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Alternative Procedures “Variances”. Judy Ellen Ciaraldi BS, MT(ASCP)SBB, CQA(ASQ) CBER, OBRR, DBA September 15, 2009. Outline. What is a variance? How do I request a variance? How does FDA evaluate variance requests? Examples of variances FDA has approved and denied

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Alternative procedures variances l.jpg

Alternative Procedures“Variances”

Judy Ellen Ciaraldi

BS, MT(ASCP)SBB, CQA(ASQ)

CBER, OBRR, DBA

September 15, 2009


Outline l.jpg
Outline

  • What is a variance?

  • How do I request a variance?

  • How does FDA evaluate variance requests?

  • Examples of variances FDA has approved and denied

  • Emergency medical situations

  • Where can I get more information?


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What is a Variance?

  • 21 CFR 640.120 - Alternative procedure

  • Provides flexibility to assure continued availability blood products

  • Alternative procedures

    • Standard procedures that will be used each time the specific situation that deviates from the regulations occurs

  • Exception

    • Singular event related to a specific donor or product

  • Variance

    • Commonly used term for 640.120 alternative procedure or exception


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Variances are not intended:

  • To create new products

  • To excuse GMP errors for all situations

  • When donor safety and product safety, purity or potency cannot be assured

  • To deviate from FD&C or PHS Acts

  • To circumvent the regulations

  • To deviate from operator’s manuals and package inserts


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Requesting a Variance

  • When should I request a variance?

    • Product was manufactured at variance with requirements in regulations,

    • There is sufficient data to show alternative procedure results in product with equal or greater safety, purity, potency and effectiveness as the required procedure,

    • There is an impact on product availability and no other option and

    • Before product is distributed or issued

  • Who should request a variance?

    • Licensed blood establishments

    • Unlicensed, registered blood establishments

    • Unregistered transfusion services


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How do I request a Variance?

  • Requests should be made in writing and approvals will be granted in writing

  • In limited circumstances, emergency requests may be made verbally and permission granted verbally

  • Verbal requests and approvals must be followed by written requests and approval

  • Approval must be obtained before distributing affected product


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How do I request a Variance? (cont.)

  • “…request an alternative procedure/exception to 21 CFR [reg that is subject to deviation], under the provisions of 21 CFR 640.120, to [describe request].”

  • Fully describe event or alt. procedure – what happened, type of donor/products affected

  • Explain why variance approval is necessary

  • Describe investigation and corrective actions

  • Include supportive data/information


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How do I request a Variance?(cont.)

  • Facility information – name, address, phone number, license number and registration number, if applicable

  • Contact information – name, mailing address, phone number

  • What if I need to request an emergency variance outside FDA’s normal business hours?

    • If no other option and can’t wait – medical director may decide and fully document


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How do I request a Variance?(cont.)

  • Written requests -

    Director, Division of Blood Applications, OBRR, CBER, FDA

    HFM-370

    c/o Document Control Center, HFM-99

    1401 Rockville Pike, Suite 200N

    Rockville, MD 20852-1448

  • Verbal requests – (301) 827-3543

  • Fax – (301) 827-3534


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How does FDA evaluate Variance requests?

  • Review precedent cases and decisions

  • Review guidance documents (HH donors, ISBT labels, infrequent plasmapheresis, storing thawed FFP for 24 hours)

  • Review supportive documentation

  • Consult with other offices that have expertise

  • Assess impact on donor or product safety

  • Assess impact on regulations and regulatory process


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Examples of Approved Variances

  • Ship auto unit to another establishment without testing for infectious diseases

    • Deviated from – 610.40(d)

    • Reason – Testing was performed on sample or donation within 30 days; unit was properly labeled; no crossover

  • Calibrate electronic (digital) thermometer less frequently than on a monthly basis

    • Deviated from – 606.60(b)

    • Reason – Calibration not specified in package insert; accuracy for requested timeframe supported by data


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E.g. Thermometer Calibration

We request an alternative procedure to 21 CFR 606.60(b), under the provisions of 21 CFR 640.120, to calibrate electronic (digital) thermometers used to monitor blood component storage devices less frequently than each month. The package inserts for the thermometers do not provide instructions for when they need to be recalibrated. We would like to calibrate our thermometers on an annual schedule. We believe the thermometers maintain their accuracy for 12 months and we are providing the following data to support this statement.

  • Monthly calibration results for 12 months showing no change in accuracy and no adjustment was needed

  • Procedures revised to include calibrating thermometers sooner or replacing them if daily checks show a drift in temperatures


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Examples of Approved Variances

  • Distribute units with ISBT barcodes on labels

    • Deviated from – 606.121(e)(1)(ii)

    • Reason – Anticoagulant does not precede the product name in ISBT format

  • Distribute RBC units that were stored at temperatures greater than 6 C for 6 hours

    • Deviated from – 640.11(a)

    • Reason – Patient’s physician will be notified and asked to approve units; medical director approved release; units will be emergency released; units will be examined before release


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E.g. ISBT Labeling

In order to implement ISBT labeling, we request an alternative procedure to 21 CFR 606.121(e)(1)(ii), under the provisions of 21 CFR 640.120, to omit the anticoagulant or modifier name immediately preceding the product name.

  • Licensed blood components – submit labels

  • Unlicensed blood components - submit a cover letter

  • Recognition and Use of a Standard for Uniform Blood and Blood Component Container Labels (9/22/06)

    • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm073362.htm


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E.g. Temperature Excursion

We request an exception to 21 CFR 640.11(a), under the provisions of 21 CFR 640.120, to distribute RBC units that were stored at temperatures greater than 1-6 C for 6 hours. We believe the units were not adversely impacted by exposure to elevated temperatures. We are including the following data to support our request.

  • Temperature charts showing the time the units were exposed to elevated temperatures and the temperatures to which they were exposed

  • Results of inspection of units for contamination or hemolysis

  • Procedures for inspecting the units again before release for signs of contamination or hemolysis

  • Procedures for notifying the medical director and patient’s physician and documenting approval by both physicians


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Examples of Approved Variances

  • Collect RBCs from donors with hereditary hemochromatosis without special labeling or physical exam

    • Deviated from – 640.3(d) and 640.3(f)

    • Reason – In guidance document; determined no risk to donor or patient; HH donors are not charged for phlebotomy

  • Store thawed FFP or thawed FP24 at 1-6 C for up to 24 hours, instead of 6 hours

    • Deviated from – 606.122(m)(3)

    • Reason – Previously discussed at BPAC; FDA intends to revise regulation


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E.g. FFP after thawing

We request an alternative procedure to 21 CFR 606.122(m)(3), under the provisions of 21 CFR 640.120, to store thawed FFP at 1-6 C for up to 24 hours, instead of 6 hours. We provide the following FDA publication to support our request.

  • Compliance Policy Guide - Sec. 253.100 Use of Units of Plasma and Fresh Frozen Plasma Which Have Been Thawed (CPG 7134.19)

    • http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm073875.htm


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Examples of Denied Variances

  • Not performing lookback on previous collections from donors who are now HIV or HCV positive

    • Deviated from – 610.46, 610.47, 610.48

    • Reason – Impact on public safety

  • Distribution of products from donors whose suitability was determined using instruments that failed QC

    • Deviated from – 606.60(a)

    • Reason – Donor suitability cannot be accurately determined


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Examples of Denied Variances

  • Distribution of autologous units for which additive solution was not added within time stated in package insert

    • Deviated from - 606.65(e)

    • Reason – Product stored at high hematocrit; unknown impact on patient

  • Distribution of RBC units for which temperature readings were missing for 2 8-hour timeframes

    • Deviated from - 606.160(b)(3)(iii) and 640.11(a)

    • Reason – Cannot determine if product was stored continuously at 1-6 C; unknown impact on product


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Other Requests(Not considered variance requests)

  • Obtain additional donor information within 24 hours after donation

    • FDA has defined this to be consistent with determining donor suitability on day of collection (640.3(a))

    • Does not include medical exam; only applies to omitted responses and clarifying info; part of deviation investigation – not common practice

    • Licensed blood establishment submit SOPs (601.12(b))

  • Thawed Plasma (5 day storage)

    • Applicable reg and reference – 606.122(m)(3) and CPG

    • New product not evaluated by FDA; not addressed in CPG

  • Donor re-entry

    • Applicable reg - 21 CFR 610.41(b)


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References for Emergency Situations

  • Records – 606.160(b)(3)(v)

  • Compatibility testing – 606.151(e)

  • Infectious disease testing – 610.40(g)(1) and 610.40(h)(1)(i)

  • Unlicensed products in interstate commerce for medical emergencies – Compliance Policy Guides (sec. 220.200)

    • http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm073860.htm

  • Emergency situation is not considered a variance if it is addressed in the references above


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Medical Decision

  • Emergency situation - rare or autologous unit, no other option available, life-threatening

  • Assess risk vs. benefit of using non-conforming product - does the deviation from regulations adversely impact the product?

  • Documentation - event, justification, deviation investigation, assess impact on product, notification and physicians’ approval

  • Documentation available for next FDA inspection


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Where can I get more information?

  • Variances for Blood Collection from Individuals with Hereditary Hemochromatosis (8/22/01)

    • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm076719.htm

    • http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/RegulationoftheBloodSupply/Variances/ucm164649.htm

  • Revision of 8/27/82 FDA Memo. Requirements for Infrequent Plasmapheresis Donors (3/10/95)

    • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/default.htm


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Where can I get more information?

  • Blood and Plasma Branch CSOs

  • Federal Register - 55 FR 10420, March 21, 1990

  • List of approved variances

    • http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/RegulationoftheBloodSupply/ExceptionsandAlternativeProcedures/default.htm

    • Not for general use

    • Each blood establishment must submit their own request


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Where can I get more information?

  • CBER mailing address

    Director, Division of Blood Applications, OBRR, CBER, FDA

    HFM-370

    c/o Document Control Center, HFM-99

    1401 Rockville Pike, Suite 200N

    Rockville, MD 20852-1448

  • Telephone – (301) 827-3543

  • Fax – (301) 827-3534