Q:

3/14/2013
We have been informed by the Pharmacy department of our medical center that all (including individual) immunotherapy mixes MUST be re-formulated every 30 days according to JACHO. Is this true? If so, how does one advance the dose if there is a new mix every 30 days?

A:

Thank you for your inquiry.

Unfortunately, if your extracts are compounded in a hospital or university pharmacy, the answer to your question is “yes.” This is because you pharmacy is under the aegis of the USP chapter 797 guideline. The individual allergist who componds vaccines in the office is not under these guidelines but under the recommendtions of the Joint Task Force who is responsible for our Allergy Parameters. We have dealt with this issue on several occasions previously on our website. The most comprehensive answer to the question is copied for you below.

In conversations with other physicians under these guidelines they have increased the frequency of injections to advance the dose.

Thank you again for your inquiry and we hope this response is helpful to you.

Previous inquiry submitted to Ask the Expert:
Expiration of allergy extracts
Question:
We are expecting a Joint Commission survey sometime later this year. As a hospital-based Clinic, we were told that we are subject to the sterility requirements of USP 797, including the use of a laminar flow hood and PPE, which we comply with. We are excluded from some aspects of 797, such as the 28-day multidose vial restriction.

The system we were utilizing for our large number of IT patients was a hybrid of a system, where we mixed down our concentrates to working (maintenance) strengths, and then withdrew the prescribed volume from THAT vial into a patient's multidose vial, and gave the vial the recommended beyond use dates per the Third Update. Some concern was raised because the patient's maintenance vials were given the full twelve month dating, even if that working strength vial was compounded several weeks before (effectively extending the expiration date by a few weeks).

My question is this - if I simply mix volumes of undiluted extracts together, can I use the shortest manufacturer's expiration date in dating the new vial? If not, what is the recommended dating? I was told that Joint Commission would allow us to follow "best practices" by our specialty representatives, as long as we had the issue in writing.

Thank you so much for your time and effort on our behalf.

Answer:
Thank you very much for your inquiry.

We have received several inquiries regarding the Joint Commission’s regulation pertaining to allergen immunotherapy administered in hospital-based clinics. I have previously asked Dr. Linda Cox who, as you know, is an internationally known expert in allergen immunotherapy and the lead author of our Parameters on Immunotherapy, to respond to these inquiries. I am copying for you below her fairly comprehensive response to this issue in general.

I am not sure that her previous answer can be applied directly to your question, and therefore I am asking her to share her thoughts with us regarding your specific inquiry as well. When I hear from Dr. Cox, I will forward her response to you.

Thank you again for your inquiry.

Ask The Expert
1/27/2011 RE: Expiration of allergy extracts
Question:
Our institution's Joint Commission has stated that vaccines for immunotherapy are also affected by the mutidose 28-day safety rule of CDC. In my opinion, it is impossible to give patients an injection from a new vial every 4 weeks. It is not practical to discard the vials after 28 days. I am just wondering if this rule has a significant effect on other allergists nationwide. How does a nationwide organization like AAAAI respond to this issue?

Answer:
Thank you for your recent inquiry.

A very similar inquiry was recently sent to our website. I have copied for you below the inquiry along with our response (dated 1/20/2011).

However, since this is the second such inquiry that we have received in a brief period of time, this issue is evidently becoming a more common problem. Therefore I am going to ask for further assistance in answering your question from Dr. Linda Cox, who is a nationally recognized expert in immunotherapy, and the lead author of the most recent Update of the Parameters on Immunotherapy used as a source of my response to the previous inquiry.

As soon as I hear from Dr. Cox, I will forward her answer to you.

Thank you again for your inquiry and we hope this response is helpful to you.

1/20/2011
Question:
Is there any official documentation that we can present to our pharmacy that allergy extracts (be it treatment extracts or patient's individually mixed vials) do not need be discarded in 28days once vials are opened? Even though they are stored in accordance with the manufacturer's guidelines.

Answer:
Thank you for your recent inquiry.

This issue was dealt with most thoroughly in the most recently updated Practice Parameters on Immunotherapy. For your convenience, I have copied below two quotes taken directly from this document. The full reference (source of the quote) is also noted after the quotes.

I hope this will be of help to you in convincing your pharmacy.

Thank you again for your inquiry.

Two quotes and reference:
Prepared allergenic products usually have expiration dates of 3 to 12 months from the date of preparation but should not extend beyond the shortest expiration date of the individual components.

There are few studies that have investigated the potency of dilutions of allergen extract mixtures over time. Expiration dates for allergen extract dilutions are somewhat empiric and not strongly evidence based. A study undertaken by the AAAAI’s Immunotherapy and Allergy Diagnostic committee designed to study the stability of a mixture of standardized extracts in 4 conditions of storage (with and without intermittent room temperature exposure and diluted in normal saline or human serum albumin) found that short ragweed at 1:10 vol/vol dilution, as measured by means of radial immunodiffusion, was stable in all conditions of storage over 12 months.430 Dust mite and cat at 1:10 and 1:100 vol/vol dilutions were also stable in all conditions of storage over 12 months, as measured by using an ELISA assay with an mAb for Der p 1, Der f 1, and Fel d 1.

SOURCE: Linda Cox, Harold Nelson, Richard Lockey, Christopher Calabria et al Allergen immunotherapy: A practice parameter third update Journal of Allergy and Clinical Immunology Vol. 127, Issue 1, Supplement, Pages S1-S55.

Sincerely,
Phil Lieberman, M.D.


Below is the response we received from Dr. Linda Cox, with the documents she mentioned with this email.

Response from Dr. Linda Cox:
As you would expect there is a bit of history on this but I will try to make it as brief as possible. The 28 day expiration dating for dilutions is from the USP compounding guideline USP is a private entity that develops guidelines/regulations for compounding. The Code of Pharmacy uses these guidelines and allergen extract preparation fall under the purview of the Pharmacy Board so technically we should all be following USP guidelines. But the JCAAI''s attorney feels following the JTF guidelines is acceptable. However, allergy practices in hospitals or universities have to adhere to Joint Commission rules, which include the USP guidelines.

The quick answer is: allergen extracts per the USP chapter 797 guideline are not held to the USP general compounding regulations, which include the 28 day labeling and laminar hoods, if certain provisions are met.-see excerpt Allergen extracts as CSPs are not subject to the personnel, environmental, and storage requirements for all CSPMicrobial Contamination Risk Levels in this chapter only when all of the following criteria are met.

And then the criteria are listed. The criteria essentially focuses on aseptic technique and are very similar to the Allergen Immunotherapy Practice Parameter 2 and 3 updates'' guidelines The following bullet in this table essentially exempts allergen extract from the 28 day expiration dating and allows for dating based on extract manufacturer or peer-reviewed publication

The label of each multidose vial of allergen extract as CSPs lists the name of one specific patient, a beyond-use date, and a storage temperature range that is assigned based on the manufacturer’s recommendations or peer-reviewed publications.

See an excerpt from one of my seminar handout which has the two 2 guidelines (USP and JTF) and the most recent ITPP-where they are table VII and VIII.

Hope this helps and does not confuse.

Linda Cox, MD

Response from Dr. Linda Cox:
This is both an easy and complicated question answer.

Easy: The shortest expiration date of the mixture would be the limiting date.

Complicated: There is really very little data on the stability of mixtures and dilutions (single or mixtures) over time. The AAAAI Immunotherapy Committee, when it was really named only the Immunotherapy Committee conducted a study that looked at the stability of standardized extract mixture dilutions in 4 conditions of storage and found that cat, dust mite and ragweed appeared to be stable at 1:10 vol/vol dilution over one year in all conditions. There were some suggestion of loss of grass potency between and 6 months particularly if stored in normal saline.

Unfortunately none of this has been written up except for in the Academy News which I have attached. I have also attached an article Greg Plunkett wrote on the subject. Table 3 demonstrates the loss of potency of grass extract found in some of the studies. so the stability of a dilution may depend on which allergen with what diluent and we even touched the proteolytic issue.

There is a summary statement of this topic from the most recent ITPP update. The last section covers the Academy study. As always hope this helps and does not confuse further

Allergen extract expiration dates.

Summary Statement

85: In determining the allergen immunotherapy extract expiration date, consideration must be given to the fact that the rate of potency loss over time is influenced by several factors separately and collectively, including (1) storage temperature, (2) presence of stabilizers and bactericidal agents, (3) concentration, (4) presence of proteolytic enzymes, and (5) volume of the storage vial. D.

The potency of concentrated allergen immunotherapy extracts (1:1 vol/vol up to 1:10 vol/vol) when kept at 48C is relatively constant and allows the extract to be used until the expiration date that is present on the label. Less concentrated allergen immunotherapy extracts are more sensitive to the effects of temperature and might not maintain their potency until the listed expiration date.425,427

The mixing of other allergens might decrease the loss of potency with time because the additional allergens might prevent adherence of proteins to the vial’s glass wall. Thus highly concentrated extracts are more stable than diluted ones. Extracts are prepared as aqueous, glycerinated, freeze-dried, and alum formulations. Aqueous and glycerin diluents are compatible for mixing standardized with nonstandardized products. Lyophilization is used to maintain the strength of the dry powder, but once the allergen immunotherapy extract is reconstituted, stabilizing agents, such as human serum albumin (0.03%) or 50% glycerin, are needed to maintain potency.427 Phenol is a preservative added to extracts to prevent growth of microorganisms. Phenol can denature proteins in allergen extracts.428,429 Human serum albumin might protect against the deleterious effect of phenol on allergen extracts.428 Human serum albumin might also prevent the loss of potency within storage vials by preventing absorption of allergen on the inner surface of the glass vial. Glycerin is also a preservative. At a concentration of 50%, glycerin appears to prevent loss of allergenic potency, possibly through inhibition of the activity of proteolytic and glycosidic enzymes that are present in certain extracts. However, it might cause discomfort when injected.221

There are few studies that have investigated the potency of dilutions of allergen extract mixtures over time. Expiration dates for allergen extract dilutions are somewhat empiric and not strongly evidence based. A study undertaken by the AAAAI’s Immunotherapy and Allergy Diagnostic committee designed to study the stability of a mixture of standardized extracts in 4 conditions of storage (with and without intermittent room temperature exposure and diluted in normal saline or human serum albumin) found that short ragweed at 1:10 vol/vol dilution, as measured by means of radial immunodiffusion, was stable in all conditions of storage over 12 months.430 Dust mite and cat at 1:10 and 1:100 vol/vol dilutions were also stable in all conditions of storage over 12 months, as measured by using an ELISA assay with an mAb for Der p 1, Der f1, and Feld 1.The expiration date of any dilution should not exceed the expiration date

J Allergy Clin Immunol, Volume 127, Number 1, Cox et al S41; Linda Cox, MD

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology