A California blood banker reports that his hospital's computer-generated Transfusion Record is an 8 1/2 x 11 inch form which contains an adhesive-backed compatibility label. At the time of crossmatch, the label is peeled off and applied to the upper portion of the blood bag above the base label. The forms supplier recently informed the inquiring blood banker that based on legal advice they will no longer produce the Transfusion Record with an adhesive-backed compatibility label out of concerns that the adhesive on the compatibility label might leach through the blood bag and cause harm to the patient, and result in legal action against the forms supplier. The inquiring Californian asks the following questions:

• Has any colleague experienced a similar notification from a forms supplier?
• Has the FDA approved adhesives for use on blood bags (dear FDA e-networkers, can you tell us?)
• What adhesive is used for blood bag base labels?
• Are there studies that examine migration of adhesive through blood bags?
• Should secondary labels (such as compatibility labels) be applied only on top of base labels?

The following responses have been received.

ADDENDA Feb. 16, 2002

1. A blood banker from Maryland reports having had the same problem with the adhesive stock for his computer-generated compatibility labels. As a result of this problem his facility was forced to switch vendors. Following is the only regulatory information that the Maryland blood banker could locate. It does differentiate between labels that are applied directly to the bag and those applied over the base label, but it's rather vague on the requirements for the latter. The responding blood banker thinks it's up to the blood bankers in the field to ask the label vendors for documentation that the label adhesives have been approved by the FDA.

Guideline for the Uniform Labeling of Blood and Blood Components. FDA August 1985. p. V-11 (The following text is verbatim. An electronic version of the document could not be found)

(Notes: (1) Appendix A contains a detailed protocol for evaluating the adhesion of labels under conditions simulating routine storage and handling of the product (2) 21CFR175.105 contains a long list of chemicals that may be used in adhesives that are applied over the base label)

GUIDELINE FOR SUBMITTING DOCUMENTATION FOR PACKAGING FOR HUMAN DRUGS AND BIOLOGICS, CDER, FDA February 1987

The following is verbatim from page 16 of the original document, III.D. Adhesives and Inks. Some substances, such as cements and lacquers used as label adhesives, are not water-based emulsions. They are usually dissolved in toluene, alcohol, naphtha, benzol, methyl ethyl ketone, or other organic solvents. When an adhesive of this type is used on plastics or elastomers, the solvent may allow migration of adhesive components into the drug. Appropriate testing should be performed to determine whether adhesive and ink components migrate through the container. If they do, adequate information to justify the use of the container system in combination with the drug product should be submitted. For all containers, testing should be conducted on the effectiveness of the adhesive under appropriate challenge conditions (e.g., temperature and humidity). If direct label imprinting is used on containers, such as on containers of injectable drug products, it is necessary that resistant ink be used so that the imprint having the required information resists the normal handling of the containers during their customary conditions of purchase and use.

ADDENDUM Feb. 25, 2002

2. A Michigan blood banker reports that her transfusion service uses a compatibility label that is imprinted as a part of the transfusion record form (similar to the inquiring blood banker from California). The compatibility label can be peeled off the transfusion record form and attached to the blood product. These forms are manufactured by a technique called 'air layering' which allows a removeable label to be part of a form. There are two adhesives involved in the particular air layered label used by the Michigan blood banker's hospital. One adhesive attaches the entire label to the form. The second adhesive is a removeable adhesive that allows the label to be peeled off the backing and applied to the blood product container. In the particular label used by the Michigan hospital, the part of the label left behind contains a copy of the printed information that they peeled off. This involves a type of NCR (No Carbon Required) material. The problem is with the removeable adhesive that works with the peel off/NCR medium. Many hospitals get these combination forms from at least one vendor that has recently objected to producing the forms (for reasons described above). The Michigan blood banker says that their forms vendor has outsourced the production of the combination forms. This has recently caused grief for the Michigan blood banker's hospital, as the outsourced labels have not been sticking to the blood bags, making the labels VERY "temporary"! In fact, when labels fall off after the blood product has been distributed to the patient care area, it has resulted in at least one Biologic Product Deviation Report to the FDA from the Michigan facility. The Michigan blood banker says that they are working on a solution that will meet their needs and be FDA compliant.

ADDENDUM March 5, 2002

3. A blood banker from Virginia wrote that they received the following e-mail from Sukza Hwangbo of the FDA regarding blood bag labels:

"We receive queries from blood label manufacturers, toxicology testing lab, and blood establishments. I hope the following statement will help those inquirers understand the issues surrounding blood bag labeling:

Adhesives from labels or other device components may leach into stored blood, and they should be evaluated for a potential health hazard. Applicants should submit data, including that for the extractability of individual adhesive ingredients, and provide an acceptable safety analysis on recipient exposure.

In certain cases, when the levels of the extractable are so low that they are impossible to measure, applicants often submit their analysis of recipient exposure extrapolated from a worst-case scenario, assuming that the entire amounts of the chemicals used in the formulation were leached into the blood.

The substances listed in the CFR Part 175.105 are chemicals that have been approved as components of articles intended for use in packaging, transporting or holding food. For the labeling of blood and blood components, the substances listed in the above CFR may be safely used when formulated as adhesives applied on secondary labels that will be placed over the original base label. For labels directly applied on the surface of blood bags, we require additional info.

When primary labels are reviewed as a part of a New Drug Application, e.g., a blood collection bag with anticoagulant solution or as a part of a device submission, e.g., a transfer bag, the FDA evaluates the safety as well as effectiveness of those articles used in primary labels by reviewing their formulations and performance data. The effectiveness of an adhesive is measured as the adhesion performance and readability evaluated under different storage conditions, e.g., condensation, smear, etc. The type of plastic film can affect the performance of adhesives.

The requirement to submit safety data may be waived for products using previously cleared adhesives, provided that appropriate references are included in the submission. We recommend that blood establishments who wish to use labels for direct use on blood bags (primary labels) select labels whose adhesives and inks have been reviewed by the FDA for their safety and effectiveness either under a new drug application, Masterfile, or a device submission.

We recommend that label manufacturers and toxicology labs review the safety data requirements listed in USP as well as in the ISO-10993, "Biological Evaluation for Medical Devices Part 1: Evaluation and Testing."

Please submit comments to the e-Network Forum.

Ira A. Shulman, MD
CBBS e-Network Forum Editor & Moderator