UPDATE: Pre-Pooled Cryo. Expiration

[Brenda K Hutson]

Perhaps many of you know this already (and there may already be a Thread; I have not had time to read on this site for awhile), but I want to update you on a topic we discussed months ago. That is the expiration of pre-pooled Cryoprecipitate, once thawed. Some people said 4 hours; others said 6. Even the AABB contradicted itself in the Technical Manual (and it was questionable whether the FDA guideline referred to pre-pooled Cryo. or not).

So, this FDA Update from Dec. 2009:

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM187348.pdf

It states on page 37:

"Thawed Cryoprecipitated AHF should be kept at room temperature and transfused as soon as possible after thawing, within 6 hours if it is a single unit (from individual donor, or pooled before freezing or administration using an FDA-cleared sterile connecting device), within....

Ah...just in time for me. Our Donor Facility is finally giving us pre-pooled Cryo.!

Brenda Hutson, CLS(ASCP)SBB

[adiescast]

Thanks Brenda, that is most helpful and timely. We are also preparing to go to cryo pooled before freezing.

[SMW]

You will need to check (carefully and detailed) and follow the guidance of the manufacturer of the licensed product. Although the individual units of Cryo may be pooled using an FDA-cleared sterile connecting device, it is very, very, very likely that the saline that was used in pooling the product was NOT added using an FDA-cleared sterile connecting device............therefore making the expiration date 4 hours after thawing the pre-pooled Cryo.

[Brenda K Hutson]

You will need to check (carefully and detailed) and follow the guidance of the manufacturer of the licensed product. Although the individual units of Cryo may be pooled using an FDA-cleared sterile connecting device, it is very, very, very likely that the saline that was used in pooling the product was NOT added using an FDA-cleared sterile connecting device............therefore making the expiration date 4 hours after thawing the pre-pooled Cryo.

The Medical Director at our Donor Facility sent me the reference and stated 6 hours (and she is very competent so I would be surprised if there was such an oversight). While I have made ALL other types of components in my career, Cryo is the one I have not made (so feel a little at a disadvatage). However, I have certainly used a sterile connecting device and I guess I would not understand the rationale of doing part of the preparation using a SCD but then having an open system by not using the SCD for the saline??

Again, not knowing exactly how Cryo. is produced, I will discuss this with the Medical Director.

Thanks,

Brenda Hutson, CLS(ASCP)SBB

[Gumby]

Listed in the CIRCULAR OF INFORMATION for the use of Human Blood and Blood Components states that pooled Cryo is only good for 4 hours after thawing. We ran into this issue when we first started using pooled Cryo. We first used the 6 hour rule and changed all of our procedures and debated this over a two month period. We had called our two suppliers and neither would give a definate answer on this issue. Since we could not get the information from our suppliers we decided to then switch to the 4 hours of expiration. Unless we receive documentation from our suppliers we will continue the 4 hour rule. After making this decision we went back and reported to the FDA that we administered 2 units of pooled cryo after the 4 hour expiration time.

[SMW]

As I understand it (and having made Cryo), the type of saline that is used and in the volume needed for a manufacturing process is not available in a packaging design that can be used with a sterlie connecting device. Perhaps if you ask a very specific question about the method your manufacturer is using to add the saline during manufacturing you may elucidate some additional information or clarification. I also understand that although there may be many facilities that distribute Cryo, the products are actually manufactured at only a few facilities/locations (and maybe your contact is not at one of those manufacturing locations?) ..........

[Brenda K Hutson]

Listed in the CIRCULAR OF INFORMATION for the use of Human Blood and Blood Components states that pooled Cryo is only good for 4 hours after thawing. We ran into this issue when we first started using pooled Cryo. We first used the 6 hour rule and changed all of our procedures and debated this over a two month period. We had called our two suppliers and neither would give a definate answer on this issue. Since we could not get the information from our suppliers we decided to then switch to the 4 hours of expiration. Unless we receive documentation from our suppliers we will continue the 4 hour rule. After making this decision we went back and reported to the FDA that we administered 2 units of pooled cryo after the 4 hour expiration time.

Are you looking at the FDA Circular of Information I gave at the beginning? This was just revised in Dec. 2009. The FDA previosly only stated 4 hours for Cryo. Pools but it was thought that perhaps they were not referring to pre-pooled Cryo. (and I think their revision shows this to be correct; I think they clarified that pre-pooled is 6 hours). If you look at that URL (I even printed out the entire FDA document), the paragraph I quoted is word for word and to me, does not leave any more doubt. But that is my opinion.

Brenda

[Gumby]

We have two supplier for our pooled cryo. We have been using pooled cryo almost exclusively for the past ten months. We use between 35-50 units of pooled cryo per week. We only keep 20 units of single donor cryo for babies. Prior to the release of pooled cryo the Hospital hired a pathologist from the ARC in South Carolina and even with her connections we were not able to get an answer from the ARC. Our two providers for pooled cryo are LifeSouth and the American Red Cross. We have found out over the first few months that if they do not give it in the first 4 hours 98% of the time it was not given during the next two hours while we had the 6 hour expiration time. So have the additional two hours will not cause a decrease in the amount of cryo that we expire.

[AMcCord]

My supplier says "Our CRYO POOLS were licensed as closed system pools. The reason they must transfuse within 4 hours is because of the thaw to pool and refreeze requirement. All blood centers are required to use the 4 hour transfusion rule." They are thawing cryo, pooling it and then refreezing it. The 'pooled before freezing' clause in the reg doesn't seem to fit the process they use for their product.

[Brenda K Hutson]

So again, not having performed this process myself, my primary question to these responses is this: If it is impossible to perform this technique, why would the FDA even have a regulation that specifically states "6 hours for pre-pooled Cryo. using SCD?" And I don't have the 2 references in front of me right now, but when we discussed this previously, there was 1 place in the Technical Manual that stated 4 hrs. for this process and 1 place that stated 6 hrs. (and I even communicated with someone at the AABB regulatory dept. regarding this).

Ok, I will not rest until I get to the bottom of this....stay tuned (if you dare).

Brenda

[AMcCord]

There may very well be more than one way of making cryo. Thaw, pool and freeze is all I know and what my supplier does, but that sure doesn't mean that's the only way.

[SMW]

Information brochure from one manufacturer is attached.......see page 2

CryoPools_20091229.pdf

[froggymork]

Let us know what you find out Brenda. I will definitely pass this onto our BB supervisor because we use prepooled cryo products but my understanding of the process was that they pooled them before freezing so I will definitely check into it! Thanks again.

[heathervaught]

We do not use saline in our pooling process -- I don't know of a blood center that is using saline (although I certainly haven't talked to them all). I have attached an overview of the process that we use in our facility.

Remember that the Technical Manual is a guide and NOT rule. The 26th edition of the AABB standards, page 53 states that the expiration for all Cryoprecipitate pools, whether pooled before storage or after, is 4 hours. If you are inspected by the FDA, then you can use only their criteria. However if you wish to pass your next AABB accreditation, then I would recommend 4 hours.

ABC Tech Dir Workshop.pdf

Edited January 11, 2010 by heathervaught
Had another thought

[Brenda K Hutson]

My supplier says "Our CRYO POOLS were licensed as closed system pools. The reason they must transfuse within 4 hours is because of the thaw to pool and refreeze requirement. All blood centers are required to use the 4 hour transfusion rule." They are thawing cryo, pooling it and then refreezing it. The 'pooled before freezing' clause in the reg doesn't seem to fit the process they use for their product.

In talking again with the Medical Director of our Supplier, she said the concept of "thawing and re-freezing" relates to Cryo., not to thawing FFP to make the Cryo. In other words, it would apply if frozen Cryo. units were thawed, then pooled, then re-frozen.

Brenda

[AMcCord]

I would also suggest that you should follow the guidelines from your supplier. In my case - 4 hours. Whether they are right or wrong, that's what we do.

[Ellen Zeigler]

I would suggest you ask your supplier if they are sterile docking the cryos and if they add saline, if they've found a supplier's product that allows them to do that. If the answers are all yes - then you have yours - 6 hours; if not, it's an open system and no different from any room temperature stored open product - 4 hours

[Brenda K Hutson]

I would also suggest that you should follow the guidelines from your supplier. In my case - 4 hours. Whether they are right or wrong, that's what we do.

If I use your rationale, then if the guidelines of your supplier are 4 hours, then you are safe regardless of what is "correct." If on the other hand the guidelines of your supplier are 6 hours and that is NOT correct, you are in trouble. I would suggest that not all suppliers even know "for certain" what the regulations are on this (from both AABB and FDA); they certainly were not clear from either agency last year.

Brenda

[AMcCord]

If I use your rationale, then if the guidelines of your supplier are 4 hours, then you are safe regardless of what is "correct." If on the other hand the guidelines of your supplier are 6 hours and that is NOT correct, you are in trouble. I would suggest that not all suppliers even know "for certain" what the regulations are on this (from both AABB and FDA); they certainly were not clear from either agency last year.

Brenda

Poor phrasing on my part to use the terms 'right' and 'wrong'. My supplier is licensed and inspected by the FDA. Their product is licensed by the FDA for 4 hours. If there is a fault there, it would be with the FDA inspector who approved the original licensing and in the additional inspectors who keep signing off on it. If my supplier says 4 hours, then 4 hours it is.

[David Anthony]

We have recently completed validation for manufacturing pooled cryo, but are struggling with both the expiration time (4 vs. 6 hours) and a recently found regulation that says saline is NOT ALLOWED in the manufacture of pooled cryo. We do not use an SCD to manufacture our pools and 2 of our pooled cryo suppliers use saline in their pool manufacturing process. can anyone enlighten us? Thanks!

[Brenda K Hutson]

We have recently completed validation for manufacturing pooled cryo, but are struggling with both the expiration time (4 vs. 6 hours) and a recently found regulation that says saline is NOT ALLOWED in the manufacture of pooled cryo. We do not use an SCD to manufacture our pools and 2 of our pooled cryo suppliers use saline in their pool manufacturing process. can anyone enlighten us? Thanks!

I think I would start by asking your supplier if they know they should not be using saline!

As far as the 4 vs. 6, I am still trying to get an answer to this. My supplier says 6 hours but others on this Thread swear it is 4. The FDA seemingly clarified it last Dec. and stated it was 6 hours if pre-pooled using a SCD. Some people have responded that there is no system to create pre-pooled Cryo. with a SCD, but I have been told otherwise. Also, the comment has been made that the exp. is 4 hours based on the regulation of thawing and re-freezing. However, I am being told that they are misunderstanding what that is in reference to; that it refers to thawing CRYO., pooling it and then re-freezing it, NOT to the usual process of "making" Cryo. which is to thaw FFP and make Cryo. That it is at that point that you pool it, then freeze it. That is not considered thawing and re-freezing.

Anyway, that is all of the information I have been able to ascertain at this point.

Since I believe it was the intent of the FDA to "clarify" this in Dec. by stating that pre-pooled Cryo. using a SCD had a 6 hour exp., and since the Medical Director at my supplier (who I know and respect) believes it to be 6 hours (and thinks some of the arguments being used for 4 hours are due to a misunderstanding of the process), I am inclined to think it is 6 hours. That being said, because I have pre-pooled Cryo. waiting for me at my supplier and do not want to wait any longer while this gets re-clarified, I think I am just going to take the conservative route and write 4 hours into the SOP. I can always change it when/if I feel more confident.

Brenda

[David Anthony]

As I understand it (and having made Cryo), the type of saline that is used and in the volume needed for a manufacturing process is not available in a packaging design that can be used with a sterlie connecting device. Perhaps if you ask a very specific question about the method your manufacturer is using to add the saline during manufacturing you may elucidate some additional information or clarification. I also understand that although there may be many facilities that distribute Cryo, the products are actually manufactured at only a few facilities/locations (and maybe your contact is not at one of those manufacturing locations?) ..........

You mentioned that you have made cryo; did you make single, or pooled or both? Did you use saline in the process? As I understand, saline is not allowed in the pre-pooled manufacture of cryo. Thank you.

[SMW]

Both single units and pooled units. Have used saline wth both single units thawed and pooled for immediate administration (open system--4 hour expiration date) and units pooled during the manufacturing process prior to freezing (open system--4 hour expiration date since saline is not added using a SCD even though Cryo units are pooled using an SCD.)

The issue of saline additon to pooled Cryo prior to freezing was asked at the most recent 2009 AABB "Ask the FDA" session. I don't beleive the transcript of that session has yet been published by the AABB but as I remember it, essentially the question asked in 2009 started with a reference to a question and response from the 2007 AABB "Ask the FDA" session that the FDA referenced 21CFR640.54((2) that states that diluent cannot be added to cryo prior to freezing. The 2009 question then asked why there were FDA licensed pooled Cryo units that contain saline added prior to the freezing process and the product label indicates the amount of saline contained in the pooled Cryo product. The FDA response was essentially if that's how the product was prepared, submitted for licensure (with appropriate and acceptable QC results) and the label indicated that saline was present, then that was acceptable. Reading between the lines, 21CFR640.54((2) means you can't add saline unless the label indicates you have added saline.

As for previous statements that the FDA clarified this in Dec.........I'm guessing this is referencing the Circular of Information?? If so, the entire section should be read when making interpretations. For example, the section for Cryoprecipitated Components includes:

"If the label indicates "Pooled Cryoprecipitated AHF", several units of Cryoprecipitated AHF have been pooled. The volume of the unit is indicated on the label and, if used, the volume of 0.9% Sodium Chloride, Injection (USP) added may be separately listed."

"Thawed Cryoprecipitated AHF should be kept at room temperature and transfused as soon as possible after thawing, within 6 hours if it is a single unit (from individual donor, or pooled before freezing or administration using an FDA-cleared sterile connecting device), and within 4 hours after entering the container (eg, to attach an administration set or to pool) without using an FDA-cleared sterile connecting device."

So my take is, it must be OK to add saline as long as it's labeled accordingly and if any part of the pooling process was done without using an FDA-cleared sterile connecting device, that makes it a 4 hour expiration date according to this document.

[Brenda K Hutson]

Both single units and pooled units. Have used saline wth both single units thawed and pooled for immediate administration (open system--4 hour expiration date) and units pooled during the manufacturing process prior to freezing (open system--4 hour expiration date since saline is not added using a SCD even though Cryo units are pooled using an SCD.)

The issue of saline additon to pooled Cryo prior to freezing was asked at the most recent 2009 AABB "Ask the FDA" session. I don't beleive the transcript of that session has yet been published by the AABB but as I remember it, essentially the question asked in 2009 started with a reference to a question and response from the 2007 AABB "Ask the FDA" session that the FDA referenced 21CFR640.54((2) that states that diluent cannot be added to cryo prior to freezing. The 2009 question then asked why there were FDA licensed pooled Cryo units that contain saline added prior to the freezing process and the product label indicates the amount of saline contained in the pooled Cryo product. The FDA response was essentially if that's how the product was prepared, submitted for licensure (with appropriate and acceptable QC results) and the label indicated that saline was present, then that was acceptable. Reading between the lines, 21CFR640.54((2) means you can't add saline unless the label indicates you have added saline.

As for previous statements that the FDA clarified this in Dec.........I'm guessing this is referencing the Circular of Information?? If so, the entire section should be read when making interpretations. For example, the section for Cryoprecipitated Components includes:

"If the label indicates "Pooled Cryoprecipitated AHF", several units of Cryoprecipitated AHF have been pooled. The volume of the unit is indicated on the label and, if used, the volume of 0.9% Sodium Chloride, Injection (USP) added may be separately listed."

"Thawed Cryoprecipitated AHF should be kept at room temperature and transfused as soon as possible after thawing, within 6 hours if it is a single unit (from individual donor, or pooled before freezing or administration using an FDA-cleared sterile connecting device), and within 4 hours after entering the container (eg, to attach an administration set or to pool) without using an FDA-cleared sterile connecting device."

So my take is, it must be OK to add saline as long as it's labeled accordingly and if any part of the pooling process was done without using an FDA-cleared sterile connecting device, that makes it a 4 hour expiration date according to this document.

With your reference to "reading between the lines," I would still keep in mind your stipulation that it was "submitted for licensure with appropriate QC results." Because yes, that CFR Reference, as well as Method 6.12 of the 16th Edition of the Technical Manual, both emphatically state that "no diluent can be added."

Your reference to the FDA Circular statement "If the label indicates....etc." I don't think it is clear from that sentence whether they are referring to Cryo. that is pre-pooled, or pooled after thawing individual units. I would not use that sentence "alone" to indicate whether or not saline can be added to a pre-pooled product.

Brenda Hutson, CLS(ASCP)SBB

[SMW]

"With your reference to "reading between the lines," I would still keep in mind your stipulation that it was "submitted for licensure with appropriate QC results." Because yes, that CFR Reference, as well as Method 6.12 of the 16th Edition of the Technical Manual, both emphatically state that "no diluent can be added.""

COMMENT: Hopefully when available the transcipt from the FDA will explain better than my memory. As I remember the FDA representative disccused it in the terms of "misbranding" if the product contained something that wasn't labeled as such but if it was labeled as such that was OK. As for the Technical Manual-------that's a textbook, not rules or regulation but merely a reference or method you may choose to use. I know there are facilities that pool cryo prior to freezing using saline and are AABB accredited facilities.

"Your reference to the FDA Circular statement "If the label indicates....etc." I don't think it is clear from that sentence whether they are referring to Cryo. that is pre-pooled, or pooled after thawing individual units. I would not use that sentence "alone" to indicate whether or not saline can be added to a pre-pooled product."

COMMENT: Pooled Cryo is Pooled Cryo regardless when it is pooled. The indications, risks etc. in the

Circular

are the same and the Codabar product code is even the same. The only thing that might be different is the expiration date depending on the method of preparation. Think of it similar to Red Blood Cells. You can separate the plasma from Whole Blood by sedimentation or centrifugation and remove the plasma in an open system or a closed system but the name of the product is the same, the indications and risks of the product are the same, the expiration period is the only thing that changes. [although with ISBT128, the product code would be different due to the open/closed method of preparation.] The same is true for Pooled Platelets--the

Circular

does not differentiate if pooled in an open or closed system other than for the expiration date.

I understand this must be a new product to you but try not to make it more complicated than necessary...and as you mentioned, one can always choose to be more restricitve than the standards without penalty, but less restrictive could put you in a precarious position. Also, don't forget the Circular is a guidance document which permits alternative approaches as approved.