.

Guidance for Industry

Revised Preventive Measures to 

Reduce the Possible Risk of 

Transmission of Creutzfeldt-Jakob 

Disease (CJD) and Variant 

Creutzfeldt-Jakob Disease (vCJD) by 

Blood and Blood Products

Additional copies of this guidance document are available from Office of Communication, 

Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Rockville, MD 20852-

1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at 

http://www.fda.gov/cber/guidelines.htm

For questions on the content of this document, contact the Division of Hematology, at 301-496-

4396.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologics Evaluation and Research (CBER)

January 2002
i

Table of Contents

I. INTRODUCTION..................................................................................................1

II. BACKGROUND ....................................................................................................2

III. EXPLANATION OF CURRENT VCJD RECOMMENDATIONS.................6

IV. RECOMMENDATIONS FOR DONOR DEFERRAL ....................................12

V. POST-DONATION INFORMATION: RECOMMENDATIONS FOR PRODUCT 

RETRIEVAL AND QUARANTINE, CONSIGNEE NOTIFICATION, AND 

BIOLOGICAL PRODUCT DEVIATION REPORTING...............................17

VI. RECOMMENDATIONS FOR RECIPIENT TRACING AND NOTIFICATION

................................................................................................................................23

VII. LABELING RECOMMENDATIONS...............................................................23

VIII. IMPLEMENTATION OF RECOMMENDATIONS.......................................25

IX. PILOT PROGRAMS TO ASSESS THE IMPACT OF GEOGRAPHIC DONOR 

DEFERRALS THAT ARE MORE STRINGENT THAN THOSE 

RECOMMENDED BY THIS GUIDANCE.......................................................25

X. REFERENCES.....................................................................................................27

APPENDIX: LIST OF EUROPEAN COUNTRIES WITH BSE, OR AT RISK OF BSE 

APPLICABLE TO DONOR DEFERRAL ........................................................29

TABLE 1: DONOR DEFERRAL, PRODUCT DISPOSITION, RECIPIENT 

NOTIFICATION FOR WHOLE BLOOD, BLOOD COMPONENTS INTENDED 

FOR TRANSFUSION, SOURCE LEUKOCYTES, AND OTHER CELLULAR 

BLOOD COMPONENTS INTENDED FOR FURTHER MANUFACTURE30

TABLE 2: DONOR DEFERRAL, PRODUCT DISPOSITION, AND RECIPIENT

NOTIFICATION FOR PLASMA AND PLASMA DERIVATIVES..............32
1

Guidance for Industry

Revised Preventive Measures to Reduce the Possible Risk of 

Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant 

Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products

This guidance document represents the agency’s current thinking on this topic. It does not create 

or confer any rights for or on any person and does not operate to bind FDA or the public. An 

alternative approach may be used if such approach satisfies the requirements of the applicable 

statute and regulations.

I. INTRODUCTION

On November 11, 1999, the Food and Drug Administration (FDA) issued a final guidance 

document for implementation entitled, “Revised Precautionary Measures to Reduce the Possible 

Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and New Variant Creutzfeldt-Jakob 

Disease (nvCJD) by Blood and Blood Products.” We, FDA, have continued to monitor 

epidemiological findings and other scientific data regarding new variant CJD. On August 29, 

2001, we issued a draft guidance for comment, entitled “Revised Preventive Measures to Reduce 

the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant CreutzfeldtJakob Disease (vCJD) by Blood and Blood Products,” which recommended new donor deferrals 

for risk of exposure to bovine spongiform encephalopathy (BSE). This guidance finalizes the 

August 29, 2001, draft guidance, and supersedes the November 11, 1999, guidance. In keeping 

with current usage, the nomenclature used in previous guidances for new variant CJD, “nvCJD,” 

has now been changed to variant CJD, or “vCJD.” We refer to all other forms of CJD as “CJD.” 

This final guidance provides comprehensive current recommendations, including new 

recommendations for deferral of donors with possible exposure to the agent of vCJD. We based 

these recommendations upon current knowledge, and advice from the FDA’s Transmissible 

Spongiform Encephalopathies Advisory Committee (TSEAC). Recommendations for all other

forms of CJD (sporadic, familial, and iatrogenic) are unchanged.

Tests are being developed to detect CJD and vCJD infections in blood and plasma donors. 

However, until suitable donor screening tests are available, FDA is recommending interim 

preventive measures that we deem to be prudent based on the available scientific data and the 

evolving state of knowledge regarding these diseases. We also expect that additional 

epidemiological information will become available as the vCJD and Bovine Spongiform 

Encephalopathy (BSE) epidemics evolve. We may update this guidance in the future, in light of 

developments in testing technology, epidemiological information, and the impact of these 

recommendations on the supply of blood and blood-derived products. 
2

FDA uses mandatory language, such as “shall,” “must,” and “require,” when referring to 

statutory or regulatory requirements. The FDA uses non-mandatory language, such as “should,” 

“may,” “can,” and “recommend” when referring to recommendations.

II. BACKGROUND

CJD is a rare but invariably fatal degenerative disease of the central nervous system, associated 

with a poorly understood transmissible agent (Refs. 1, 2). Sporadic CJD cases occur at low 

frequency by an unknown mechanism. CJD may also be acquired by exogenous (usually 

iatrogenic) exposure to infectious material; or may be familial, caused by a genetic mutation of 

the prion protein gene. Clinical latency for iatrogenic CJD may exceed 30 years, based upon 

observations following point exposures to contaminated materials. 

In 1996, a previously unrecognized variant of CJD, vCJD, was identified in the United Kingdom 

(U.K.) (Ref. 3). vCJD is distinguished from CJD by differences in clinical presentation and 

neuropathologic changes, summarized below (Refs. 3-8). 

Differences in clinical 

presentation

vCJD CJD

Age of onset Earlier Later

Median age at death 28 years 68 years

Psychiatric and sensory 

symptoms

Frequent in early course 

of illness

Appear later in course of 

illness

 EEG changes Absence of diagnostic 

EEG changes

Diagnostic EEG changes 

commonly seen

Duration of illness 

(median) (Ref. 7)

13 months 4 months

Neuropathologic features Florid prion protein 

plaques, surrounded by 

spongiform changes

Florid plaques 

uncommon

Immunohistochemistry 

(Ref. 8) 

Abnormal prion protein 

detectable in lymphoid 

tissues

Abnormal prion protein 

not detected in lymphoid 

tissues

The concentration of abnormal prion protein seen in vCJD lymphoid tissues has led to concerns 

that transmission of vCJD by blood might be a greater risk than for CJD (Ref. 9).

Neuropathologic examination of brain tissue is required to confirm a diagnosis of vCJD. A 

confirmed (or definite) case of vCJD is currently defined by the following neuropathologic 

findings: 

1) numerous widespread kuru-type amyloid plaques, surrounded by vacuoles, in both the 

cerebellum and cerebrum (“florid plaques”); 
3

2) spongiform change most evident in the basal ganglia and thalamus, with sparse 

distribution in the cerebral cortex; and 

3) high density accumulation of abnormal prion protein, particularly in the cerebrum and 

cerebellum as shown by immunohistochemistry.

A clinical diagnosis of “suspected” vCJD can be made based upon certain clinical features, if 

adequate neuropathology specimens are unavailable. Although recommended diagnostic 

evaluations and criteria for vCJD are evolving, at present the Centers for Disease Control and 

Prevention (CDC) classifies cases in the U.S. with all of the following features as suspected 

vCJD:

1. Current age (if alive) or age at death <55.

2. Persistent painful sensory symptoms and/or psychiatric symptoms at clinical 

presentation.

3. Dementia, and delayed development (>4 months after illness onset) of ataxia, plus at 

least one of the following three neurologic signs: myoclonus, chorea, or dystonia.

4. A normal or abnormal EEG, but not the diagnostic EEG changes often seen in classic 

CJD.

5. Duration of illness of at least 6 months.

6. Routine investigations do not suggest an alternative, non-CJD diagnosis.

7. A history of possible exposure to BSE, e.g., having been a resident or traveler to a 

BSE-affected country from 1980 to the present.

8. No history of iatrogenic exposure to CJD, such as receipt of a dura mater graft, or 

human pituitary-derived hormones.

9. Absence of a prion protein gene mutation, or, if this has not been determined, no 

history of CJD in a first degree relative.

To date more than 100 patients, mostly in the United Kingdom (U.K.), as well as five patients in 

France, have been diagnosed with vCJD. The size of the vCJD epidemic cannot yet be 

determined, but is believed to be increasing in the U.K. (Refs. 10-11). No cases of vCJD have 

been identified in the U.S., except for one U.K. resident with vCJD who traveled to California in 

2001 for medical care. Laboratory and epidemiologic studies have linked vCJD to the epidemic 

of BSE in the U.K. (Refs. 12-13). In the U.K., BSE probably first occurred in cattle in 1980, 

peaked in 1992, and fell to low levels by 1996, as a result of control measures. BSE prevalence, 

while lower than in the U.K., appears to be increasing in some European countries, and the peak 

levels of those epidemics cannot yet be ascertained (Refs. 14-15). In September 2001, the first 

case of BSE was reported in Asia (Ref. 16). BSE has not been reported, to date, in U.S. cattle.

On December 11, 1996, we issued a memorandum to all registered blood and plasma 

establishments and all establishments engaged in manufacturing plasma derivatives entitled 

“Revised Precautionary Measures to Reduce the Possible Risk of Transmission of CreutzfeldtJakob Disease (CJD) by Blood and Blood Products.” We recommended, as a preventive 

measure, that you, the manufacturer, should quarantine and destroy in-date Source Plasma and 

plasma derivatives, and in-date transfusion products prepared from donors who were at increased 

risk for developing CJD or who were subsequently diagnosed with CJD. We also recommended 
4

permanent deferral of donors with CJD or CJD risks, unless, in cases of a family member with 

CJD, the donor underwent genetic testing which demonstrated absence of a familial-CJD 

associated abnormality of the prion protein gene. We did not make specific recommendations for 

vCJD in that document. Changes to those recommendations were announced on September 8, 

1998, and were incorporated into the August 1999 guidance, which was revised and updated in 

November 1999. These changes were:

1) that you no longer withdraw plasma derivatives containing plasma from donors with 

CJD or CJD risk factors; 

2) that you withdraw all material collected from donors diagnosed with vCJD or 

suspected vCJD; and 

3) that you defer donors based on their potential exposure to BSE in the U.K., or 

injection of insulin made from bovine sources in the U.K. 

We changed the 1996 recommendation to withdraw plasma derivatives containing plasma from 

donors with CJD or CJD risk, because of recently published epidemiological and laboratory data 

which provided additional assurance that transmission of CJD by blood and blood products is 

unlikely. This evidence included five case-control studies of over 600 CJD cases, two lookback 

studies of recipients of products from CJD patients, and two autopsy studies of patients with 

hemophilia (Refs. 17-23). None of these studies linked CJD to receipt of blood or blood 

products. In addition, mortality surveillance by the CDC of 3,642 CJD deaths over 16 years 

(later updated to 4,468 reports), showed that none of these cases were reported to have 

conditions associated with frequent receipt of blood and blood products (hemophilia, 

thalassemia, or sickle cell disease) (Ref. 24). Finally, experimental studies in animal models for 

CJD suggested that manufacturing procedures used for plasma derivatives could lower the 

amount of infectious material present in plasma derivatives compared with whatever levels may 

be present in blood (Refs. 25-26). 

In contrast to CJD, vCJD is an emerging disease with unique clinical and pathological 

characteristics. Few experimental or epidemiological studies of vCJD transmissibility by blood 

components or plasma derivatives have been published, and it is uncertain whether human blood 

can transmit the vCJD agent. Because the potential for transmission is unknown, as a preventive 

measure, we recommended, in August 1999, that you withdraw blood components and 

derivatives collected from donors diagnosed with vCJD. As a further preventive measure, we 

also recommended that you defer donors who resided in the U.K. for a total of 6 months or more, 

between 1980 and 1996. Approximately 87% of donor exposure-days to BSE in the U.K. were 

eliminated by this donor deferral. The period from 1980 through 1996 reflects the peak years of 

the U.K. BSE epidemic, and recognizes the measures implemented in the U.K. since 1996, that 

are designed to keep BSE out of the human food chain (Ref. 27). As other countries institute 

similar food chain protections against BSE, we will reconsider the current donor deferrals. 

Since we published the November 1999 guidance, the vCJD and BSE epidemics have continued 

to evolve. More BSE cases have been reported in Europe, including new reports of BSE in 

Spain, Italy, Germany, the Czech Republic, Greece, Slovakia, Slovenia, Austria, and Finland. 

BSE was recently identified in Japan (Ref. 16). Furthermore, transmission of BSE appears to 

have been experimentally achieved by transfusion in a single sheep (Ref. 28), heightening 

concerns about possible transmissibility of the vCJD agent by human blood. On June 6-7, 2000, 
5

the TSEAC met to discuss deferral of donors from countries affected by BSE. The TSEAC 

voted not to recommend new donor deferrals for European exposures outside of the U.K. at that 

time. This decision was based on observations that 1) the extent of the BSE epidemic in Europe 

was undetermined and 2) donor deferrals for U.K. residence had only recently been fully 

implemented, and the potential for adverse impact on the availability of blood and blood 

products had not been fully appreciated. The TSEAC also recommended against changing the 

U.K. donor deferral period to one more stringent than 6 months. 

At its meeting on January 18-19, 2001, the TSEAC reviewed more recent epidemiological 

information on exposure to BSE in European countries, and again considered donor deferrals for 

vCJD risk. The TSEAC again voted that epidemiological and other currently available scientific 

information did not support changing the current deferral for donors who resided in the U.K. 

The TSEAC did recommend that deferrals be considered for donors who were exposed to beef 

products exported from the U.K. to U.S. military bases in Europe, and to France; and for donors 

potentially exposed to BSE since 1980 in France, Portugal, or the Republic of Ireland. In 

response to advice from the TSEAC that FDA should consider a donor deferral recommendation 

for residence or travel in Portugal and Republic of Ireland (i.e., countries where BSE exposure 

was not related to human consumption of British beef per se), we decided to reexamine the issue 

with the TSEAC. Therefore, the TSEAC met again June 28-29, 2001, to consider the estimated 

potential human exposures to the BSE agent in the U.K. and other parts of Europe, as well as risk 

reduction and donor loss estimates that would be associated with tightened geographic donor 

deferrals. At this meeting, the TSEAC considered three deferral options (including the option 

proposed by the TSEAC at its January 2001 meeting) and voted to recommend the deferral 

policies which form the basis of these recommendations (Ref. 29). 

Rationale for New Geographic Donor Deferrals 

This guidance document contains comprehensive revised recommendations based upon advisory 

committee discussions, public comments to the docket and at advisory committee meetings, and 

internal Public Health Service and FDA deliberations. We have developed recommendations for 

donor deferral, product retrieval, and quarantine and disposition based upon consideration of risk 

in the donor and product, and the effect that withdrawals and deferrals might have on the supply 

of life- and health-sustaining blood, blood components and plasma derivatives. In particular, 

donors with vCJD are distinguished from those with CJD or CJD risk factors, because of very 

limited historical and epidemiological experience with vCJD, known pathological differences 

between CJD and vCJD, and uncertainty about the potential for vCJD transmission by blood 

transfusion. 

The new recommendations reflect an attempt to minimize the possible risk of vCJD transmission 

from blood and blood products consistent with maintaining their availability. We estimated that 

the recommended new donor deferrals will result in a 90% reduction in total person-days of riskweighted donor exposure to the agent of vCJD. We calculated risk as the sum of relative riskweighted person-days exposure in the United Kingdom (weight =1.0), France (weight = 0.05), 

other European countries (weight = 0.015), and members of the U.S. military and their 

dependents (weight = 0.35). 
6

Donor loss under this policy is projected to be approximately 5%, based upon our recent analysis 

of data from the 1999 multi-center blood donor travel survey (Ref. 29), which was conducted 

using methodology described for Retrovirus Epidemiology Donor Studies (Ref. 30). We 

recognize that these deferrals may adversely affect the available supply of blood and plasma 

derivatives and that supplies need to be monitored closely. This impact will vary locally and 

regionally depending upon the dynamics of supply and demand and other characteristics such as 

demographics of the donor populations. More specifically, travel prevalence to the U.K. and 

other parts of Europe may be as much as 50% higher in urban coastal cities with corresponding 

lower travel in central and rural areas of the U.S. (Ref. 14). 

Since the publication of draft guidance in August 2001, BSE has been diagnosed in Japan. The 

source of this outbreak is likely to have been meat-and-bone meal, imported from the U.K. The 

news media has reported that other countries may also have received U.K. meat-and-bone meal 

(Ref. 31). We may consider additional deferrals based upon possible exposure to BSE in Asia or 

elsewhere after the currently recommended deferrals have been implemented, their impact is 

assessed, and additional information about the potential level of BSE exposure and food chain 

controls is acquired. 

In anticipation of the new geographic deferral recommendation, we strongly encourage proactive 

planning to ensure blood supply adequacy before, during, and after implementation. Steps to 

moderate supply impact may include assertively increasing collection volume before 

implementation, and careful monitoring of the blood supply and demand factors before, during, 

and after implementation. To moderate the impact on the blood supply, we recommend that you 

implement donor deferrals in two separate phases (sections IV. D. 2., IV. D. 3., and VIII.). 

Considering the importance of an adequate blood supply, we will reconsider our 

recommendations as appropriate based on the impact of the expanded donor deferrals on the 

availability of blood products. 

III. EXPLANATION OF CURRENT vCJD RECOMMENDATIONS

A. Exposure to British Beef in the U.K.

The vCJD epidemic in the U.K. continues to increase (Ref. 11, and CJD Statistics from 

the British Department of Health, at www.doh.gov.uk). To increase protection of the 

U.S. blood supply, we now recommend that you defer blood and plasma donors who 

have traveled or resided in the U.K. for a cumulative period of 3 or more months between 

1980 and the end of 1996. 

B. Exposure to British Beef Products Distributed Outside of the U.K.

The TSEAC recognized two types of risk outside of the U.K. These include: exposure to 

BSE from infected cows in the country of residence (“indigenous”), and exposure to BSE 

from bovine products exported from the U.K. during the BSE epidemic (prior to full 

implementation of food control measures in 1996). 
 7

Available data suggest that France imported a substantial amount of beef from the U.K. 

during the peak years of the BSE epidemic (Ref. 32). Approximately 5% of beef 

consumed in France is estimated to have come from the U.K., and the number of French 

vCJD cases (three confirmed and two probable) is approximately 4.4% of those in the U.K 

(Ref. 33). It is currently speculated that the French vCJD cases were infected by 

consumption of British beef in France, since none of the individuals had lived in the 

U.K., and the indigenous French BSE epidemic is relatively smaller and more recent than 

that in the U.K. Substantial amounts of British beef also were exported to the 

Netherlands, but it appears that much of this meat was exported from the Netherlands to a 

variety of other countries (Ref. 32).

On January 18, 2001, the TSEAC voted to defer potential donors who resided in France 

for 10 years or more, from 1980 until the present. The suggested 10 year (120 month) 

deferral period for France reflected an estimated 5% risk of exposure to BSE, compared 

to exposure of donors who resided in the U.K. for at least 6 months. Based upon a 

revised deferral criterion of 3 months for exposure in the U.K., we now recommend 

deferral of blood and plasma donors with a history of 5 or more years of cumulative 

residence or travel in France since 1980.

Some U.S. military personnel, civilian military personnel, and their dependents in Europe 

also potentially were exposed to British beef procured for use on U.S. military bases 

between 1980 and 1996. British beef was distributed to U.S. military bases North of the 

Alps (Germany, United Kingdom, Belgium, and the Netherlands) between 1980 and 

1990, and South of the Alps (Greece, Turkey, Spain, Portugal, and Italy), between 1980 

and 1996. While exposure varied widely, it is estimated that in some areas, up to 35% of 

beef consumed on U.S. military bases in Europe came from the United Kingdom (Ref. 

14). The TSEAC recommended deferring such donors, but advised that more 

information was needed to assess the impact of deferral for various time periods in 

Europe on the supply of blood products. 

Due to the potential exposure to U.K. beef on U.S. military bases in Europe, we 

recommend that you should indefinitely defer current and former U.S. military personnel, 

civilian military personnel, and their dependents who were stationed at European bases 

for 6 months or more during the time periods outlined above. Based upon information 

provided by the Department of Defense, we estimate that approximately 1.8% of current 

U.S. blood donors may be deferred by this recommendation. 

C. Indigenous BSE Exposure Outside the U.K.

BSE in Europe is likely to have originated from infected cattle and cattle feed that were 

exported from the U.K. to other parts of Europe. The risk of human exposure to the BSE 

agent in any country is based upon several factors, including the prevalence of BSE and 

the presence of control measures to prevent the BSE agent from entering the human food 

chain. Control measures include: 
8

• active surveillance through testing of slaughtered cattle more than 30 months old 

for BSE, 

• exclusion of high-risk material e.g., brain, other neural tissue, lymphoid tissues, 

intestines from human food, 

• a ban on human consumption of slaughtered cattle more than 30 months old, 

• prohibition of mechanically recovered meat,

• a ban on mammalian-derived feed for ruminants, 

• use of certain rendering processes, and 

• additional herd control and surveillance (Ref. 15). 

The timing and degree to which the European countries have implemented such controls 

has varied (Refs. 15, 32). The current prevalence of BSE in each country is uncertain 

because active surveillance of the epidemic has not been completely implemented. (Refs. 

14, 15, 29, 32). The Scientific Steering Committee on the Geographical Risk of BSE 

(SSC GBR) reported that in the United Kingdom and Portugal, the prevalence of BSE is 

greater than 100 cows/million in cattle over 24 months of age (Ref. 15). These countries 

have been categorized as “Level IV.” Because of the comparatively high BSE prevalence 

in Portugal, the TSEAC recommended in January 2001 that donors who have resided in 

Portugal for 10 years or more between 1980 and the present should be deferred. The 

BSE epidemic in Ireland was estimated to be nearly as large in absolute numbers as that 

in Portugal, although Ireland was classified as “Level III” by the SSC GBR. After 

limited discussion, the TSEAC, by a narrow margin, recommended deferral of donors 

who resided in the Republic of Ireland for 10 years or more since 1980. 

BSE has been detected in many, but not all, European countries, and the increase or 

decrease of BSE in many countries is not predictable (Refs. 14, 32). In addition, food 

chain control measures (and their enforcement) also vary, and cannot be assured for all 

time periods in question. Because of these uncertainties, and the evolving BSE epidemic, 

donor deferrals on a country-by-country basis are not practical at this time. FDA 

therefore has developed a uniform recommendation for donor deferral based on exposure 

in Europe outside of the U.K. The highest prevalence of BSE that has been observed in a 

European country with a strong surveillance program (Switzerland) is approximately 

1.5% of the BSE prevalence that was observed for the United Kingdom between 1980 

and 1996. Also, residents in France consumed up to 5% British beef during the epidemic 

period, and other Europeans, less. Therefore, the current estimated maximum risk of 

BSE exposure in Europe is approximately 1.5-5% of that in the United Kingdom. 

Assuming a “worst-case” relative risk of 5% per day of exposure, a European donor 

deferral of 5 years (60 months) is equivalent to the new 3-month deferral for cumulative 

travel or residence in the United Kingdom. This is the basis for our current 

recommendation to exclude from transfusion use, blood and blood components from 

donors with a history of 5 or more years of residence or travel in Europe outside of the 

U.K.

To date, transmission of vCJD by human blood or plasma has not been demonstrated, and 

no laboratory or epidemiological studies have demonstrated infectivity of blood from 

vCJD donors (Ref. 29). Experimental assays of blood samples from small numbers of 
9

vCJD patients showed that abnormal vCJD-associated prion proteins and infectivity 

could not be detected, but the tests used were not sensitive enough to detect very low 

levels of infectious material, if present (Refs. 34, 35). However, blood from animals 

experimentally infected with transmissible spongiform encephalopathy (TSE) agents 

contains low levels of infectivity, and TSE infection, including BSE, has been transmitted 

by blood in some experiments (Refs. 25, 28, 32, 36-38). For this reason, the 

transmission of vCJD by blood components and plasma derivatives is considered a 

theoretical possibility. The risk of vCJD transmission by plasma derivatives is based 

upon the infectivity, if any, of plasma during vCJD infection, the prevalence of vCJD in 

the donor population, the size of the plasma pool for fractionation, and the removal of 

vCJD infectivity during the manufacturing process. Model TSE agents are removed from 

plasma products by manufacturing steps such as precipitation, depth filtration, and 

column chromatography (Refs. 36, 39-41). Additionally, unpublished data provided to 

FDA suggest that the vCJD agent is similarly reduced by some manufacturing steps.

The relative risks and benefits of excluding plasma donors who have lived or traveled in 

Europe for 5 years or more have not been established. In particular, the effect of such a 

donor deferral upon the supply of life and health-sustaining plasma derivatives has not 

been determined, but could be significant (Ref. 29). 

In contrast to blood, plasma derivatives are highly processed materials. Considering the 

estimated low prevalence of vCJD infections in Europe compared to the U.K., the likely 

ability of plasma fractionation processes to reduce TSE infectivity, and the uncertain 

effect of a deferral upon the supply of plasma derivatives, we do not recommend that you 

defer Source Plasma donors who have lived or traveled in Europe for 5 or more years. 

However, in consideration of the rela tively greater risk of vCJD in persons with exposure 

to beef products from the U.K., you should not collect Source Plasma and recovered 

plasma from donors with a history of travel or residence in the U.K., U.S. military bases 

in Europe, and in France, as described in sections III.A. and III.B. 

Consistent with this recommendation, recovered plasma collected prior to deferral, from 

donors with 5 years or more travel or residence in Europe, is still acceptable for 

manufacturing of plasma derivatives. However, in order to prevent possible accidental 

use of blood and blood components for transfusion, you should not continue to collect 

recovered plasma from Whole Blood donors who have been deferred for history of 

European residence. You may make an exception in the case of plasma or serum donors 

if they are participating in a CBER approved program that allows collection of plasma or 

serum solely for use in manufacturing of non-injectable products. Blood donors who are 

deferred for history of European travel or residence remain eligible to donate Source 

Plasma because there is no possibility that such collections will generate blood 

components for transfusion. However, we believe that recovered plasma collected from 

these donors after deferral implementation becomes unsuitable, because of the risk that 

blood and blood components from such donors may inadvertently be transfused. We will 

continue to evaluate this recommendation in light of evolving experimental and 

epidemiological information. 
10

Given these considerations, we recommend that you defer donors of Whole Blood and 

blood components intended for transfusion, Source Leukocytes, and recovered plasma, 

but not donors of Source Plasma, who have resided in Europe for a cumulative period of 

5 years or more, between 1980 and the present. 

NOTE: We will refer to donor deferrals both for risk of exposure to BSE due to 

residence in BSE countries, or consumption of British beef products, as “geographic risk 

deferrals.” 

D. Theoretical Exposure to vCJD by Transfusion

There are no known cases of vCJD transmission by blood transfusion to humans. In the 

U.K., at least 20 people are known to have received blood or blood components from 

donors who later developed vCJD. To date, none of these recipients has been diagnosed 

with vCJD (Ref. 14). However, BSE has apparently been transmitted from one sheep to 

another by transfusion (Ref. 28). Another study suggests that the BSE agent can adapt to 

primate hosts, thus potentially enhancing the possibility of transfusion transmission of 

vCJD from a vCJD-incubating donor (Ref. 42). Therefore, as a preventive measure, you 

should defer donors who have received transfusions of blood or blood components in the 

U.K. from 1980 to the present. 

E. Exposure to Bovine Insulin

No cases of transmission of vCJD have been reported in recipients of bovine insulin or 

other injectable products manufactured in BSE-affected countries. However, as a 

safeguard, most material from cattle in BSE countries should not be used in the 

manufacture of FDA regulated products (59 FR 44591, August 29, 1994). We are aware 

that some diabetic patients have imported bovine insulin for personal use. Additionally, 

some insulin products legally distributed in the U.S. since 1980 were manufactured from 

cattle in the United Kingdom. Therefore, as a preventive measure, you should 

indefinitely defer blood donors who have injected bovine insulin since 1980, unless you 

can confirm that the product was not manufactured after 1980 from cattle in the United 

Kingdom.

F. Filing Reports of Biological Product Deviations

The biological products deviations rule requires blood establishments to file a report of 

biological product deviation (BPDR) when the deviation meets the standard set out in 21 

CFR 606.171. If product was distributed, the regulation requires an establishment to 

report to FDA events that 

- Occurred while the product was in the establishment's control; and

- EITHER represent a deviation from current good manufacturing practice, applicable 

regulations, applicable standards, or established specifications; OR represent an 

unexpected or unforeseeable event; and

- may affect the safety, purity or potency of that product.
11

Some establishments have asked questions about BPDR reporting in the context of these 

donor deferral recommendations. 

Example #1: On the first day after implementing new donor criteria, the establishment 

learns that one of its repeat donors lived for seven years in France between 1981 and 

1988. Should the establishment file a BPDR with respect to units previously collected 

from that donor, if those units were distributed?

The regulation does not require the establishment to file a BPDR. At the time of 

donation, collection from that donor did not represent a deviation from current good 

manufacturing practice, applicable regulations, applicable standards, or established 

specifications. Nor was the collection an unexpected or unforeseeable event. The agency 

foresees that establishments will collect donations from such donors until establishments 

implement the new deferral recommendations. 

Example #2: One year after implementing new donor criteria, the establishment learns 

that one of its repeat donors lived in France between 1981 and 1988. The donor donated 

Source Plasma eight weeks earlier, and whole blood five months earlier. Despite the 

donor's unsuitability under the new donor criteria, the establishment accepted those 

donations. Should the establishment file a BPDR with respect to those units, if those 

units were distributed?

The establishment should file a BPDR. At the time of the donations, collection from that 

donor represented a deviation from current good manufacturing practice, applicable 

regulations, applicable standards, or established specifications. 

Example #3: Before implementing new donor criteria, the establishment learns that one 

of its repeat donors has developed CJD or vCJD. The donor donated whole blood three 

months earlier, and has a long history of donating. Should the establishment file a BPDR 

with respect to units previously collected from that donor, if those units were distributed? 

The establishment should file a BPDR. Collection from that donor represented an 

unexpected or unforeseeable event that may affect the safety, purity, and potency of the 

product. Neither blood establishments nor the agency expect and foresee that 

establishments will collect donations from individuals with CJD or vCJD. 

G. Definitions

Audio CASI - computer assisted interactive donor questioning program that is 

accompanied by an audio component. The donor reads the questions on the computer 

and hears the questions through a speaker or headphones.

Blood components intended for transfusion - Red Blood Cells, Platelets, Plasma, 

Cryoprecipitate, or Granulocytes derived from human blood collected by either manual 

whole blood collection or automated apheresis techniques and intended to be transfused 

to human recipients.
 12

Military employee or dependent - individual is a member of the one of the U.S. military 

services (Army, Air Force, Navy, Marines, Coast Guard), a civilian employee of one of 

the U.S. military services or a dependent (e.g., spouse, child, parent, etc.) of a member of 

the one of the U.S. services or of an civilian employee of the one of the U.S. services. 

Recovered Plasma - unlicensed raw material obtained from Whole Blood or as a byproduct of apheresis procedures (e.g., plateletpheresis), in conjunction with preparing 

transfusion blood components and Source Leukocytes intended for further manufacturing 

into injectable and non-injectable products.

Source Leukocytes - blood component derived from human blood that is collected by 

either manual or automated apheresis techniques and is intended for further 

manufacturing into injectable products, like interferon. Source Leukocyte donors may 

donate once every 8 weeks or more frequently and must meet Whole Blood or Source 

Plasma donor suitability criteria depending on the type and frequency of donation.

Source Plasma Donors

• Frequent Source Plasma donor - donor who donates more frequently than once 

every 4 weeks. These donors must undergo an annual physical examination (21 

CFR 640.63(b)) and a Serum Protein Electrophoresis measurement at least every 

4 months (21 CFR 640.65(b)(1)).

• Infrequent Source Plasma donor - donor who donates less frequently than once 

every 4 weeks. These donors meet the Whole Blood donor suitability criteria 

described in 21 CFR 640.3 and do not need to undergo an annual physical 

examination or a Serum Protein Electrophoresis measurement.

IV. RECOMMENDATIONS FOR DONOR DEFERRAL

A. Recommended Donor Deferral Criteria

Donor deferrals 1-7 are for all donors. Donor deferral 8 (residence in Europe for 5 years 

or more between 1980 and the present), is for all donors with the exception of donors of 

Source Plasma. 

1. You should permanently defer donors who have been diagnosed with vCJD or 

any other form of CJD.

2. You should permanently defer donors at increased risk for CJD (as identified by 

questions in section IV.B, Questions 2 and 3). Donors are considered to have an 

increased risk for CJD if they have received a dura mater transplant, or human 

pituitary-derived growth hormone. Donors with one or more blood relatives 

diagnosed with CJD (as identified in section IV.B., Question 1) are also 

considered to be at increased risk of CJD, and should be indefinitely deferred 

(see section IV.C. for donor reentry recommendations).
13

3. You should indefinitely defer donors who have spent three months or more 

cumulatively in the U.K. from the beginning of 1980 through the end of 1996.

4. You should indefinitely defer donors who have spent 5 years or more 

cumulatively in France from 1980 to the present.

5. You should indefinitely defer former or current U.S. military personnel, civilian 

military personnel, and their dependents as follows: 

a. individuals who resided at U.S. military bases in Northern Europe 

(Germany, United Kingdom, Belgium, and the Netherlands) for 6 months 

or more, from 1980 through 1990 or,

b. individuals who resided at U.S. military bases elsewhere in Europe 

(Greece, Turkey, Spain, Portugal, and Italy) for 6 months or more, from 

1980 through 1996.

6. You should indefinitely defer donors who have received a transfusion of blood or 

blood components in the U.K. between 1980 and the present. 

7. You should indefinitely defer donors who have injected bovine insulin since 

1980, unless you can confirm that the product was not manufactured after 1980 

from U.K. cattle. 

8. You should indefinitely defer donors of Whole Blood, blood components for 

transfusion, and Source Leukocytes, who have lived cumulatively for 5 years or 

more in Europe from 1980 until the present. (Note this criterion includes time 

spent in the U.K. from 1980 through 1996 and time spent in France from 1980 to 

the present.) Unless otherwise unsuitable, these donors remain eligible for 

Source Plasma donation. 

NOTE: Donors who are otherwise deferred based upon the above recommendations 

2-8, may continue to donate if they are participating in a CBER-approved program 

that allows collection of blood components solely for use in manufacturing of noninjectable products. We recommend special labeling for products obtained from 

such donors (see section VII.A.). 

B. Recommended Questions to Identify Donors at an Increased Risk for CJD

You should question frequent Source Plasma donors at the first donation following 

implementation of the recommendations in this guidance, and annually thereafter. You 

should question donors of Whole Blood and blood components, infrequent Source 

Plasma donors and Source Leukocyte donors at each donation. Question 2 may be asked 

only once, since pituitary-derived growth hormone is no longer being manufactured or 

administered. If the donor is not familiar with the term “Creutzfeldt-Jakob Disease,” you 

may take that as a negative response. These questions are similar to those in the 
14

November 11, 1999, guidance. We consider donors who answer “Yes” to any of the 

questions below to have an increased risk for developing CJD. 

Question 1) Have any of your blood relatives had Creutzfeldt-Jakob Disease? 

Question 2) Have you ever received growth hormone made from human pituitary 

glands?

NOTE: If the donor is uncertain about his or her treatment, the 

following question describing human pituitary-derived growth 

hormone injections may be asked: “Was the hormone treatment 

given repeatedly by injection?” This question only needs to be 

asked once, since human pituitary growth hormone is no longer 

available. 

Question 3) Have you received a dura mater (or brain covering) graft?

This question may be preceded by the more general, “Have you 

ever had brain surgery?” You need to ask the specific question 

only if the donor responds “yes,” to the general question.

C. Recommendations for Donor Reentry After Donor Deferral for Risk of 

Familial CJD

If you defer a donor because of family history of CJD, you may reenter that donor if:

1) The diagnosis of CJD in the family member(s) is confidently excluded, or 

CJD in the family member(s) is iatrogenic, or the family member(s) is(are) not 

a blood relative(s); or 

2) Laboratory testing (gene sequencing) shows that the donor does not have a 

mutation associated with familial CJD. 

D. Recommended Questions for Identifying Donors at Risk for Exposure to 

BSE

1. Method of Donor Questioning

Due to the added complexity of screening donors for cumulative periods of 

potential exposure to BSE, a trained staff member should administer the revised 

geographic donor deferral criteria by face-to-face interview to each new donor (as 

defined in your SOP). Instead of face-to-face interviews, you may use a 

computerized interactive donor interview program that includes an audio 

component (audio-CASI) (Refs. 43, 44). You should submit your changes to your 

donor interview procedure according to 21 CFR 601.12. For repeat donors, you 

may use alternative methods for introducing and emphasizing the new questions. 

Your alternative method should provide the repeat donor with a detailed 
15

description of the changes to the donor questionnaire, to highlight any new 

questions and modifications.

2. Timing of Implementation 

In order to attenuate the impact of deferrals on the blood supply, you may 

implement deferrals in two separate phases. Phase I comprises deferral for 

cumulative time spent in the U.K. and France, deferral for military employees, 

and their dependents, and for recipients of transfusion in the U.K. Phase II 

comprises deferral of donors of Whole Blood and blood components for 

transfusion, Source Leukocytes, and other cellular blood components for 

manufacture into injectable products (but not Source Plasma) who have traveled 

to, or lived in, Europe for 5 years or more, between 1980 and the present. We 

recommend that you implement Phase I by May 31, 2002, and Phase II by 

October 31, 2002. 

3. Donor Questions

You should indefinitely defer donors who answer “Yes” to the following 

questions:

Phase I: To identify donors with geographic risk of BSE exposure.

Since 1980, have you ever lived in, or traveled to Europe?

a. If the donor answers no, you need not take any further action.

b. If the donor answers yes, ask the following questions:

1) Between 1980 through 1996 did you spend time that adds up to 3 

months or more in the U.K. (England, Northern Ireland, Scotland, 

Wales, the Isle of Man, the Channel Islands, Gibraltar, or the 

Falkland Islands)?

2) Since 1980 have you received a transfusion of blood, platelets, 

plasma, cryoprecipitate, or granulocytes in the U.K. (England, 

Northern Ireland, Scotland, Wales, the Isle of Man, the Channel 

Islands, Gibraltar, or the Falkland Islands)?

3) Since 1980 have you spent time that adds up to 5 years or more in 

France?

4) Between 1980 through 1996, were you a member of U.S. military, 

a civilian military employee or a dependent of a member of the 

U.S. military?
16

If the donor answers no, you need not take any further action.

If the donor answers yes, ask the following question:

Did you spend a total time of 6 months or more associated with a 

military base in any of the following countries:

• From 1980 through 1990 in Belgium, the 

Netherlands, or Germany.

• From 1980 through 1996 in Spain, Portugal, Turkey, 

Italy, or Greece.

NOTE: For Questions 1) and 4), you only need to question donors 

once, because these questions encompass a discrete time frame. 

You should administer Questions 2) and 3) to frequent Source

Plasma donors at intervals of no greater than 4 months, and to all 

other donors, at each donation. 

Phase II: To identify donors who have additional geographic risk of BSE 

exposure. 

For donors of Whole Blood, components intended for transfusion, and Source 

Leukocytes, you should substitute the following for question 3) in Phase I 

(section IV.D.3.): 

Question) Since 1980 have you spent time that adds up to 5 years or more 

in Europe (including time spent in the U.K. from 1980 through 

1996)?

Donors deferred based on this question remain eligible to donate Source 

Plasma, unless they are otherwise unsuitable. 

For Donors of Source Plasma, however, you should continue to ask Question 

3) from Phase I (section IV.D.3.): 

Question 3) Since 1980 have you spent time that adds up to 5 years or 

more in France?

European countries with BSE risk that FDA has identified as a basis for donor 

deferral are listed in the Appendix to this document. We will periodically issue 

new guidance to update the list of countrie s with BSE risk, to be used as a basis 

for donor deferral.
17

4. To identify donors who have been injected with bovine insulin since 1980, 

you should ask donors with diabetes the following question: 

Question 5) Since 1980, have you ever injected bovine (beef) insulin?

Since the above question applies to a subset of potential donors, you may ask it as 

a secondary question to a general medication question if a donor responds that 

they have taken insulin. If the donor answers “yes” or “I don’t know” to the 

question, you should indefinitely defer that donor, unless it can be documented 

that the product was not manufactured from cattle in the United Kingdom after 

1980.

NOTE: Donors of Whole Blood, blood components, Source Leukocytes, and 

Source Plasma who otherwise should be indefinitely deferred based on their 

response to the questions specified in sections IV.D.3., and IV.D.4. may continue 

to donate if they are participating in a CBER-approved program that allows 

collection of blood components solely for use in manufacturing of non-injectable 

products. We recommend special labeling for products obtained from such 

donors. (See section VII.A.)

V. POST-DONATION INFORMATION: RECOMMENDATIONS FOR PRODUCT 

RETRIEVAL AND QUARANTINE, CONSIGNEE NOTIFICATION, AND 

BIOLOGICAL PRODUCT DEVIATION REPORTING

A. Whole Blood and Blood Components Intended For Transfusion, Cellular 

Blood Components Intended For Further Manufacture Into Injectable 

Products, and Source Plasma From Donors With CJD Or CJD Risk Factors

1. Product Disposition

If you receive post-donation information about a donor with CJD or CJD risk 

factors, you should immediately retrieve and quarantine for subsequent 

destruction all in-date blood components (including Whole Blood, blood 

components intended for transfusion, Source Leukocytes, and Source Plasma), all 

in and out-of-date cellular blood components intended for manufacturing into 

injectable products, and all recovered plasma that are under your control. You 

should, within one week of receiving post-donation information, notify all 

consignees to immediately retrieve and quarantine implicated components for 

subsequent destruction.

NOTE: If you have sent Source Plasma or recovered plasma to a consignee and 

receive post donation information about a donor with CJD or CJD risk factors, at 

a time when you know the plasma units have been pooled, you should not conduct 

product retrieval or consignee notification for those units.
18

2. Biological Product Deviation Reports

You should file a BPDR (21 CFR 606.171) if the product was distributed. 

B. Whole Blood and Blood Components Intended For Transfusion, Source 

Leukocytes and Other Cellular Blood Components Intended For Further 

Manufacture Into Injectable Products, From Donors With Geographic Risk 

Deferrals and/or Exposure to Bovine Insulin Made in the U.K. Since 1980

1. Phase I deferrals

a. Product Disposition

If you receive post donation information about a donor with Phase I 

geographic risk factors, you should immediately retrieve and quarantine 

for subsequent destruction all in-date blood components (including Whole 

Blood, blood components intended for transfusion, and Source 

Leukocytes), and all in and out-of-date cellular blood components 

intended for manufacturing into injectable products, that are under your 

control. You should, within one week of receiving post-donation 

information, notify all consignees to immediately retrieve and quarantine 

implicated components for subsequent destruction.

b. Biological Product Deviation Reports

i) Components collected before implementation of donor deferral:

 A BPDR is not required.

ii) Components collected after implementation of donor deferral: 

You should file a BPDR (21 CFR 606.171) if the product has been 

distributed. 

2. Phase II deferrals

a. Product Disposition

i) Products collected before implementation of donor deferral:

If you receive post donation information about a donor with Phase 

II geographic risk factors, we do not recommend that you conduct 

quarantine, retrieval, or consignee notification for produc ts 

collected before implementation of Phase II donor deferrals. We 

make this recommendation based on the low amount of BSE 

exposure in non-U.K. Europe as a whole, and to mitigate the 

expected impact upon supply of donor deferrals for 5 years or 
19

more residence in Europe.

ii) Products collected after implementation of donor deferral:

If you receive post-donation information about a donor with Phase 

II geographic deferrals, you should immediately retrieve and 

quarantine for subsequent destruction all in-date blood components 

(including Whole Blood, blood components intended for 

transfusion, and Source Leukocytes), and all in and out-of-date 

cellular blood components intended for manufacturing into 

injectable products, that are under your control. You should, 

within one week of receiving post-donation information, notify all 

consignees to immediately retrieve and quarantine implicated 

components for subsequent destruction.

b. Biological Product Deviation Reports

i) Components collected before implementation of donor deferral:

A BPDR is not required.

ii) Components collected after implementation of donor deferral:

You should file a BPDR (21 CFR 606.171) if the product has been 

distributed.

3. Donors with exposure to bovine insulin made in the U.K. since 1980

a. Product Disposition

If you receive post-donation information about a donor exposure to 

bovine insulin made in the U.K. since 1980, you should immediately 

retrieve and quarantine for subsequent destruction all in-date blood 

components (including Whole Blood, blood components intended for 

transfusion, Source Leukocytes), and all in and out-of-date cellular 

blood components intended for manufacturing into injectable products, 

that are under your control. You should, within one week of receiving 

post-donation information, notify all consignees to immediately 

retrieve and quarantine implicated components for subsequent 

destruction.

b. Biological Product Deviation Reports

You should file a BPDR (21 CFR 606.171) if the product has been 

distributed. 
20

C. Source Plasma and Recovered Plasma from Donors with Geographic Risk 

Deferrals and/or Exposure to Bovine Insulin Made in the U.K. Since 1980

1. Product Disposition

a. Products collected prior to implementation of donor deferral:

We do not recommend quarantine, retrieval, or consignee notification 

if components were collected before donor deferral implementation.

b. Products collected after implementation of donor deferral:

If you receive post-donation information about a donor with 

geographic risk factors, or exposure to bovine insulin made in the U.K. 

since 1980, you should immediately retrieve and quarantine for 

subsequent destruction all in-date Source Plasma and all recovered 

plasma under your control. You should, within one week of receiving 

post-donation information, notify all consignees to immediately 

retrieve and quarantine implicated components for subsequent 

destruction.

NOTE: If you have sent Source Plasma or recovered plasma to a 

consignee and receive post donation information about a donor with 

geographic risk factors, or exposure to bovine insulin from the U.K. at 

a time when you know the plasma units have been pooled, you should 

not conduct product retrieval or consignee notification for those units.

2. Biological Product Deviation Reports

a. Components collected prior to implementation of donor deferral:

A BPDR is not required.

b. Components collected after implementation of donor deferral 

You should file a BPDR (21 CFR 606.171) if the product has been 

distributed.

D. Whole Blood and Blood Components Intended For Transfusion, Recovered 

Plasma, Source Leukocytes, Other Cellular Blood Components Intended For 

Manufacturing Into Injectable Products, and Source Plasma From Donors 

With vCJD, Suspected vCJD, or CJD Diagnosis and Age <55 Years

1. Product Disposition

If you receive post-donation information about a donor with vCJD, suspected 
21

vCJD, or CJD diagnosis and age <55 years, you should immediately retrieve and 

quarantine for subsequent destruction, all in-date blood components (including 

Whole Blood, blood components intended for transfusion, Source Leukocytes, 

and Source Plasma), all recovered plasma, and all in and out-of-date cellular 

blood components intended for manufacturing into injectable products, that are 

under your control. You should, within one week of receiving post-donation 

information, notify all consignees to immediately retrieve and quarantine 

implicated components, for subsequent destruction.

You may save the collected material for use in research on vCJD by qualified 

laboratories (see section VII.A. for labeling recommendations). 

2. Biological Product Deviation Reports

The regulations require you to file a BPDR as soon as possible and in no event 

later than 45 calendar days after you discover the event (21 CFR 606.171(c)). We 

request that you notify the FDA as soon as possible, and do not wait 45 days, 

about events involving the collection of donations from donors later diagnosed 

with vCJD or suspected vCJD. FDA will respond to telephone inquiries (301) 

827-6190, in order to facilitate speedy notifications. We intend to consult with 

the CJD Surveillance Unit of the Division of Viral and Rickettsial Diseases of the 

CDC, (404) 639-3091, in the event that we receive a report of a donor with vCJD 

or suspected vCJD.

E. Plasma Derivatives

1. Plasma derivatives from donors with CJD or CJD risk factors, or geographic 

risk deferrals (as defined in section IV.D.):

We are not recommending that you withdraw pooled plasma, intermediates, 

and plasma derivatives manufactured from these donors.

2. Plasma derivatives from donors diagnosed with vCJD, or suspected vCJD

a. Product Disposition 

If you receive post-donation information about a donor with vCJD or 

suspected vCJD, you should immediately retrieve and quarantine for 

subsequent destruction any pooled plasma, intermediates, derivatives, and 

any other material containing plasma from such a donor. Alternatively, 

you may save the material for use in research on vCJD by qualified 

laboratories (see section VII.A. for labeling recommendations). You 

should not use such material for non-injectable products. 

You should, within a week of receiving a post-donation report of vCJD or 

suspected vCJD diagnosis, notify all consignees to immediately retrieve 
22

and quarantine for subsequent destruction pooled plasma, intermediates, 

and derivatives, and any other materials containing plasma from the vCJD 

donor. 

b. Biological Product Deviation Reports

The regulations require you to file a BPDR as soon as possible and in no 

event later than 45 calendar days after you discover the event (21 CFR 

606.171(c)). We request that you notify the FDA as soon as possible, and 

do not wait 45 days, about events involving the collection of donations 

from donors later diagnosed with vCJD or suspected vCJD. FDA will 

respond to telephone inquiries (301) 827-6190, in order to facilitate 

speedy notifications. We intend to consult with the CJD Surveillance 

Unit of the Division of Viral and Rickettsial Diseases of the CDC, (404) 

639-3091, in the event that we receive a report of a donor with vCJD or 

suspected vCJD.

3. Plasma derivatives from donors with a physician’s clinical or pathological 

diagnosis of CJD and age less than 55 years:

a. Product Disposition

We will make recommendations to quarantine and withdraw plasma 

derivatives from such donors on a case-by-case basis, depending upon 

results of the investigation. We may recommend quarantine and 

withdrawal of products if available information is ambiguous, and does 

not clearly eliminate the possibility of vCJD. You should treat 

quarantined and withdrawn material from such donors in the same manner 

as for vCJD (see section V.D.).

b. Biological Product Deviation Reports

The regulations require you to file a BPDR as soon as possible and in no 

event later than 45 calendar days after you discover the event (21 CFR 

606.171(c)). We request that you notify the FDA as soon as possible, and 

do not wait 45 days, about events involving the use of material from 

donors with CJD diagnosis and age <55. FDA will respond to telephone 

inquiries (301) 827-6190, in order to facilitate speedy notifications. We 

intend to consult with the CJD Surveillance Unit of the Division of Viral 

and Rickettsial Diseases of the CDC, (404) 639-3091, in the event that we 

receive a report of a donor with CJD diagnosis and age <55. 

F. Disposal of Retrieved and Quarantined Products

TSE agents are quite resistant to most disinfecting regimens. There is no current 

consensus on specific details of decontamination requirements for blood products. 
23

However, methods of destruction of TSE-implicated material include steam autoclaving 

at 132°C for 1-4 hours, incineration, or treatment with 1 N NaOH or concentrated sodium 

hypochlorite for at least 1 hour. These treatments are known to diminish (but may not 

completely eliminate) infectivity (Refs. 45-49). 

You may save blood components and plasma derivatives from donors with vCJD, or 

which have been withdrawn because the donor might have vCJD, to use in research on 

vCJD by qualified laboratories (see section VII.A. for labeling recommendations).

VI. RECOMMENDATIONS FOR RECIPIENT TRACING AND NOTIFICATION

It may be appropriate to identify blood components for transfusion prepared from prior 

collections from any donor found to have CJD, vCJD, suspected vCJD, risk factors for CJD, or if 

withdrawal is recommended in cases under investigation for vCJD (CJD diagnosis and age <55). 

In those situations, consignee notification could enable the consignee to inform the physician, or 

other qualified personnel responsible for the care of the recipients, so that recipient tracing and 

medically appropriate notification and counseling may be performed at the discretion of health 

care providers. 

For transfusible components from a donor with one family member diagnosed with CJD, or with 

risk factors for vCJD (due to geographic risk deferral, transfusion in the U.K. between 1980 and 

the present, or due to injection of bovine insulin), we believe it is not appropriate to conduct 

tracing and notification of recipients of prior donations. 

It may be appropriate to identify plasma derivatives prepared from prior collections from any 

donor found to have vCJD, suspected vCJD, or if withdrawal is recommended in cases under 

investigation for vCJD (CJD diagnosis and age <55). In those situations, consignee notification 

could enable the consignee to inform the physician, or other qualified personnel responsible for 

the care of the recipients, so that recipient tracing and medically appropriate notification and 

counseling may be performed at the discretion of health care providers.

VII. LABELING RECOMMENDATIONS

A. Labeling of Blood and Blood Components from Deferred Donors for 

Research, or Intended for Further Manufacture into Non-Injectable 

Products

You should label blood and blood components from donors with CJD, who are at 

increased risk for CJD, or who have potential exposure to the agent of vCJD with the 

following statements:

1. “Biohazard”;
24

2. “Collected from a donor determined to be at risk for CJD”; or “Collected 

from a donor diagnosed with CJD”; or “Collected from a donor with potential 

risk of exposure to variant CJD”; and

3. “Caution: For laboratory research use only”; or “Caution: For use in 

manufacturing non-injectable products only.”

You should not use blood or blood components from donors diagnosed with vCJD for 

further manufacture into non-injectable products. However blood components and 

plasma derivatives from donors with vCJD, suspected vCJD, or which have been 

withdrawn on a case-by-case basis for suspicion of vCJD, may be used in laboratory 

research on vCJD by qualified laboratories. You should label these products with the 

following statements:

1. “Biohazard”;

2. “Collected from a donor with variant CJD”; and

3. “Caution: Only for laboratory research on variant CJD”.

B. Labeling of Non-Implicated Products

No transmission of CJD or vCJD by human blood, blood components or plasma 

derivatives has been documented to date. However, as a prudent notice, we recommend 

that all blood, blood components and plasma-derived products include labeling to address 

the theoretical risk. Because albumin has never been known to transmit viral diseases, 

and because laboratory experiments suggest that albumin is less likely to contain CJDlike agents than other plasma fractions, the package insert for albumin, and products 

containing albumin, may contain a more specific statement.

1. For Whole Blood and blood components intended for transfusion, the Circular 

of Information should be revised to include under “Side Effects and Hazards,” 

the following statement: 

“Because this product is made from human blood, it may carry a 

risk of transmitting infectious agents, e.g., viruses, and 

theoretically, the Creutzfeldt-Jakob disease (CJD) agent.” 

Until the circular is revised, you may insert or attach this statement to the 

current circular.

2. For plasma-derived products other than albumin, you should revise the 

package insert warning section to include the following statement:

“Because this product is made from human blood, it may carry a 

risk of transmitting infectious agents, e.g., viruses, and 

theoretically, the Creutzfeldt-Jakob disease (CJD) agent.”
25

3. For plasma-derived albumin, you should revise the package insert warning 

section to include the following statement: 

“Albumin is a derivative of human blood. Based on effective 

donor screening and product manufacturing processes, it carries an 

extremely remote risk for transmission of viral diseases. A 

theoretical risk for transmission of Creutzfeldt-Jakob disease 

(CJD) also is considered extremely remote. No cases of 

transmission of viral diseases or CJD have ever been identified for 

albumin.”

4. For products containing plasma-derived albumin, you should revise the 

package insert warning section to include the following statement: 

“This product contains albumin, a derivative of human blood. 

Based on effective donor screening and product manufacturing 

processes, it carries an extremely remote risk for transmission of 

viral diseases. A theoretical risk for transmission of CreutzfeldtJakob disease (CJD) also is considered extremely remote. No 

cases of transmission of viral diseases or CJD have ever been 

identified for albumin.”

VIII. IMPLEMENTATION OF RECOMMENDATIONS

We recommend that you implement, by May 31, 2002, all recommendations contained in this 

guidance including labeling, with the exception of the Phase II deferral, described in section 

IV.D.3. (deferral of donors who have lived in Europe for five years or more, 1980 - present). 

We recommend that you implement, by October 31, 2002, the Phase II deferral (section IV.D.3.). 

You may implement these changes without prior approval from the agency. Licensed blood 

establishments should report the changes to FDA in the following manner:

• Report changes in your donor questionnaire in your annual report (21 CFR 601.12(d)).

• Submit labeling changes as a Changes Being Effected supplement (21 CFR 601.12(f)(2)). 

IX. PILOT PROGRAMS TO ASSESS THE IMPACT OF GEOGRAPHIC DONOR 

DEFERRALS THAT ARE MORE STRINGENT THAN THOSE 

RECOMMENDED BY THIS GUIDANCE 

A more stringent geographic donor deferral policy (deferral for a cumulative period of 6 months 

or more in Europe since 1980 or a cumulative period of 3 months or more in the United 
26

Kingdom since 1980) was proposed as an initiative in early 2001 by a member of the blood 

industry. Based upon the BSE geographic relative risk model proposed by the FDA and CDC 

and reviewed by the TSEAC (Ref. 30), both the industry-proposed and FDA-proposed deferrals 

result in an estimated one-log reduction of theoretical risk (Ref. 30). Importantly, the donor loss 

for the industry proposal, if implemented on a national basis, is estimated by FDA to be at least 

8-9% (3-4% higher then the FDA-recommended policy). 

In response to this industry initiative, some blood establishments may wish to implement 

geographic donor deferrals that are more stringent than the FDA-recommended policy. We are 

concerned that blood availability may be more severely affected by more stringent periods of 

deferral than those outlined by this draft guidance. If you wish to implement donor deferrals 

other than those recommended in this guidance, you should undertake such pilot programs only 

as a part of a carefully structured plan that includes the following elements: 

Prior to implementation: 

♦ Demonstrate an augmented donor recruitment program sufficient to offset projected 

donor losses, 

♦ Define an endpoint (or stopping rules) for the pilot program at which time deferral 

policy will be determined or an additional pilot period will be implemented,

♦ Define a contingency plan for maintaining blood supplies in the event that local 

recruitment efforts are insufficient to meet patient demand, and

During the pilot period:

♦ Monitor the loss of donors, the nature and effectiveness of donor recruitment efforts, 

and fluctuations in hospital demand for blood products.
27

X. REFERENCES

1. Am. J. Pathol. 1995 146:785-811.

2. Ann. Neurol. 1979 5:177-88.

3. Lancet 1996 347:921-5.

4. Lancet 1997 350:903-7.

5. Lancet 1997 350:908-10.

6. FEMS Immunol. Med. Microbiol. 1998 21:91-5.

7. Br. Med. J. 1996 315:389-95.

8. Lancet 1999 353:183-9.

9. Vox Sang 1998 75:178-80.

10. Nature 2000 406:583-4.

11. Lancet 2000 356:481-2.

12. Nature 1996 383:685-90.

13. Nature 1997 389:498-501.

14. TSEAC Transcripts, January 18-19, 2001:

 http://www.fda.gov/ohrms/dockets/ac/cber01.htm

15. Scientific Steering Committee on the Geographical Risk of BSE:

 http://europa.eu/int/comm/food/fs/sc/ssc/outcome_en.html

16. http://www.aphis.usda.gov/lpa/press/2001/09/japanbse.txt

17. Neurol. 1996 46:1287-91.

18. Lancet 1993 341:205-7.

19. Lancet 1998 351:1081-5.

20. Lancet 1994 343:298-9.

21. Transfusion 1997 37(suppl):2S.

22. Transfusion 1998 38:817-20.

23. Thromb. Haemost. 1998 80:909-11.

24. Em. Inf. Diseases 1996 2(4):333-7.

25. Transfusion 1998 38:810-16.

26. TSEAC Transcripts, December 18, 1998:

http://www.fda.gov/ohrms/dockets/ac/cber98t.htm

27. http://www.defra.gov.uk/animalh/bse/public-health/public-health-index.htm 

28. Lancet 2000 356:999-1000.

29. TSEAC Transcripts June 28, 2001:

www.fda.gov/ohrms/dockets/ac/cber01.htm#transmissible

30. J. Am. Med. Assoc. 1997 277:967-72.

31. Sunday London Times, February 4, 2001

32. TSEAC Transcripts June 1-2, 2000:

http://www.fda.gov/ohrms/dockets/ac/cber00.htm

33. www.invs.sante.fr/publications/mcj/donnees_mcj.html

34. Wadsworth, Lancet 358: 171-80, 2001

35. Bruce, Lancet 358:208-9, 2001

36. Transfusion 1999 39: 1169-78. 

37. Arch. Virol. 1989 108:145-9. 

38. Arch. Virol. 1984 82:105-9. 

39. Transfusion 2001 41: 449-55. 
28

40. Vox Sang 2000 78: 86-95. 

41. Annals of Medicine 2000 32: 501-13.

42. Proc. Natl. Acad. Sci. 2001 98: 4142-7.

43. Mayo et. al. Transfusion 1991, 31(5): 166-74

44. Turner et al. Science 1998, 280: 867-73.

45. Biologicals 1992 20:155-58.

46. Arch. Virol. 1994 139:313-26 

47. Univ. Calif. San Francisco Biologics Safety Manual: 

http://www.ehs.ucsf.edu/manuals/BSM/appendix%20L.html

48. WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies, Report 

of a WHO Consultation 23-26 March 1999, Publication Number 

WHO/CDS/CSR/APH/2000.3.

49. CDC Interim CJD Infection Control Guidelines

www.cdc.gov/ncidod/diseases/cjd/cjd_inf_ctrl_qa.htm
29

APPENDIX: LIST OF EUROPEAN COUNTRIES WITH BSE, OR AT RISK OF BSE 

APPLICABLE TO DONOR DEFERRAL 

The list below includes all European countries on the current U.S. Department of Agriculture 

(USDA) BSE list (January 6, 1998). The current USDA list of countries with BSE or at risk of 

BSE may be found at 9 CFR 94.18(a). 

European Countries List to be Used for Deferral of Donors Based on Geographic Risk of BSE 

Albania, Austria, Belgium, Bosnia-Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, 

Finland, France, Germany, Greece, Hungary, Republic of Ireland, Italy, Liechtenstein, 

Luxembourg, Macedonia, Netherlands, Norway, Poland, Portugal, Romania, Slovak Republic, 

Slovenia, Spain, Sweden, Switzerland, United Kingdom1, and Federal Republic of Yugoslavia.

1 For purposes of this guidance, the United Kingdom should be taken to include all of the 

following: England, Northern Ireland, Scotland, Wales, the Isle of Man, the Channel Islands, 

Gibraltar, and the Falkland Islands.
30

TABLE 1: DONOR DEFERRAL, PRODUCT DISPOSITION, RECIPIENT NOTIFICATION FOR WHOLE BLOOD, BLOOD 

COMPONENTS INTENDED FOR TRANSFUSION, SOURCE LEUKOCYTES, AND OTHER CELLULAR BLOOD

COMPONENTS INTENDED FOR FURTHER MANUFACTURE

Risk Deferral Disposition of Product

BPDR

(21 CFR 606.171) 

for previously 

distributed product

Recipient 

Tracing/Notification

Diagnosed with vCJD, or 

suspected vCJD, CJD, or CJD and 

age <55

Permanent

Immediately retrieve, quarantine/notify 

consignees for all in-date products and all 

out-of-date cellular blood components 

intended for manufacturing into injectable 

products.

Yes

Consignee notified, 

consignee informs 

responsible caretaker for 

discretionary recipient 

notification, counseling

Risk factors for CJD: Receipt of 

pituitary-derived growth hormone, 

or dura mater transplant

Family history of CJD in >1 

family member

Permanent

Indefinite; reentry if genetic 

testing does not reveal CJDassociated prion protein allele

Immediately retrieve, quarantine/notify 

consignees for all in-date products and all 

out-of-date cellular blood components 

intended for manufacturing into injectable 

products.

Yes

Consignee notified, 

consignee informs 

responsible caretaker for 

discretionary recipient 

notification, counseling

CJD in only 1 family member Indefinite; reentry if genetic 

testing does not reveal CJDassociated prion protein allele

Immediately retrieve, quarantine/notify 

consignees for all in-date products and all 

out-of-date cellular blood components 

intended for manufacturing into injectable 

products.

Yes No

No – if prior to 

deferral 

implementation

Yes - if after 

deferral 

implementation

Phase I Geographic donor No

deferrals (U.K. >3 months 1980-

1996; France >5 years 1980-

present; military in Europe as 

specified, transfusion in U.K. 

since 1980)

Indefinite

Immediately retrieve, quarantine/notify 

consignees for all in-date products and all 

out-of-date cellular blood components 

intended for manufacturing into injectable 

products.
31

TABLE 1 : Continued

Risk Deferral Disposition of Product

BPDR

(21 CFR 606.171) 

for previously 

distributed product

Recipient 

Tracing/Notification

Collected prior to deferral implementation 

- No retrieval, quarantine, consignee 

notification

No – if prior to 

deferral 

implementation

Phase II Geographic donor 

deferrals (Europe >5 years 1980-

present)

Indefinite Collected after deferral implemented –

Immediately retrieve, quarantine/notify 

consignees for all in-date products and all 

out-of-date cellular blood components 

intended for manufacturing into injectable 

products.

Yes - if after 

deferral 

implementation

No

Bovine insulin injection Indefinite, donor reentry if 

proof of non-U.K. insulin 

source

Immediately retrieve, quarantine/notify 

consignees for all in-date products and all 

out-of-date cellular blood components 

intended for manufacturing into injectable 

products.

Yes No
32

TABLE 2: DONOR DEFERRAL, PRODUCT DISPOSITION, AND RECIPIENT NOTIFICATION FOR PLASMA AND PLASMA 

DERIVATIVES1

Risk Deferral Disposition of Product

BPDR (21 CFR 

606.171) for previously 

distributed product

Recipient 

Tracing/

Notification 

SP and RP: Collected prior to deferral implementation- No retrieval, 

quarantine, consignee notification

No – if prior to deferral 

implementation

SP and RP: Collected after deferral implementation – Immediately 

retrieve, quarantine, notify consignees of in-date SP and all RP unless 

known to be previously pooled

Yes- if after deferral 

implementation

Phase I Geographic donor 

deferrals (U.K. >3 months 1980-

1996; France >5 years 1980-

present; military in Europe as 

specified, transfusion in U.K. 

since 1980) Indefinite

PD: No retrieval, quarantine, consignee notification No 

No

Phase II Geographic donor 

deferrals (Europe >5 years 1980-

present)

SP

No deferral

SP: All phase I deferrals remain in place, e.g., U.K. > 3 months 1980-

1996; France > 5 years 1980-present; military in Europe as specified; 

transfusion in the U.K. since 1980. There is no Phase II deferral for SP. 

Not applicable 

RP: Collected prior to deferral implementation- No retrieval, quarantine, 

consignee notification

RP: Collected after deferral implementation: Immediately retrieve, 

quarantine, notify consignees for all RP unless known to be previously 

pooled

No- if collected prior to 

deferral implementation

Yes – if collected after 

deferral implementation

Phase II Geographic donor 

deferrals (Europe >5 years 1980-

present)

RP 

Indefinite

PD: No retrieval, quarantine, consignee notification No

No

Bovine insulin injection Indefinite, 

donor reentry 

if proof of 

non-U.K. 

insulin source

SP and RP: Immediately retrieve, quarantine/notify consignees for in-date 

SP and all RP unless plasma known to be previously pooled

PD: No retrieval, quarantine, consignee notification

Yes

No

No

No

 

1

 Abbreviations: SP, Source Plasma; RP, recovered plasma; PD, plasma derivatives; BPDR, Biological Products Deviation Report
33

TABLE 2: Continued

Risk Deferral Disposition of Product

BPDR (21 CFR 

606.171) for 

previously distributed 

product

Recipient 

Tracing/Notification

Diagnosed with vCJD, suspected 

vCJD

Permanent SP and RP: Immediately retrieve, 

quarantine/notify consignees for in-date SP and 

all RP 

PD: Immediately retrieve, quarantine, notify 

consignees 

Yes 

Yes

Consignee notified, 

consignee informs 

responsible caretaker 

for discretionary 

recipient notification, 

counseling

Diagnosed with CJD and age <55 Permanent SP and RP: Disposition decided case-by-case 

depending upon investigation results 

PD: Disposition decided case-by-case 

depending upon investigation results

Yes

Decided upon caseby-case 

Case-by-case 

recommendation, 

depending upon 

investigation results 

Diagnosed CJD (and age >55) Permanent SP and RP: Immediately retrieve, 

quarantine/notify consignees for in-date SP and 

all RP unless known to be previously pooled

PD: No retrieval, quarantine, consignee 

notification

Yes

No

No

No

Risk factors for CJD: Receipt of 

pituitary-derived growth hormone, or 

dura mater transplant

 Family history of CJD in >1 family 

member 

Permanent

Indefinite

SP and RP: Immediately retrieve, 

quarantine/notify consignees for in-date SP and 

all RP unless known to be previously pooled

PD: No retrieval, quarantine, consignee 

notification

Yes

No

No

No

CJD in only 1 family member Indefinite; reentry if genetic 

testing does not reveal CJDassociated prion protein 

allele

SP and RP: Immediately retrieve, 

quarantine/notify consignees in-date SP and all 

RP unless known to be previously pooled

PD: No retrieval, quarantine, consignee 

notification

Yes

No

No

No