What is the acceptable upper limit of storage temperature for FFP, and its scientific basis?
A colleague in India reports that in his country, Fresh Frozen Plasma (FFP) must be stored frozen at minus 30 centigrade or colder. He would like to know if any e-network colleague is aware of the basis for the United States standard that FFP be stored at minus 18 centigrade or colder. He would especially appreciate scientific references to make an argument before his government that would justify changing the product's upper storage temperature from minus 30C to minus 18C.
The following responses were received.
- A transfusion medicine physician in the Netherlands reports that the optimal storage temperature of fresh frozen plasma is minus 30 degrees centigrade or colder as is generally agreed upon in Europe and as can be read in "The guide to the preparation, use and quality assurance of blood components", Council of Europe Publishing, ISBN 92-871-3530-4. The scientific background of this choice is the following:
Plasma is a solution of proteins and salt in water. Freezing of such a solution results in the formation of pure water ice until the eutectic freezing point at minus 23 degrees centrigrade is reached and then also the solutes like proteins and salts start to form crystals. Finally, the total plasma mixture has frozen solid after the eutectic point temperature has been reached. During this freezing process the remaining liquid gradually becomes an ever more concentrated solution of the salts and proteins. At the start of the freezing process the plasma was already acid from the citrate anti-coagulant and so the remaining liquid is also becoming more and more acid during this concentration process.
Labile proteins like factor VIII and other clotting enzymes will denature when exposed for a long time to these highly concentrated acid salt solutions. During the frozen storage, the freezer with plasma will be opened and closed regularly in a blood bank, and increases in temperature inside a freezer of up to 5 degrees centigrade can easily occur. At any temperature higher than minus 23 degrees centrigrade the original eutectic mixture of salts, proteins and water will become liquid again and the deteriation of the labile proteins will resume. If you keep the average storage temperature of the frozen plasma below minus 30 degrees centigrade, you avoid the critical eutectic temperature and the plasma will maintain its original quality. In his opinion, storage at minus 18 degrees centigrade is not the right temperature for fresh frozen plasma as the quality of the plasma at this temperature will diminish within 3 months to an unacceptable level.
- Editor's Note: FDA regulations require that FFP be stored at a temperature no higher than -18C, and AABB Standards
state: 'Fresh Frozen Plasma shall be prepared from a whole blood or apheresis collection and frozen at less than or equal to -18C within the time frame required for the anticoagulant or collection process'. Although this appears to allow blood banks and transfusion services to store FFP at temperatures as "warm" as -18C, at the USC hospitals we maintain the FFP in freezers at around -30C. It would be interesting to learn the routine storage temperature of FFP in other transfusion services. Does any colleague store FFP as 'warm' as around -18C? What is the actual practice in the field?
ADDENDA Jan. 15, 2003
- A Swiss blood banker reports that the European requirements for storage of FFP changed last year. The council of Europe guide to the preparation, use and quality assurance of blood components now states the following:
- Plasma should be frozen in a system that will allow complete freezing within one hour to a temperature below -30°C
- optimal storage temperature is at -25°C or lower
- 24 months at below -25°C
- 3 months at -18°C to -25°C
ADDENDA Jan. 30, 2003
- A hospital transfusion service compliance officer who works in Southern California and who prefers the school colors "Blue and Gold" to the cross town rival's "Cardinal and Gold" reports that several years ago Ann Hoppe (formerly with FDA/CBER) provided her (and several other AABB Assessors) with a copy of a booklet that Ms. Hoppe had written, entitled '21CFR part 606 and 21 CFR 640 (annotated)'. In this booklet (which was made available in 1996 by the Abbott Quality Institute to many of their clients and customers around the world) are some of Ms. Hoppe's personal notes that appear in the margins of her CFR. It was a "nonofficial document", a collection of her notes and personal interpretations. Germane to the current discussion about storage of FFP are the comments on page 57 of the booklet that pertain to the requirement that plasma must be stored at 18C or colder. Verbatim from the booklet it says 'A piece of history: The minus 18C was selected because most small facilities used household type freezers, and a survey of several Sears-Roebuck freezers indicated that the minus 18 was the coldest temperature consistently achieved. Most national authorities today (sic) do not consider minus 18C adequate for 12 months storage.
ADDENDA Feb. 3, 2003
- A transfusion medicine physician wonders if it would be appropriate for the AABB and/or the FDA to consider updating the USA standards/regulations regarding the maximum allowable temperature for frozen storage of FFP. Is it possible that the scientific data suggest that storage of FFP at -18C might be too warm to ensure optimal quality when stored up to a full year?
ADDENDA Feb. 12, 2003
- A colleague from New Zealand reports that he believes that the published data justifying the storage temperature of less than -25C for fresh frozen plasma (FFP) appears to be almost exclusively based on the freezing of saline at or about -23C. He states that he is not aware of good studies that indicate clinically significant deterioration of plasma proteins over short periods of a few months, with all due respect to the comments made above by others. He is of the opinion that the conditions chosen by both European regulators (i.e. to store FFP colder than -25C), appear to be based on a regulator's perspective of scientific excellence. The New Zealand colleague wonders if there is another perspective that should be part of the evaluation. He asks "How long does it take to supply FFP to a clinician after an urgent request is initiated? Although use of FFP is not always time-critical, in many cases it is time-critical for a bleeding patient. The request is often made when the product is needed, not when it is finally received for use." In his experience thawing two 280-300ml units of FFP takes approximately 20-25min. (Editor's note: Modern thawing equipment in use at the Editor's institution can thaw FFP in 10-20 minutes. More importantly, current FDA thinking allows blood banks to store frozen plasma that has been thawed for up to 5 days at 4C as 'thawed plasma'. This thawed plasma can be maintained in the blood bank inventory for immediate use, so that there is no delay in providing this product. The availability of thawed plasma may overcome concerns to store FFP at a warmer temperature of -18 to -22C to achieve thawing sooner than FFP starting at -30C, although the difference is only of the order of 5 minutes (most of the thawing time is required to provide heat to overcome the latent heat of freezing).) The New Zealand colleague also mentions that clinical timeliness of service by blood banks has not had much study but seems to him to be just as important as this issue of technical excellence of storage. In his center in New Zealand it has been the practice to hold main stocks of FFP at -30C and to maintain a small subsidiary stock of 1-4 weeks usage at -18 to -22C. He notes the comment from the Swiss commentator in this discussion - perhaps the same approach is envisaged.
Some questions are asked by the New Zealand colleague (verbatim) "Is there a place for clinical pragmatism over temperature of storage of FFP to shorten the time delay for supply? Issues rarely exist in isolation and we should look at the downside of delays in supply and the balance of competing interests. Where is the hard data of a potential clinical problem from holding FFP for a short period (not exceeding e.g. 3 months) at a temperature of -18 to -22C? What harm may arise for recipients from delay in receiving FFP where a clinically signficant dilutional or other coagulopathy is present and requires FFP?"
Submit comments to the e-Network Forum at firstname.lastname@example.org
Ira A. Shulman, MD
CBBS e-Network Forum Senior Editor & Moderator
W. Tait Stevens, MD
CBBS e-Network Forum Editor & Moderator
Elizabeth M. St. Lezin, MD
CBBS e-Network Forum Associate Editor & Moderator
James Iqbal, MD
CBBS e-Network Forum Associate Editor & Moderator
The e-Network Forum is supported in part by the California Blood Bank Society (CBBS) and the American Red Cross Blood Services (ARCBS) and endorses collegial discussion among blood banking and transfusion medicine professionals. However, neither the CBBS nor the ARCBS in any way endorse the specific views and opinions expressed in the forum. The forum is not intended as a substitute for medical or legal advice and the content should not be relied upon for any medical or legal purposes. Readers should make their own determinations as to: (i) what constitutes appropriate medical, technical, and administrative practices, and (ii) how best to comply with laws and regulations relevant to their questions. For the latter, they should consider consulting, as to any medical matters, a qualified physician, and, as to any legal matters, an attorney familiar with related state and federal laws. The user of the forum, by accessing same, assumes all risks arising out of such use and releases CBBS and their respective members, directors, officers and agents from and against any loss, damage, claim or liability arising out of such use of the Forum.