Proposed FDA requirement to lower the current storage temperature for FFP (-18 C or less) and to list all donor tests on the product label

A transfusion medicine physician in Sacramento wonders if colleagues are familiar with the document "Revisions to Labeling and Storage Requirements for Blood and Blood Components, Including Source Plasma" that appears in the Federal Register, Vol. 68, No. 146, 7-30-03 Docket No. 2003N-0211? The inquiring physician hopes to stimulate a discussion of this proposal which he feels will have a potentially large impact on the storage temperature of frozen plasma products, for both hospitals and blood centers, and which may be costly. Comments are due by Oct. 28, 2003.

According to the inquiring physician, the FDA says in the document (41 pages) that the reason the storage temperatures are being lowered is to protect heat labile factors. The inquiring physician wonders if the change in storage temperatures is to be in harmony with European practice. He concludes with the opinion that the U.S. has many years of clinical experience that seems to support that the current storage temperature for FFP (< -18 C) is adequate and asks if there are "old" if not new data on the levels of Factor VIII, Factor V and fibrinogen in FFP and Cryo AHF after a year of storage at < -18 C. Does anyone know where this data might be located? Secondly, there are other items of impact in this document that the physician suggests people need to read, evaluate and comment upon. One other change of note will require that all FDA-required tests performed on a donor unit be listed on the label of each product. He asks "Isn't this what the Circular of Information is for? Like a drug insert?"

The following responses have been received.

ADDENDA Oct. 6, 2003

1. Editor's NOTE: A Sacramento transfusion medicine physician asks if there are "old" if not new data on the levels of Factor VIII, Factor V and fibrinogen in FFP and Cryo AHF after a year of storage at < -18 C. While the following link does not offer the requested data, colleagues might find the discussion here to be of interest in the context of the current discussion that has been raised by the Sacramento physician.

ADDENDA Oct. 7, 2003

2. A colleague at an academic medical center in Los Angeles (which is the crosstown rival to the Editor's academic institution) offers this comment. The proposal states that these components will expire in 3 months if stored between -18C and -25C, but will expire in 24 months if stored (continuously) at < -25C. She wonders "from an operational standpoint, what if the frozen component is usually stored at < -25C but the temperature drifted to the -18C to -25C range on one occasion?" She expects that would cause the frozen material to expire three months from that event (not to exceed the original expiration date), but the situation is not addressed in the Proposed Rule. Additionally, she is concerned that if a blood supplier stores frozen components at < -25C and applies a 24-month expiration label, but the receiving facility stores the frozen components at -20C, she expects that the receiving facility would need to revise the expiration date and re-label the product to 3 months from receipt. Or, if a facility normally stores at < -25C but the freezer rises to above -25C but < -18C, it would seem that one would be required to relabel all products that had been stored in that freezer with a new (3-month) expiration date. That could be a tremendous increase in workload, not to mention the increased opportunity for error." She adds, "If the proposed rule is adopted as written, most of the computerized transfusion services and hospitals that have donor centers would need to revise their computer systems to apply a 3-month (or 24-month) expiration date to these products; that is additional validation of the computer system. Would this involve a change in the component bar-codes (labeling) as well? With this in mind, she does not see how someone would think that the implementation of these changes would 'pose no additional compliance / regulatory burden'." Additionally, while the proposed rule states that they believe this is consistent with current practice, she does not agree.
   
   She continues with "The definitions/requirements for storage are quite similar to the requirements defined by the Council of Europe. When reviewing their guidelines however, it is important to know how the Council of Europe defines Fresh Frozen Plasma. Their definition of FFP (from a whole blood collection) is a product that is separated "preferably within 6 hours and not more than 18 (eighteen) hours after collection." Freezing of Apheresis FFP however "should commence within 6 hrs of completion of the procedure. Where use is made of a special device validated to rapidly cool the plasma to +20C to +24C and maintain the temperature in that range, the plasma can be held at that temperature for up to 24 hours prior (to) freezing." If FFP in the US has to be placed in the freezer within 6 or 8 hours, this (operationally) presents different issues than having up to 18 hours or 24 hours to freeze the product and still call it FFP."
   
   Finally, she states that "While the other labeling changes defined in the proposed rule are good changes that truly will lead us on in the preparation and implementation of ISBT-128", she cannot say that the proposed changes in storage requirements are as simple or as clear.

ADDENDA Oct. 8, 2003

3. A colleague in Sacramento who works with the physician who submitted the initial question that started this discussion agrees with the colleague in posting #2 above. The Sacramento colleague says "Hopefully she and others will submit comments to FDA representing the impact(s) that the proposed rules would have on their facilities. Comments are the only way to affect FDA thinking and the proposal. We urge others to comment."
   
   
4. A transfusion medicine physician in Amsterdam reports that data published by Kotitschke R, Morfeld F, Kirchmaier C.M, Koerner K and Kohler M in Infusion Therapy and Transfusion Medicine (2000;27:174-180) , under the title "Stability of fresh frozen plasma: results of 36-month storage at -20 °C, -25 °C, -30 °C and -40 °C. Multicenter study of the Section 'Blood Plasma Constituents' of the Deutsche Gesellschaft fur Transfusionsmedizin und Immunhamatologie (DGTI)", may have the data that the Sacramento physician is seeking. The Amsterdam colleague adds that part of these data were also published in Infusionsther Transfusionsmed 1997, vol. 24 p. 397-403.

ADDENDA Oct. 14, 2003

5. A transfusion medicine physician in Southern California reports having completed reading the full text, English version of the first article that was referenced by the FDA as evidence supporting the recommended change in FFP, i.e. "Stability of Fresh Frozen Plasma Results of 36-month storage at -20°C, -25°C, -30°C and -40°C", by Kotitschke et al in Infusionstherapie Transfusionmedizin 2000;27174-180. In the opinion of the responding physician, the aforementioned article did not seem to be a very well controlled study. The following comments are provided by this physician:
   • "The time to freeze the plasma varied from 6 - 24 hours
   • The plasma was pooled into pools of 15 - 144 donors. The reporting physician did not see how this is applicable to US practice, since we do not pool our FFP
   • The storage temperature variations for freezing ranged from -30°C to -50°C
   • The blood types that are pooled are only defined in the third pool and this pool is predominantly group O which is well known to be low in coagulation factors, specifically FVIII
   • The FFP was stored by three different institutions at four different temperatures
   • There was no baseline determination of coagulation factor activity prior to freezing to determine the degree to which freezing alters the activity
   • By their own admission there was little or no control of the study design (p. 176). Each center was left to determine what parameters they would test and at what temperatures they would store the FFP.
   • Finally, the factor assays were conducted by 13 different labs."
   The responding physician saw very little in this study that would be applicable to FFP as it is collected and stored in the United States, and at best suggests that there should be no problems extending the storage time for FFP to two or three years rather than the storage time that has been proposed.
   
   Another paper was evaluated, entitled "Degradation Products of Factor VIII Which Can Lead to Increased Immunogenicity” by Josic et al in Vox Sang 1999;77(suppl 1):90-99. This paper looked at 12 cases of inhibitor formation that were reported in Germany and 8 in Belgium - to see if there was any consistency between these cases.
   • All of these cases involved patients who had been infused with Octavi Solvent/Detergent (SD)-treated plasma
   • The inhibitors appeared in previously treated patients who had greater than 50 exposures to the SD plasma; however most of the patients with inhibitors exhibited no symptoms. They were discovered only by “Pharmacovigilance”
   • Since the investigators saw the inhibitors in patients treated in the two mentioned countries but not in Portugal they looked for differences in the source material and manufacturing process. It was found that patients with inhibitors had received SD Plasma with a 40 kDa peptide in the plasma
   • Using Kaplan-Mayer projections they looked at the relationship between time, inhibitor appearance and the number of 40 kDa positive batches made since patients with FVIII inhibitors had received preparations from one or more 40 kDa marker-positive batches
   • It was shown that the marker was not linked to the pasteurization process but to the quality of the source plasma or cryoprecipitate. It was ultimately shown that elevated levels of markers of coagulation activation were tied to the occurrence of the 40 kDa marker in the final product. What affected the quality of the source plasma is not mentioned
   • This fragment was then shown to be a degradation fragment of FVIII and that this fragment could be either already present in the source material or due to heating of unstable FVIII degradation products.
   The conclusion of this paper states: "The problem of inhibitor potential can be avoided if appropriate preventive measures are taken." They do not state what these measures are supposed to be. They go on to state that "further work is needed to prove non-neoantigenicity and to reinforce the scientific findings, and to characterize pilot batches."
   
   The responding physician was unimpressed with the assertions made by this paper as being definitive in any way. He did not see any correlation between this study and plasma storage in the US in that this did not mention storage times or temperatures - just that there was some degradation. The most glaring difference that the responding physician sees is that this deals only with Solvent-Detergent treated plasma, not FFP. Additionally, this "problem" was seen in only 12 patients in three countries, in whom nearly all were totally asymptomatic."

ADDENDA Oct. 22, 2003

6. A Quality Manager at a blood bank in Spain reports that as the colleague from Sacramento points out, the definition of FFP by the Council of Europe differs from the CFR. The Spanish colleague states "This definition is more lenient in the component preparation phase, because you can store whole blood at 22-24ºC overnight before plasma separation, not longer than 18 hours. There are several reasons for this:
   • Europe depends heavily on random donor platelets. This could not be obtained if blood is cooled to 4º C.
   • The widespread use of NPBI butanediol plates, to cool blood to 22º C, has proven easy and cheap to simplify component preparation.
   • Quality controls and clinical results of FFP obtained this way show no significative difference from FFP obtained in the more orthodox way.
   The Dutch have published several papers reporting their results. However, European regulations are more strict regarding storage, and the FDA proposal would apply. This means that in Europe you have to use better freezers, but component preparation is easier."

The colleague continues saying that from the practical point of view,

• "If you control freezer temperature with a centralized computer system, it is easier to review how long your FFP has been out of temperature. We have stated that if plasma has stayed longer than 1% of its life above the designated temperature, it should be relabeled accordingly.
• Hospital blood banks can program their software to their actual expiration dates, if their freezers do not reach below –25º C. This way, when they register plasma, they don't have to relabel the products, provided they validate a system to control expiration date. After this experience, one would suggest that FDA assumed the whole European experience, not only the hard part."

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