

Quality Notification
QN-RDS-CoreLab-2022-067
RDS / Immunology
Case Investigation & Resolution
Version 2
01-Dec-2022

Elecsys® Folate III signal loss issue

Product Quant. GMMI Lot No.
Elecsys Folate III N/A 07559992 190 596881
Elecsys Folate III N/A 07559992 190 648223
Elecsys Folate III N/A 07559992 160 596894
Elecsys Folate III N/A 07027290 190 590062
Elecsys Folate RBC N/A 05944295 190 596898
Elecsys Folate RBC N/A 05944295 160 596898
Elecsys Folate III N/A 07559992 190 657860
Elecsys Folate III N/A 07559992 160 657973
Elecsys Folate RBC N/A 05944295 190 657986
Elecsys Folate RBC N/A 05944295 160 657986

Instrument/System cobas e 411 analyzer a618

cobas e 601 module a619
cobas e 602 module a2325
cobas e 801 module a2497
cobas e 402 analytical unit a9494

Component Reagent

Target Group Application

Details Customer action

Affiliate action
Control results affected
Sample results affected
Feedback required by Affiliate

Feedback Due Date 01-Mar-2023

10
Template Version 1.9 Roche internal
 
Elecsys® Folate III signal loss issue

Executive Summary
The information from Version 2 of this QN is shown in blue.

We regret to inform that based on feedback from complaints and internal investigations we confirmed a signal loss
issue with the following Elecsys® Folate III reagent kit lots:

- Elecsys® Folate III kit lot 590062 (GMMI 07027290 190) for cobas e 801 and cobas e 402
- Elecsys® Folate III kit lot 596881 (GMMI 07559992 190) for cobas e 411, cobas e 601, and cobas e 602.

The following lots: Elecsys® Folate III kit lot 596894 (GMMI 07559992 160) and Elecsys® Folate RBC kit lot 596898
(GMMIs 05944295 190/160) have been produced in the same production event as the affected Elecsys® Folate III
kit lot 596881 (GMMI 07559992 190) and are considered to also be affected by the issue.

This Notification provides information on timelines of availability of new lots, bridging solutions, and workarounds
for the affected lots.

Version 2 of this QN informs about additional affected lots with the signal loss issue for cobas e 411, cobas e 601,
and cobas e 602:
- Elecsys Folate III kit lot 657860 (GMMI 07559992 190)
- Elecsys Folate III kit lot 657973 (GMMI 07559992 160)
- Elecsys Folate RBC kit lot 657986 (GMMIs 05944295 190/160)

Escalated Case Number CN-694142

CAPA No. 290008217

Change History
Version Date Description
1 24-May-2022 Initial release

2 01-Dec-2022 Information added about additional affected lots 657860, 657973, and
657986

Subject
We regret to inform that based on feedback from complaints and internal investigations we confirmed a signal loss
issue with the following Elecsys® Folate III reagent kit lots:

- Elecsys® Folate III kit lot 590062 (GMMI 07027290 190) for cobas e 801 and cobas e 402
- Elecsys® Folate III kit lot 596881 (GMMI 07559992 190) for cobas e 411, cobas e 601, and cobas e 602.

Customer complaints obtained mainly regarding:

- Tendency for high QC recovery (sometimes high out-of-specifications >+3SD)
- Reduced calibration stability (need for frequent calibration)
- Low calibration signals

Quality Notification | Immunology | QN-RDS-CoreLab-2022-067 | Version 2 | Template Version 1.9 2/9

Roche internal
 
Elecsys® Folate III signal loss issue

- Failed calibrations due to low calibration factor and/or minimum signal error.

For Elecsys® Folate III kit lot 590062 (GMMI 07027290 190), both applications: Folate serum/plasma (for USA:
Folate serum) and Folate RBC applications are affected.

The following lots: Elecsys® Folate III kit lot 596894 (GMMI 07559992 160) and Elecsys® Folate RBC kit lot 596898
(GMMIs 05944295 190/160) have been produced in the same production event as the affected Elecsys® Folate III
kit lot 596881 (GMMI 07559992 190) and are considered to also be affected by the issue.

Based on internal data at R&D and real world data monitoring, Elecsys Folate III kit lot 657860 (GMMI 07559992
190) is also affected with the signal loss issue.
The following lots: Elecsys® Folate III kit lot 657973 (GMMI 07559992 160) and Elecsys® Folate RBC kit lot 657986
(GMMIs 05944295 190/160) have been produced in the same production event as the affected Elecsys® Folate III
kit lot 657860 (GMMI 07559992 190) and are considered to also be affected by the issue.
No escalated complaints have been obtained yet for the affected lots 657860, 657973, and 657986.

Based on currently available data, no further Elecsys® Folate III and Elecsys® Folate RBC lots are affected by the
issue, refer to Table 1 for an overview.

Table 1. Overview of currently not expired lots:

Assay
Instruments Not affected Affected
GMMI number
cobas e 411 596881 (exp. Jun/2023)
Elecsys® Folate III
cobas e 601 651618 (exp. Jul/2023) 648223 (exp. Jun/2023, bridging solution)
07559992 190
cobas e 602 657860 (exp. Dec/2023)
cobas e 411
Elecsys® Folate III 596894 (exp. Aug/2023)
cobas e 601 651630 (exp. Jul/2023)
07559992 160 657973 (exp. Jun/2024)
cobas e 602
Elecsys® Folate III cobas e 801 651508 (exp. Apr/2024)
590062 (exp. Aug/2023)
07027290 190 cobas e 402 657684 (exp. Jun/2024)
cobas e 411
Elecsys® Folate RBC 596898 (exp. Aug/2023)
cobas e 601 -
05944295 190/160 657986 (exp. Jun/2024)
cobas e 602

Impact for customers:

1) The continuous signal loss causes reduced calibration stability leading to increased QC and sample recovery
over time after calibration.

During internal investigation, the claims for the calibration frequency as per respective Method Sheets were tested
for the affected reagent kit lots 590062 and 596881 and 657860 using PreciControl® Varia and native samples.
The claim for the calibration frequency when using the same reagent lot (“lot calibration”) was not fulfilled for
reagent kit lots 590062 and 596881 and 657860.
The claim for the calibration frequency when using the same reagent kit on the analyzer (“reagent
pack/cassette/R.Pack calibration”) was not fulfilled for reagent kit lot 590062.
(Acceptance criterion: deviation ≤0.6 ng/mL for samples up to 4 ng/mL and deviation ≤15% for samples >4
ng/mL compared to the recovery on the day of calibration).

Therefore more frequent calibration to what is claimed in the respective Method Sheets is needed for all affected
lots that are showing signal loss (refer to Actions for customers in section “Important Information”).

Quality Notification | Immunology | QN-RDS-CoreLab-2022-067 | Version 2 | Template Version 1.9 3/9

Roche internal
 
Elecsys® Folate III signal loss issue

2) Failed calibration due to violation of the calibration factor and/or minimum signal calibration criteria may occur.
As the signals for the affected lots decrease continuously over time, the probability for failed calibrations increases.

CN-694142 has been set up as the parent case and CAPA 290008217 has been initiated for processing this issue.

Root Cause
Root cause investigation is currently ongoing. Current investigation results indicate the R2 reagent component of
the affected reagent kit lots as a possible root cause.
Version 2:
Internal investigations confirmed that the issue is due to the R2 reagent component of the affected kits.
In depth investigations are still on-going for further clarifications on the root cause.
Until the root cause investigation is finalized, real world data monitoring is on-going for all lots.

Risk Assessment
Frequency of Occurrence
The issue affects all kits of the affected lots.

Detectability
The reported issue is indicated in the increasing QC recovery and/or failed calibration. The continuous signal loss
leads to decreased calibration stability. If the calibration fails and/or the QC is out of the specified ranges, no
patient sample results should be measured/released.

Severity
Summary HHE-RDS-CoreLab-2022-014 Version 2

The reported issue is indicated in the increasing QC recovery and/or failed calibration. The continuous signal loss
leads to decreased calibration stability. If the calibration fails and/or the QC is out of the specified ranges, no
patient sample results should be measured/released.

The maximal observed bias was +46% at the low-concentration sample (true concentration 3.21 ng/mL, value
obtained 4.67 ng/mL). According to WHO folate concentrations in serum and red blood cells for determining folate
status in all age groups:
o 3 - 5.9 ng/mL possible deficiency
o < 3 ng/mL deficiency
Therefore, the medical decision is not affected.

In addition, according to good clinical practice, additional diagnostics is required before a medical decision is
taken. More specifically for:

 Folate status:
o serum folate is considered an indicator of recent folate intake and a single measurement cannot
be used to differentiate between a transitory decrease in dietary folate intake and chronic
deficiency states;
o red blood cell folate concentrations are useful to indicate long-term folate status, because
erythrocytes have a 120-day lifespan. Anyway, only high levels of 2 circulating homocysteine are
considered a functional indicator of folate deficiency.
 Megaloblastic anemia:

Quality Notification | Immunology | QN-RDS-CoreLab-2022-067 | Version 2 | Template Version 1.9 4/9

Roche internal
 
Elecsys® Folate III signal loss issue

o only once macrocytosis has been identified, differential diagnosis should begin to determine the
potential cause. The diagnostic algorithms include several other tests such as complete blood
count (CBC), hemoglobin, mean corpuscular hemoglobin concentration (MCHC), mean
corpuscular volume (MCV), vitamin B12 level (cobalamin), intrinsic factor antibodies, parietal cell
antibodies, or gastrin level to identify pernicious anemia, liver function tests, and others.
 Pregnant women:
o a daily oral folic acid supplementation with 400 µg (0.4 mg) folic acid is highly recommended to
prevent pregnancy complications and birth defects without monitoring of folate levels.

Therefore, a medical risk due to the observed issue should be considered as highly unlikely.

Important Information

Internal actions

The following internal actions are ongoing in order to mitigate the situation in the field:

1. The production of new reagent lots has been accelerated. The following new reagent lots are expected
to be available approx. end of June 2022 (current plan):

- For cobas e 801 and cobas e 402:

a) Lot 651508 (Elecsys® Folate III, GMMI 07027290 190), expected availability on stock in calendar week 26

- For cobas e 411, cobas e 601, and cobas e 602:

a) Lot 651618 (Elecsys® Folate III, GMMI 07559992 190), expected availability on stock in calendar week 25
or 26
b) Lot 651630 (Elecsys® Folate III, GMMI 07559992 160), expected availability on stock in calendar week 25
or 26

2. Bridging solution: To mitigate the situation for customers that may already observe failed calibrations due to
violation of the minimum signal criterion, lower minimum signals will be provided for the affected lots. The
purpose is to ensure calibratability until the new production lots are available. With lower minimum signals the
frequency of failed calibrations due to minimum signal violation is reduced and calibratability is ensured for a
longer time.
Internal testing at R&D confirmed that the lower minimum signals are acceptable and that reliable sample recovery
is provided (given that frequent calibration is performed as stated in “Actions for customers” below).

The lower minimum signals will be implemented as such:

- For cobas e 801 and cobas e 402:

Elecsys® Folate III GMMI 07027290 190

New e-files for the affected reagent kit lot 590062 (Elecsys® Folate III, GMMI 07027290 190) were published
containing lower minimum signal criteria for calibration. When a new reagent kit from this lot is registered on the
instrument, the updated version (V2) of the reagent lot-specific e-files will be automatically used (no action from

Quality Notification | Immunology | QN-RDS-CoreLab-2022-067 | Version 2 | Template Version 1.9 5/9

Roche internal
 
Elecsys® Folate III signal loss issue

the customer needed). The customers will only need to download updated CalSet (and if applicable PC Varia) e-
barcodes via the regular download process (see “Actions for customers”).
IMPORTANT: Frequent calibration as stated below (see “Actions for customers”) is still needed.

- For cobas e 411, cobas e 601, and cobas e 602:

Elecsys® Folate III GMMI 07559992 190

For these instruments, it was technically not possible to provide lower minimum signals via updated e-files. Instead,
the affected reagent kit lot 596881 (GMMI 07559992 190) was restandardized and will be released as a new lot
Elecsys® Folate III kit lot 648223 (GMMI 07559992 190) with lower minimum signal criteria. This reagent kit lot
648223 is planned to be available on stock in calendar week 22.
This reagent lot will therefore also exhibit signal loss, however lower minimum signal criteria enable calibratability
for a longer time.
The performance of reagent kit lot 648223 was confirmed during the respective restandardization action.
IMPORTANT: Frequent calibration as stated below (see “Actions for customers”) is still needed.

Elecsys® Folate III GMMI 07559992 160

For Elecsys® Folate III (GMMI 07559992 160), no bridging solution with lowered minimum signals will be provided,
since the previous non-affected reagent kit lot 536848 is still available on stock. The next reagent kit lot 651630
(GMMI 07559992 160) is planned to be available in calendar week 25 or 26.
Until then, we recommend not to sell the affected reagent kit lot 596894 (GMMI 07559992 160) to the customer
site and to resort to the previous, unaffected reagent kit lot 536848.

Elecsys® Folate RBC GMMIs 05944295 190/160

For Elecsys® Folate RBC (GMMI 05944295 190/160), no bridging solution with lowered minimum signals will be
provided, since the previous non-affected reagent kit lot 536839 is still available on stock. The next Elecsys® Folate
RBC kit lots are currently planned for Sep/2022.
Until then, we recommend not to sell the affected reagent kit lot 596898 (GMMIs 05944295 190/160) to the
customer site and to resort to the previous, unaffected reagent kit lot 536839.

Version 2:

The production of new reagent lots has been accelerated. According to current plan, the following new reagent
lots will be available for cobas e 411, cobas e 601, and cobas e 602 instruments:
- Lot 703991 (Elecsys® Folate III, GMMI 07559992 190), expected availability on stock 31-Jan-2023
- Lot 703999 (Elecsys® Folate III, GMMI 07559992 160), expected availability on stock 31-Jan-2023
- Lot 704003 (Elecsys® Folate RBC, GMMI 05944295 190/160), expected availability on stock 09-Feb-2023

Actions for customers:

Following workaround is applicable for use of reagent kit lots 590062, 596881, 596894, 596898,
648223, 657860, 657973, 657986:

- As the signal loss leads to reduced calibration stability, increased calibration frequency to what is stated in
the Method Sheet is needed. With this, high out-of-range QC values are prevented and reliable performance is
ensured. The recommendation for the calibration frequency shown below is based on data from internal
investigation taking into account also the different throughput at different customer sites:

Quality Notification | Immunology | QN-RDS-CoreLab-2022-067 | Version 2 | Template Version 1.9 6/9

Roche internal
 
Elecsys® Folate III signal loss issue

a) When using the same reagent lot, renewed calibration (“lot calibration”) should be performed
as such:

For lots 590062, 596881, 596894, 596898, and 648223:

=> For customers with throughput of one or more reagent kits per day: every 3 days.
=> For customers with throughput of less than one reagent kit per day: calibrate each new reagent kit.

For lots 657860, 657973, 657986:

=> For customers with throughput of one or more reagent kits per week: every 7 days.
=> For customers with throughput of less than one reagent kit per week: calibrate each new reagent kit.

Note: Lot calibration can be performed only if the reagent kit has been registered less than 24 hours before
the calibration. Otherwise, the calibration is valid only for the particular kit (“reagent pack/cassette/R.Pack
calibration”).
Specifically for cobas e 402: if a lot calibration fails due to invalid calibration factor, please follow the steps in
entry N3-0089 in SIT.

b) When using the same reagent kit on the analyzer, renewed calibration (“reagent
pack/cassette/R.Pack calibration”) should be performed as such:

For lots 590062, 596881, 596894, 596898, and 648223:

=> Every 3 days, independent of the throughput.

For Lots 657860, 657973, 657986:

=> Every 7 days, independent of the throughput.

- The customer should load only the number of reagent kits needed for one day (minimization of onboard
time).

- The reagent packs should be controlled as described in the method sheet – controls for the various
concentrations should be run individually at least once every 24 hours when the test is in use, once per reagent kit,
and following each calibration to monitor the performance of the reagent kit.

- If the control values are out of the specified target range, a new calibration should be performed. Then the
reagent kit should be controlled as described above, accompanied by invalidating/retesting of patient samples
according to the relevant QC regiment.

- To exclude any local factors, the instrument maintenance status must be up-to-date as per Operator’s
manual. Instruments occasionally yielding lower signals (e.g. due to suboptimal maintenance, old measuring cells
etc.) have higher probability of calibration failures due to the issue. To minimize such effects, all maintenance and
service needs to be up-to-date.

- In case the calibration fails, the reagent kit cannot be used, and a new reagent kit must be used.

If after performing of all above-mentioned actions the calibration still fails, or QC is consistently out of the specified
range, the customer should switch to another available reagent lot (when available).

Quality Notification | Immunology | QN-RDS-CoreLab-2022-067 | Version 2 | Template Version 1.9 7/9

Roche internal
 
Elecsys® Folate III signal loss issue

Additional information/recommendations

Credit notes can be obtained for all reagent lots listed in the header of the QN.

Additional recommendation for customers using reagent kit lot 596881 (Elecsys® Folate III, GMMI 07559992
190) on cobas e 411, cobas e 601, and cobas e 602:
Until the bridging reagent kit lot 648223 is available, customers that already experience calibration failures with
reagent kit lot 596881 due to minimum signal violation, may switch to reagent kit lot 590062 if they have access to
cobas e 801 or cobas e 402 instruments, as lower minimum signals are already available for this lot.

Additional information for customers already using the affected reagent kit lot 590062 (Elecsys® Folate III,
GMMI 07027290 190) on cobas e 801 or cobas e 402:
New e-files containing lower minimum signal criteria for calibration were published for reagent kit lot 590062 for
all applicable instruments.
Due to the update of the reagent lot-specific e-files, the e-barcodes for CalSet lots 499796 and 564253 and PC V1
bottle lot 573355 (PC Varia kit lot 579472) also had to be updated. The new versions are:
- CalSet lot 499796: version 504 on e801, version 103 on e402
- CalSet lot 564253: version 503 on e801, version 103 on e402
- PC V1 bottle lot 573355 (PC Varia kit lot 579472): version 105 on e801, version 104 on e402
Customers using these CalSet and PC Varia lots will need to download the respective updated e-barcodes via the
regular Parameter Download process as described in the respective Operator’s Manuals/User Guides.

Version 2:

As the signals for the affected lots decrease continuously over time, the probability for failed calibrations increases.
Therefore, it is recommended to avoid building mid/long-term local stock of the affected lots.

If customers still use the previously affected reagent kit lots:

- Lot 590062 (Elecsys® Folate III, GMMI 07027290 190) on cobas e 801, cobas e 402
- Lots 596881, 648223 (Elecsys® Folate III, GMMI 07559992 190) on cobas e 411, cobas e 601, cobas e 602
- Lot 596894 (Elecsys® Folate III, GMMI 07559992 160) on cobas e 411, cobas e 601, cobas e 602
- Lot 596898 (Elecsys® Folate RBC, GMMIs 05944295 190/160) on cobas e 411, cobas e 601, cobas e 602
It is recommended to immediately switch to any other available lot in order to avoid calibration failures due to
minimum signal violation. Non-affected lots or lots with higher signal levels are available.

Additional recommendation for customers using reagent kit lots 657860 (Elecsys® Folate III, GMMI
07559992 190) and 657973 (Elecsys® Folate III, GMMI 07559992 160) on cobas e 411, cobas e 601, and cobas e
602:
Until the next reagent kit lots are available, customers that already experience calibration failures due to minimum
signal violation may switch to non-affected lots 651508 or 657684 if they have access to cobas e 801 or cobas e
402 instruments, or to non-affected reagent kit lots 651618 and 651630 respectively (if available).

Additional recommendation for customers using reagent kit lot 657986 (Elecsys® Folate RBC, GMMIs
05944295 190/160) on cobas e 411, cobas e 601, and cobas e 602:
Until the next reagent kit lots are available, customers that already experience calibration failures due to minimum
signal violation, may switch to non-affected reagent kit lots 651508 or 657684 if they have access to cobas e 801
or cobas e 402 instruments.

Quality Notification | Immunology | QN-RDS-CoreLab-2022-067 | Version 2 | Template Version 1.9 8/9

Roche internal
 
Elecsys® Folate III signal loss issue

Actions
Internal Actions - CAPA 290008217 initiated for processing of this issue.
- Production and release of new lots 6515xx is ongoing. => done
- Release of bridging lot 648223 is ongoing. => done
- New e-files published for reagent kit lot 590062 and linked CalSet lots 499796 and
564253 and PC Varia lot 579472. => done
- Root cause analysis is ongoing.
Version 2:
- Production and release of new lots 703991, 703999, 704003 is ongoing
- Real world data monitoring is ongoing
Actions for Affiliates - Inform affected customers about the issue and the workarounds/recommendations.
- Where applicable, we recommend not to sell kit lots 596894 (GMMI 07559992 160)
and 596898 (GMMIs 05944295 190/160) to the customer site and to resort to the
previous, unaffected reagent lots 536848 and 536839, respectively.
- Feedback is to be provided in the QN Feedback Form at the Global Q&R website as
soon as all customers have been informed about the issue of this QN.
Version 2:
- Inform affected customers about the additional affected lots 657860 (GMMI 07559992
190), 657973 (GMMI 07559992 160), and 657986 (GMMIs 05944295 190/160) and the
workarounds/recommendations.
- Avoid mid/long-term local stock of the affected lots
- If applicable, it is recommended to convert customers still using the previously
affected lots 590062 (GMMI 07027290 190); 596881, 648223 (GMMI 07559992 190);
596894 (GMMI 07559992 160); 596898 (GMMIs 05944295 190/160) to other available
lots.
- Feedback is to be provided in the QN Feedback Form at the Global Q&R website as
soon as all customers have been informed about the issue of this QN.

Contact
Please do not hesitate to contact us in case of questions regarding the information provided.

Best regards,

Author Reviewer
Dr. Kalina Atkovska Cornelia Götz
Senior Scientist PMQ International Product Manager - Diagnostics
Post-Market Quality Reagent Portfolio & Cross-LCT Projects IBT
Case Handling and Affiliate Support EMEA/LatAm 4

Quality Notification | Immunology | QN-RDS-CoreLab-2022-067 | Version 2 | Template Version 1.9 9/9

Roche internal