect the structure or 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 (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. 
 
Our investigator’s observations were noted on the Form FDA 483 (FDA 483), List of Inspectional Observations that was issued to your firm. These violations include, but are not limited to, the following:
 
1.  Failure to establish and maintain adequate procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example, the underlying cause of the following non-conformities was not investigated and corrective actions were not identified:
 
  • The Material Discrepancy Report Number 090315, dated 3/15/09, documents that the caps on PT assay lot FHS 10-090309-20A appeared to be twisted due to wrong thread on caps. The cap thread was non-compatible with the vials. Your firm ordered caps for the first time from a catalog of this particular supplier and they were not compatible with the vials. Your firm did not document the results of the investigation including the name of the supplier, the lot number of the incoming product, and if any other lots of finished device were affected. There is no documented evidence that an investigation was conducted or that any actions were taken to prevent future non-conformances.
  • The Customer Support Report Number 100823, dated 8/23/10, and Customer Support Report Number 100128, dated 2/3/10, document that a customer was given a wrong Certificate of Analysis for APTT Lot Number A04-100702-N05, Calcium Chloride C04-091015-N05, APTT Lot Number A04-0909060-N05, and Calcium Chloride C04-081212-N05. There is no documented evidence that an investigation was conducted or that any actions were taken to prevent future non-conformances.
  • The Customer Support Report Number 100128, dated 2/3/10, documents that Control Level 2 1mL - CAT. NO. C.BMD.CON2-01ML-8AB, had two different expiry dates: 7/2011 and 7/2012. There is no documented evidence that an investigation was conducted or that any actions were taken to prevent future non-conformances.
  • The Customer Support Report Number 090920, dated 9/29/09, documents that a customer received a non-conforming manual for the QC400 analyzer. There is no documented evidence that an investigation was conducted or that any actions were taken to prevent future non-conformances.
 
2.  Failure to adequately ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use, as required by 21 CFR 820.70(g). For example, the (b)(4) used to (b)(4) has not been demonstrated to operate consistently at the specified operational parameters. 
 
3.  Failure to establish and maintain adequate procedures for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics, as required by 21 CFR 820.250(a). For example, regarding sampling used during acceptance activities, your firm has not established a sampling plan based on a valid statistical rationale. Further, the number of units sampled and inspected for physical appearance is not documented. The following products were received, sampled, inspected, and accepted without a valid statistical rationale for the sample size selected:
 
  • On 6/18/09, (b)(4) White Plastic Caps were accepted.
  • On 6/23/09, (b)(4) Clear Vials were accepted.
  • On 2/19/09, (b)(4) Vials were accepted.
  • On 2/23/10, (b)(4) White Caps for use with (b)(4) vials; (b)(4) 5mL (b)(4) Vials; (b)(4) 20mL (b)(4) Vials; and  (b)(4) Rubber Stoppers for use with (b)(4) vials were accepted.
  • On 4/29/11, the firm received (b)(4) White Caps for use with (b)(4) vials; (b)(4) 5mL (b)(4) Vials; and (b)(4) Rubber Stoppers for use with (b)(4) vials were accepted.
 
Your firm received, sampled and inspected only one bottle on each of the following (b)(4) shipments to check for discoloration and wetness. However, there is no statistical rationale for the current sampling plan:
 
  • On 3/25/11, (b)(4) bottles of 250g of (b)(4) were accepted.
  • On 8/27/09, (b)(4) bottles of 250g of (b)(4) were accepted.
  • On 10/21/09, (b)(4) of (b)(4) were accepted.
 
4.  Failure to adequately review, evaluate, and investigate any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications, as required by 21 CFR 820.198(c). For example, the procedure (b)(4) revision 1.2, dated 11/30/10, (b)(4) does not include requirements to ensure that all complaints are investigated where necessary. Further, there is no documented evidence that the following customer complaints were investigated:
 
  • Customer Support Report Number 100111, dated 1/11/10, which reports temperature problems and lack of oscillation of beads on the QC4000 analyzer. The record does not document the analyzer's lot number, if the product was returned or the underlying cause of the non-conformance.
  • Customer Support Report Number 090929, dated 9/29/09, which reports that customer calibration data (documented in the product's manual) was unusable. The record does not document the analyzer's lot number or the underlying cause of the non-conformance.
  • Customer Support Report Number 100128, dated 2/3/10, which reports that Control Level 2 was labeled with two different expiration dates, that the order of Control Level 3 was not complete, and that an incorrect Certificate of Analysis was sent for the APTT. The record does not document the Controls' and the APTT's lot number or the underlying cause of the non-conformance.
 
5.  Failure to establish and maintain adequate procedures to ensure that all purchased or otherwise received product and service conform to specified requirements, as required by 21 CFR 820.50. For example, the procedure, (b)(4) revision 1.2, dated 1/28/11, states that if the (b)(4) is not returned within a reasonable time, the supplier shall be rejected. However, at least one supplier was approved without obtaining the (b)(4)
 
The procedure, (b)(4) also does not ensure that an agreement is established, where possible, so that the suppliers, contractors and consultants agree to notify the firm of changes that may affect the quality of a finished device.
 
6.  Failure to establish and maintain adequate procedures for acceptance activities, as required by 21 CFR 820.80(a). For example, the Procedure (b)(4) revision 1.2, dated 1/28/11, was not implemented.
 
  • The following products were accepted without conforming to specifications:
 
a)   Normal Pooled Plasma was accepted on 7/13/10 without a Certificate of Negativity.
b)   Normal Pooled Plasma was accepted on 6/15/10 without a Certificate of Negativity.
c)   Normal Pooled Plasma was accepted on 5/4/10 without a Certificate of Negativity.
d)   Normal Pooled Plasma was accepted on 4/6/10 without a Certificate of Negativity.
e)   Normal Pooled Plasma was accepted on 5/4/10 with Certificate of Negativity lacking results for Syphilis testing.
f)    Normal Pooled Plasma was accepted on 7/21/09 with Certificate of Negativity lacking results for Syphilis testing.
g)   Normal Pooled Plasma was accepted on 5/6/09 with Certificate of Negativity lacking results for Syphilis testing.
h)   Normal Pooled Plasma was accepted on 4/1/09 with Certificate of Negativity lacking results for Syphilis testing.
 
  • The document (b)(4) does not include specifications to test the caps. According to Material Discrepancy Report Number 090315, on 3/15/09, your firm found that the caps used during the manufacture of the PT product, lot number FHS10-090309-20A, had the wrong thread.
 
7.  Failure to establish and maintain adequate procedures to ensure that all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid results, as required by 21 CFR 820.72(a). For example, your firm was unable to confirm, during the course of the inspection, with documented evidence, that the following equipment was calibrated and routinely maintained:
 
  • According to the (b)(4), the equipment required weekly and monthly maintenance. In addition, the catalog indicates that the (b)(4) Your firm has no documentation that preventive maintenance was conducted.
  • According to the (b)(4) for the (b)(4), the equipment requires weekly, monthly, and annual maintenance and annual calibration of the (b)(4). Your firm has no documentation that preventive maintenance was conducted.
 
8.  Failure to establish and maintain adequate procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient, as required by 21 CFR 820.30(c). For example, your firm failed to address the following ambiguous or conflicting requirements:
 
  • The (b)(4) documents that the requirements for (b)(4) are:    

Control
PT Assay
APTT Assay
Level I
10-14 seconds
25-35 seconds
Level II
14-20 seconds
45-65 seconds
Level III
23-30 seconds
70-100 seconds

  • The (b)(4) dated 09/01, documents that the requirements for (b)(4) are:

Control
PT Assay
APTT Assay
Normal Range (Level I)
8 – 16 seconds
27-35 seconds
Slightly Elevated (Level II)
1.5 times a normal PT
2 times PT Level II
Severely Elevated (Level III)
2.5 times a normal PT
2 times PT Level II

  • The (b)(4) date 09/01, states that the (b)(4) contain (b)(4) and requires the product insert to contain hazard warnings and recommended (b)(4) procedures. Your firm neglected to include the hazard warnings or recommended disposal procedures as the Canadian Hazardous Product Act only considers (b)(4) to be hazardous in concentrations greater than (b)(4) weight.
  • The firm failed to document the design input requirements for the packaging materials included the vial, caps and stoppers used to manufacture the coagulation controls. According to Design Change Control Number 030609, dated 6/9/03, your firm changed from (b)(4) vials to (b)(4) vials. According to Design Change Control Number 060209, dated 2/9/06, your firm changed to (b)(4) vials, introduced (b)(4) vials, and introduced (b)(4) bulk packaging of finished product.
  • Your firm failed to document the design input requirement for the labeling of bulk or individual units.
             
9.  Failure to establish and maintain adequate procedures for verifying the device design, as required by 21 CFR 820.30(f). For example, the review of the Design Plan and Risk Analysis revealed the following inputs:
 
  •  (b)(4) documented in the document (b)(4)

Control
PT Assay
APTT Assay
Level I
10-14 seconds
25-35 seconds
Level II
14-20 seconds
45-65 seconds
Level III
23-30 seconds
70-100 seconds

  • (b)(4) documented in the (b)(4) “ dated 09/01:

Control
PT Assay
APTT Assay
Normal Range (Level I)
8 – 16 seconds
27-35 seconds
Slightly Elevated (Level II)
1.5 times a normal PT
2 times PT Level II
Severely Elevated (Level III)
2.5 times a normal PT
2 times PT Level II

  • Expected precision document (b)(4): less than (b)(4) CV.
  • The (b)(4) dated 7/09, documents that the (b)(4) are to be (b)(4) to prevent (b)(4) to be shipped in the wrong temperature or in the wrong type of container.
 
The review of design output verifications revealed:
 
  • Record (b)(4) revision 1.0 dated 6/02, documents the following failures to meet specifications:
 
Table 11.1.1: (b)(4)

Control Level
(b)(4) of (b)(4)
Level 3 (High abnormal)
61.2 (Failed as per requirements document on (b)(4)

 
Table 11.1.2: Day to Day Precision Results using (b)(4)

           
Control Level        
(b)(4) of (b)(4)
Average
 
Level 3
61.8 (Failed as per requirements document on (b)(4)

 
Table 11.2.1: (b)(4)

Control Level
PT values of (b)(4)
Level 3 (High abnormal)
32.6 (Failed as per requirements document on (b)(4))

           
Table 11.2.2: Day to Day Precision Results using  (b)(4)

           
Control Level        
(b)(4) of (b)(4)
Average
 
Level 3
31.6 (Failed as per requirements document on (b)(4)

           
Table 11.3.1: Vital to Vital Precision Results using (b)(4)

           
Control Level        
(b)(4) of (b)(4)
Average
 
Level 3
61.6 (Failed as per requirements document on (b)(4)

 
**Table 11.3.1: Vital to Vital Precision Results using (b)(4)

           
Control Level        
PT values 
Average
 
Level 3
34.2 (Failed as per requirements document on (b)(4)

 
Table 11.5.1: PT: Stability of Reconstituted Vital Controls with (b)(4) assay

           
Control Level        
(b)(4)
6 hrs at 2-8 ºC
Level 3
37.1 (Failed as per requirements document on (b)(4)

 
Table 11.5.1: PT: Stability of (b)(4) Vital Controls with (b)(4) assay

           
Control Level        
(b)(4)
6 hrs at 2-8 ºC
Level 3
65.2 (Failed as per requirements document on (b)(4)

 
Table 11.6.1: Stability of (b)(4) controls (b)(4) Results

           
Control Level        
(b)(4) of (b)(4)
41/2 weeks at 2-8 ºC
 
Level 3
36.2 (Failed as per requirements document on (b)(4)

 
The Real Time Shipping Study shows that the %CV is (b)(4) and failed to meet specifications as follows:
 
Table 2.1: Shipping Stability Round Trip (b)(4)

Test
%CV
(b)(4)
(b)(4)

 
Table 2.2 Shipping Stability (b)(4)

Test
%CV Change between (b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)

 
The firm failed to document why different testing equipment was used during this validation and why the deviations were acceptable.
 
10.  Failure to establish and maintain adequate 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, the procedure (b)(4) revision 1.1, dated 1/10/06, section 5.9 (b)(4) states that (b)(4) shall be documented using Form 9.3: (b)(4) However, the following design changes were not documented:
 
  • The product inserts for (b)(4) revision 1.0, dated 3/16/03, were changed. The design changes made to the inserts for (b)(4), revision 3.2, dated 2/2010, were not documented, verified, reviewed, and approved as per procedure (b)(4)" Further, there is no documented evidence that the new (b)(4)" documented in the inserts, revision 3.2, meets the design inputs documented in the "(b)(4) dated 11/2000.
  • According to document (b)(4)," dated 1/30/03, the firm conducted a validation study for the use of (b)(4) vials. However, record (b)(4) revision 1.5, dated 6/23/05, documents that your firm is currently using (b)(4) vials sizes 5mL, 10mL and 20mL. There is no documented evidence that this design change was verified, validated, reviewed, and approved as per procedure (b)(4)."
 
11.  Failure to establish and maintain adequate procedures for validating the device design, as required by 21 CFR 820.30(g). For example, the following validation reports are incomplete:
 
  • Document (b)(4)" revision 1.0, dated 6/2002, does not document the product's lot numbers, the reference product's identity including lot numbers, and the equipment used during the PT Stability of (b)(4)  Vital controls with (b)(4) assay study, and (b)(4) study. Further, your firm was unable to produce documented specifications for the expected results.
  • Document (b)(4)," dated 1/2003, does not document the product's lot numbers, the reference product's identity including lot numbers, and the equipment used during the validation. Further, your firm was unable to produce documented specifications for the expected results.
  • Document (b)(4) does not document the interpretation of the stability study results that support the claimed shelf-life for QuikCoag Coagulation Plasma of (b)(4). Further, your firm was unable to produce documented specifications for the expected results.
 
12.  Failure to establish and maintain adequate procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the devices design development, as required by 21 CFR 820.30(e). For example, the procedure (b)(4) revision 1.1, effective date 1/10/06, section 5.6, (b)(4) does not specify the requirement to include an individual with no direct responsibility for the design stage begin reviewed. 
 
13.  Failure to establish and maintain adequate procedures to control all documents, as required by 21 CFR 820.40. For example, the (b)(4) revision 1.2 dated 3/21/06 does not adequately ensure that records of changes to documents include a description of the change and when the change becomes effective. Your firm only maintains a (b)(4) which lists the documents that were changed, the new version and the approval. The (b)(4) does not record a description of the change or when the change became effective. Your firm implemented a new system to assign lot numbers according to an email dated 1/28/22. However, the Work Instruction
 
14.  WI057 (b)(4) revision 1.0, dated 3/1/10, and Work Instruction WI058 (b)(4) revision 1.0, dated 3/1/10, were not updated when the change became effective.
 
The procedure (b)(4) does not ensure that authorized personnel review all documents affecting quality for adequacy. For example, your firm maintains a (b)(4)” to reference a list of records which document the stages of design controls. However, the (b)(4) does not include document identifiers such as dates, revision, etc. In addition, the firm was unable to trace back the documents referenced in the checklist.
 
The procedure (b)(4) does not reflect your firm’s current practices. For example, your firm no longer (b)(4)
 
A follow up inspection will be required to assure that corrections and/or corrective actions are adequate. 
 
U.S. 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 deviations 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, including 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 action (including any systemic corrective actions) 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.  Please provide a translation of documentation not in English to facilitate our review.
 
Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Operations Branch, White Oak Building 66, Rm 2609, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #227736 when replying. If you have any questions about the contents of this letter, please contact: James Woods at (301) 796-6225.
 
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/                                                                    
Alberto Gutierrez
Director
Office of In Vitro Diagnostic Device
Evaluation and Safety
Center for Devices and
Radiological Health