Quantimetrix = Corporation, Warning Letter

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Department of Health and Human Services	Public Health Service Food and Drug = Administration
	Los Angeles District 19701 Fairchild Irving, CA=20 92612-2506

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REOUESTED

May 17, 2007

W/L 12-07

Edward T. Cleek, CEO
Quantimetrix Corporation
2005 Manhattan = Beach=20 Blvd.
Redondo Beach, CA 90278

Dear Mr. Cleek:

During an inspection of your firm located in Redondo Beach, CA on = November=20 27, 2006 through February 6, 2007, investigators from the United States = Food and=20 Drug Administration (FDA) determined that your firm manufactures = Spinalscopics,=20 Synovialscopics, QuanTscopics, DipandSpins, GlycoHemosure, and the = Lipopprint=20 Subfractionation System. Under section 201(h) of the Federal Food, Drug, = and=20 Cosmetic Act (the Act), 21 U.S.C. 321(h), these products are devices = because=20 they are intended for use in the diagnosis of disease or other = conditions or in=20 the cure, mitigation, treatment, or prevention of disease, or are = intended to=20 affect the structure or function of the body.

This inspection revealed that these devices are adulterated within = the=20 meaning of section 501(h) of the Act (21 U.S.C. =A7 351(h)), in that the = methods=20 used in, or the facilities or controls used for, their manufacture, = packing,=20 storage, or installation are not in conformity with the Current Good=20 Manufacturing Practice (CGMP) requirements of the Quality System (QS) = regulation=20 found at Title 21, Code of Federal Regulations = (C.F.R.), Part=20 820. We received responses from Edward Cleek, CEO and Bernice Navarro, = QA/RA=20 Manager and Site Representative dated February 27, 2007 concerning our=20 investigator's observations noted on the Form FDA 483, List of = Inspectional=20 Observations that was issued to you and a subsequent progress report = dated April=20 18, 2007. We address these responses below, in relation to each of the = noted=20 violations. These violations include, but are not limited to, the = following:=20

1) Management with executive responsibility did not ensure that an = adequate=20 and effective quality system was fully implemented and maintained at all = levels=20 of the organization [21 C.F.R. 820.20]. Specifically,

(a) There was a decision to become an alternate supplier for=20 [redacted] for use in the production of your = Spinalscopics,=20 QuanTiscopics, Synovialscopics and DipandSpin controls.=20 [redacted] were made by R&D using unapproved = procedures.=20 The documentation for the stabilized cell lots produced by R&D = between=20 2001 and 2003 does not demonstrate that the cells were made to your = own=20 procedures; the process was not validated; the accelerated stability = studies=20 were not complete; and the assignment of expiration dates was = inconsistent=20 with the prepared Component Specification Record and Certificate of = Analysis.=20

(b) Procedures and instructions regarding the recording of test = results=20 were not always followed as demonstrated through review of = records/laboratory=20 books for the preservative challenge (3/04), the = [redacted]=20 the extended expiration date of Spinalscopics (lot=20 [redacted]), and the design history records of = GlycoHemosure.=20

We have reviewed your response and have concluded that it is = inadequate=20 because for observation 1(a) you have not addressed corrective action = for=20 product previously distributed and currently in use.

2) Production processes were not developed to ensure that a device = conforms=20 to its specifications [21 C.F.R. 820.70(a)]. Specifically, R&D = batches=20 of [redacted] were prepared and used in the production = of=20 finished devices, Spinalscopics (lot #s [redacted]),=20 QuanTscopics (lot #s [redacted]), Synovialscopics (lot=20 #s [redacted), and Dip & Spin (lot #s=20 [redacted])

We have reviewed your response and have concluded that it is = inadequate=20 because you have not addressed corrective action for product previously=20 distributed and currently in use.

3) Not all of the actions needed to correct and prevent the = recurrence of=20 nonconforming product and other quality problems were identified. = Specifically,=20 your firm documented decreasing [redacted] = Spinalscopics, lot=20 #46170, during the accelerated stability testing for extending the = expiration=20 date and there was no nonconformance prepared for the decreasing = [redacted] [21 C.F.R. 820.100(a)(3)].

We have reviewed your response and have concluded that it is = inadequate=20 because you did not identify the root cause of this deficiency which = would be=20 corrected by the additional training.

4) A process, with results which cannot be fully verified by = subsequent=20 inspection and test, was not adequately, fully validated and approved = according=20 to established procedures [21 C.F.R. 820.75(a)]. Specifically,

(a) [redacted] of the Lipoprint System LDL = subfraction=20 kits are manufactured in part by mixing [redacted]. = Those=20 mixing processes were not validated. This is a repeat observation. =

(b) [redacted] are [redacted] for = use in=20 Spinalscopics, QuanTscopics, Synovialscopies and Dip & Spin = controls.=20 Those processes were not validated.

(c) The acceptance criteria listed under the protocol section in = the=20 Preservative Validation Report for the Replacement of=20 [redacted] in Urine Dipstick Products (dated 3/31/04) = did not=20 have a clear definition of:

(1) How tubes are rated by presence and concentration of growth. =
(2)=20 The set distance for placement of the saturated disks on the plate. =
(3)=20 Method for measuring zones of inhibition in millimeters.
(4) = Quantified=20 number of bacteria for the acceptance criteria.

(d) There was no raw data to substantiate all computer generated = tables=20 generated for the Preservative Validation Report for the Replacement = of=20 [redacted] in Urine Dipstick Products (dated = 3/31/04).

(e) There was no protocol or documentation that the validation for = the=20 [redacted] filling machine has been performed. This = equipment=20 was used to fill vials of finished devices.

(f) There was no protocol or documentation that the validation for = cap=20 torquing has been performed. Your firm received [redacted]=20 two complaints for product leakage = [redacted].=20

We have reviewed your response and have concluded that it is = inadequate=20 because for observation 4(a) you have not addressed why this repeat = observation=20 had not been corrected after the 2003 inspection; for observation 4(b) = you have=20 not addressed product currently on the market; and for observations 4(c) = and=20 4(e) you have not explained the length of time until completion which = appears to=20 be excessive.

5) Employee training was not fully documented [21 C.F.R. 820.25(b)].=20 Specifically,

(a) There was no documented training for the CEO, President, or = Quality=20 Control Manager in the firm's current quality manual (includes the = firm's=20 quality policy), Revision F.

(b) There was no documented training for the Lead Auditor=20 [redacted] or 2006 auditors, [redacted] = and=20 [redacted] in the firm's Internal Audit Procedure, QSP-17, = Revision=20 C.

Your response to this observation appears to be adequate.

6) Employees were not adequately trained [21 C.F.R. 820.25(b)]. = Specifically,=20

(a) Only 16 out of approximately 60 employees received training in = cGMP on=20 1/11/05 and no additional group training was held in 2006.

(b) Out of 11 initial training records reviewed, only 1 person=20 ([redacted] was documented as receiving cGMP training = on=20 1/11/05 and again on 9/9/05. This employee was not documented as = receiving the=20 group training on 1/11/05.

(c) Employees were not always = trained on=20 changes to procedures and records.

(d) SOP-01-031, Quantimetrix Personnel Training indicates = management=20 follow-up in the effectiveness of training is to be performed via an=20 oral/written examination with the results documented. Out of 11 plus = training=20 files reviewed, there were no documented training examination results=20 maintained.

Your response to this observation appears to be adequate.

7) Employees were not made aware of device defects that could occur = when they=20 improperly perform their jobs [21 C.F.R. 820.25(b)(1)]. = Specifically,

(a) A correction was made to the percentage of recovery on 10/3/05, = from [redacted] % to [redacted] % = that=20 caused [redacted] at [redacted] = degree C not=20 to be within the [redacted] % specification. There = was no=20 nonconformance prepared.

(b) During real time stability, inaccurate recordings of WBC and = RBC counts=20 for Spinalscopics, Level 1, lot [redacted] caused the = product=20 to be outside the 1-10 [redacted] ranges. There was = no=20 nonconformance prepared for the out of [redacted] = ranges.=20

(c) During real time stability, inaccurate recordings of=20 [redacted] and [redacted] for Spinalscopics, = Level=20 1, lot [redacted] caused the product to be outside=20 the [redacted] range for [redacted]. = There=20 was no nonconformance prepared for the out of = [redacted]=20 range.

(d) Single [redacted] recordings for=20 [redacted] and [redacted] for = devices in the=20 firm's real time stability program (Spinalscopics, lot=20 [redacted]) are not made in accordance with the = stability=20 procedure, which requires recording the averaging of=20 [redacted] units at each test interval. =

We have reviewed your response and have concluded that it is = inadequate=20 because you have not addressed why the nonconformances were not = prepared; we are=20 therefore unable to evaluate your corrective action.

8) Quality audits were not conducted at sufficient regular intervals = as=20 prescribed by internal procedure to verify that the quality system is = effective=20 in fulfilling the quality system objectives [21 C.F.R. 820.22]. = Specifically,=20 the Internal Audit Procedure states the audit schedule is based on = ensuring all=20 elements of ISO 13485, IVD Directive and CMDCAS ISO 13485 are audited = for not=20 less than [redacted]

(a) The Quality Control Department is scheduled for auditing during = the 1st=20 quarter of a year. No auditing of this department was conducted in = 2006. The=20 last documented audit of this department occurred on 3/28/05.

(b) Sales & Marketing is scheduled for auditing during the 3rd = Quarter=20 of a year. No audit of this department was done in 2006. =

We have reviewed your response and have concluded that it is = inadequate=20 because you have not addressed the lack of audits in 2006 and have not = planned=20 the corrective action for completion until the third quarter of = 2007.

9) Individuals who conduct quality audits have direct responsibility = for the=20 matters being audited, in violation of 21 C.F.R. 820.22. Specifically, = one=20 [redacted] of the individuals who audited manufacturing = on=20 3/6/06 had direct responsibility over the area he audited.

We have reviewed your response and have concluded that it is = inadequate=20 because you have not addressed how [redacted] was = assigned to=20 audit an area he had direct responsibility for and how management will = correct=20 that from happening in the future.

10) The Design History File was not established or maintained for the = Liproprint LDL and HDL Subfraction System [21 C.F.R. 820.30(j)].

We have reviewed your response and have concluded that it is = inadequate=20 because you have not explained why it will take one year for correction. =

11) The Design History File does not demonstrate that the design was=20 developed following the approved design plan and the design control = requirements=20 of 21 CFR 820. Specifically, the design history file (DHF) for = GlycoHemosure,=20 Hemoglobin Alc (HbAlc) Control is incomplete or procedures were not = followed.=20 [21 C.F.R. 820.30(j)].

(a) The designated project leader did not maintain or update the = file as=20 required by your firm's design control procedure. There were unsigned = computer=20 generated copies for design activities (e.g. approval of design = output,=20 approval of 12/31/03 minutes for release of device to market). [21 = C.F.R.=20 820.30(a)].

(b) The Design Input procedure for defining design inputs was not = followed=20 for the design inputs approved on 6/20/03. [21 C.F.R. 820.30(c)].

(c) Design outputs did not include test methods and a device master = record.=20 [21 C.F.R. 820.30(d)].

(d) The risk analysis is incomplete in that the risk analysis = report dated=20 4/17/04, risk analysis for GlycoHemosure HbAlc Control Level 1 and 2 = did not=20 include the risks of microbial growth or contamination within the = product.=20 Additionally the risk analysis was not performed according to = established=20 procedures, SOP-12 007, Risk Analysis Procedure, which requires the = risk=20 analysis to be performed utilizing the [redacted] = approach=20 but was not conducted or documented in this
manner. [21 C.F.R. = 820.30(g)].=20

(e) Acceptance criteria were not defined prior to performance of=20 verification activities. For example, the GlycoHemosure device was = developed=20 for use on immunoassay or HPLC instruments. There is no acceptance = criteria=20 defined for the DCA 2000 instrument. [21 C.F.R. 820.80].

(f) Not all design reviews identified the independent person (e.g. = 8/8/03,=20 9/29/03 and 12/31/03). [21 C.F.R. 820.30(e)].

(g) The 8/8/03 = dated=20 Meeting Minutes states a validation report (manufacturing process) = will be=20 based on three production batches by 12/31/03. No validation report = has been=20 written because only [redacted] production lots have = been=20 manufactured (lot #s [redacted]. [21 C.F.R. 820.75].=20

Your response to this observation appears to be adequate but we are = concerned=20 that the corrections are scheduled for completion in the third quarter = of 2007.=20 Your response should explain the need for this length of time.

12) The Design History File does not demonstrate that the design was=20 developed following the approved design plan and the design control = requirements=20 of 21 CFR 820. Specifically, the firm's design control procedures were = not=20 followed for the Spinalscopics Control. There was no design plan in the = DHF,=20 there were no approved design inputs, and the risk analysis was not = performed=20 according to the firm's procedure, which requires the use of the=20 [redacted] approach. The DHF also lacks documentation = of design=20 design validation, design review, and design transfer activities.

Your response to this observation appears to be adequate but we are = concerned=20 that the correction is scheduled for completion in the third quarter of = 2007.=20 Your response should explain the need for this length of time.

13) Acceptance records did not include the results of certain = acceptance=20 activities [21 C.F.R. 820.80(e)(1)]. Specifically, real time stability = tests are=20 not conducted according to the firm's Stability Procedure. For example, =

(a) The most recent production lot of = [redacted]=20 has not been entered into the firm's real time stability = program.=20

(b) The most recent production lot of = [redacted]=20 has not been entered into the firm's real time stability = program.=20

(c) No real time stability testing was performed at the=20 [redacted] interval month because reagents were not on hand = to=20 perform the stability test (Worksheet for Dipper, lot # = [redacted]=20

(d) No real time stability testing was performed on GlycoHemosure, = lot=20 # [redacted] at the [redacted] month = interval because the firm did not retain a sufficient amount of = product in=20 inventory to perform the stability testing.

(e) Real time = stability=20 testing was not performed on GlycoHemosure Control, lot #=20 [redacted] in a timely manner at the=20 [redacted] months interval and no testing was performed = during the=20 [redacted] months interval. However, the expiration = date was=20 extended to 3/06.

(f) No real time stability testing of open and closed vials was = performed=20 on Spinalscopics, lot # [redacted] at the=20 [redacted] months interval. Accelerated stability on = closed=20 vials (only) was performed in 10/06 to support the extended expiration = date of=20 11/07.

We have reviewed your response and have concluded that it is = inadequate=20 because you did not explain why the nonconformance in observation 13(c) = was not=20 issued so that your corrective action could be evaluated; you did not = explain=20 your logic that allows the conclusion that the expiration date extension = in=20 observation 13(e) was appropriate; and for observation 13(f) you have = not=20 addressed product potentially on the market with inadequately supported=20 expiration dates.

14) Software used as part of the production quality system was not = validated=20 for its intended use according to an established protocol [21 C.F.R. = 820.70(i)].=20 Specifically,

(a) Spreadsheets intended to check for outliers and calculate mean, = SC, %=20 CV, value assignments for finished devices.

(b) Complaint = handling=20 software

(c) Quantrol database program

15) Procedures to ensure that all purchased or otherwise received = product and=20 services conform to specified requirements were not established [21 = C.F.R.=20 820.50]. Specifically, independent laboratories evaluated production = lots for=20 the purpose of contributing to the device value assignments. Those = laboratories=20 were not on the approved vendor list.

16) Corrective and preventive action activities were not documented,=20 including the actions needed to correct or prevent recurrence of = nonconforming=20 product and other quality problems, and implementation of corrective and = preventive actions [21 C.F.R. 820.100(b)]. Specifically,

(a) In 9/2000, the packaging of Lipoprint System LDL kits was = changed by=20 adding [redacted] in the [redacted]. = There=20 were no records of the corresponding packaging validation. The = corrective=20 action is incomplete in that the packaging validation did not show=20 repeatability, did not identify how many tubes were included in the = transport=20 stress test performed during the validation, and did not specify the = shipping=20 details, i.e., weight of the shipping carton. This is a repeat = observation.=20

(b) Temperature recording charts for [redacted] = indicated=20 temperatures were outside the acceptable range on at least four (4) = occasions.=20 The corrective action required investigating the effect of temperature = fluctuations on the product when the freezers were not within the = acceptable=20 range. This evaluation was not performed.

(c) Release testing results for Lipoprint lot # [redacted]=20 were outside the acceptable range. There were no records = indicating=20 that the department supervisor was notified and there was no = documentation of=20 investigation/analysis for root cause. The firm's corrective action = included=20 retraining employees in cGMP practices. There is no documentation to = show=20 training of all employees.

Your response to this observation appears to be adequate but we are = concerned=20 that the corrections are scheduled for completion in the fourth quarter = of 2007.=20 Your response should explain the need for this length of time. Also, you = have=20 not addressed why observation 16(a) was not corrected after the 2003=20 inspection.

17) There was no corrective and preventive procedure to determine = when=20 verification can be conducted in lieu of validation [21 C.F.R. = 820.100(a)(4)].=20 Specifically, Corrective and Preventive Action Procedure, QSR-14, = effective=20 7/14/06, Rev J requires the QA/RA Department to determine the need for=20 validating an action only. The procedure does not address verifying = actions.=20

Your response to this observation appears to be adequate.

18) Appropriate sources of quality data were not adequately analyzed = to=20 identify existing and potential causes of nonconforming product and = other=20 quality problems [21 C.F.R.820.100(a)(1)]. Specifically, trend reports,=20 presented during management reviews, for data sources (e.g. power points = of=20 technical supports, complaints) from May 2005-May 2006 were not = problem/product=20 specific.

19) A justification for not reporting the correction or removal = action to FDA=20 that included conclusions and reviews by a designated person was not = included in=20 the correction or removal records [21 C.F.R. 806.20(b)(4)]. = Specifically, there=20 was no justification maintained for not reporting to FDA:

(a) A June 19, 2006 technical update suggesting the=20 [redacted] dilution of [redacted] controls = for use=20 with the Icon 25 hCG kits due to possible partial or inhibition of = reactivity,=20 presenting as a weak positive or a false negative.

(b) A March = 31, 2006=20 technical update limiting the use of The Dipper, Dropper, and Dropper = Plus=20 controls with pregnancy test kits.

(c) A January 26, 2006 technical update revising the Quan Test = Human=20 Protein Standards product insert changing the referenced NIST from SRM = 927a=20 (obsolete) to NIST SRM927c.

(d) A March 24, 2005 technical update reporting errors in the = product=20 insert in the values and ranges for the International System of Units = for the=20 HDL Plus Control.

(e) A July 26, 2006 technical update = correcting=20 errors in the Visual table used with The Dipper, The Dropper and The = Dropper=20 Plus Visual Examination.

(f) A January 11, 2006 technical update correcting the expected = range for=20 specific gravity for The Dipper, The Dropper, and The Dropper Plus. =

(g) A June 16, 2006 technical update revising the expected range of = [redacted] and [redacted] for the = Dip and=20 Spin control material.

(h) A November 8, 2006 technical update revising the expected range = for [redacted] in response to customer inquiries = concerning=20 the [redacted] for Spinalscopics: Spinal Fluid Cell = Count=20 control.

(i) A January 6, 2006 technical update revising the reporting units = from=20 mg/dL to mg/L for Microalbumin using The Dipper, Dropper, Dropper = Plus, and=20 DipandSpin urine dipstick control material.

(j) A January 9, = 2006=20 technical update correcting errors in the product insert for the Dip = &=20 Spin.

We have reviewed your response and have concluded that it is = inadequate=20 because you have not directly addressed the issue of why the = justifications you=20 provided in your response were not part of the record required by 21 = C.F.R=20 820.20, Furthermore, the agency disagrees that the corrections = referenced in=20 observations 19(a) and (h) are not reportable because of serious = consequences=20 that could result from the incorrect validation of pregnancy test kit=20 performance in 19(a) or the potential need for an additional spinal tap = in=20 19(h).

20) Complaint handling procedures for complaints were not implemented = [21=20 C.F.R. 820.198(a)]. Specifically, [redacted] of=20 [redacted] complaints reviewed exhibited failures of = the=20 device, its labeling, or packaging to meet specifications. These = complaints were=20 not investigated.[redacted] of [redacted]=20 complaints did not include the reason for no investigation. =

We have reviewed the documentation you submitted in your progress = report and=20 concluded it is not adequate because not all of the complaints covered = by this=20 observation were addressed. Furthermore, you have provided documents = dated prior=20 to the inspection which were not available during the inspection. You = should=20 explain why they were previously unavailable.

21) Records of a complaint investigation did not include appropriate=20 corrective action [21 C.F.R. 820.198(e)(7)]. Specifically, microbial = testing of=20 Synovialscopics Control was performed on 4/19/05 as part of an = investigation=20 into a complaint of microbial contamination. Although there were no=20 positive/negative controls run when the microbial test was performed, no = corrective action was taken.

We have reviewed the documents submitted in your progress report and = note the=20 changes made to the manufacturing record. Your response to this = observation=20 appears to be adequate and we will confirm the adequacy of those = corrections at=20 your next inspection.

22) Written MDR procedures were not developed [21 C.F.R. 803.17].=20 Specifically, SOP 12-004, Medical Reporting, effective date 04/04/06, = was=20 developed to comply with reporting to the Competent Authority, not to = FDA.

Your response to this observation appears to be adequate.

23) Schedules for the adjustment, cleaning and other maintenance of = equipment=20 were not implemented [21 C.F.R. 820.70(g)(1)]. Specifically, two = instrument=20 S/N [redacted] and S/N [redacted] used = during=20 testing of finished devices were observed on 11/27/06 as requiring = preventative=20 maintenance.

Your response to this observation appears to be adequate.

You should take prompt action to correct the violations addressed in = this=20 letter. Failure to promptly correct these violations may result in = regulatory=20 action being initiated by the Food and Drug Administration without = further=20 notice. These actions include, but are not limited to, seizure, = injunction,=20 and/or civil money penalties. Also, federal agencies are advised of the = issuance=20 of all Warning Letters about devices so that they may take this = information into=20 account when considering the award of contracts. Additionally, premarket = approval applications for Class III devices to which the Quality System=20 regulation deviations are reasonably related will not be approved until = the=20 violations have been corrected. Requests for Certificates to Foreign = Governments=20 will not be granted until the violations related to the subject devices = have=20 been corrected.

Please notify this office in writing within fifteen (15) working days = from=20 the date you receive this letter of the specific steps you have taken to = correct=20 the noted violations, including an explanation of how you plan to = prevent these=20 violations, or similar violations, from occurring again. Include = documentation=20 of the corrective action you have taken. If your planned corrections = will occur=20 over time, please include a timetable for implementation of those = corrections.=20 If corrective action cannot be completed within 15 working days, state = the=20 reason for the delay and the time within which the corrections will be=20 completed.

Your response should be sent to:

Pamela B. Schweikert
Director, Compliance = Branch
United=20 States Food and Drug Administration
19701 Fairchild
Irvine, CA=20 92612-2506

If you have any questions about the content of this letter please = contact:=20 John J. Stamp, Compliance Officer at = 949-608-[redacted].

Finally, you should know that this letter is not intended to be an=20 all-inclusive list of the violations at your facility. It is your = responsibility=20 to ensure compliance with applicable laws and regulations administered = by FDA.=20 The specific violations noted in this letter and in the Inspectional=20 Observations, Form FDA 483 (FDA 483), issued at the closeout of the = inspection=20 may be symptomatic of serious problems in your firm's manufacturing and = quality=20 assurance systems. You should investigate and determine the causes of = the=20 violations, and take prompt actions to correct the violations and to = bring your=20 products into compliance.

Sincerely,

/S/

Alonza E. Cruse
Los Angeles District Director

cc: Department of Health Services
Food and Drug Branch P.O. =
Box=20 997413, MS-7602
Sacramento, CA 95899-7413

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