Amb a 1 Units - an arbitrary unit for the major allergen in short ragweed

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Issue migrated from trac ticket # 30

priority: major | resolution: fixed

2009-07-18 16:58:07: gschadow@pragmaticdata.com created the issue

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FDA would like to add the following unit of measure to UCUM:

Amb a 1 Units/ML – an arbitrary unit for the measurement of Amb a 1, a 38 kD glycoprotein that is the major allergen in short ragweed pollen allergen extracts. The amount of Amb a 1 units are determined by an in-vitro comparison of a test short ragweed extract to a FDA CBER Amb a 1 reference standard.

Further material submitted by the requestor is this explanation:

Antigen E and Amb a 1 are synonymous. Antigen E is the old term that was in the regulations for allergenics back in the 80s. The more up-to-date scientific name is Amb a 1. However, you will still have manufacturers using the old term of Antigen E since that is in their license.

In the old regulations (which have since been removed), the Radial Immuno Diffusion (RID) method for determining Antigen E potency was specified. The number of units/ml is simply that which is obtained by comparison of a test sample (lot for release) against the US reference standard that has a labeled content of Antigen E (also a US reference preparation of anti-antigen E serum is used in the test). The requirement is for the assayed value of the US reference for antigen E to be within +/- 25% of the labeled value.

The general working theory is that a Unit/mL of Antigen E(Amb a 1) is equivalent to a microgram of AntigenE(Amb a 1)/mL but we are still looking for solid references discussing this fact - this was not an FDA mandated unit expression due to the incorporation of the old methods specified under the regulation into the firm's BLAs under 52 FR 37605. FDA has not since initiated the legal process required under the 680s for a unit change (see below discussion on BAU/mL). The benefit of a unit change for allergenics always has to be balanced against the risk to patients on incorrect dosing that may occur despite all best education efforts when such a change is made.

In summary:

1. Amb a 1 is the up-to-date term for the short ragweed pollen allergen that was originally described as Antigen E. They are synonyms. Although Antigen E is no longer used in the scientific literature, its meaning is unambiguous. The manufacturers are still licensed to use Antigen E as the designation.
2. Therefore, Amb a 1 U = AgE U
3. The relationship between AgE U and BAU (350 AgE U/mL = 100,000 BAU/mL) was based on studies done decades ago, reportedly on 15 study subjects. CBER considered mandating a conversion to BAU/mL in the labeling of short ragweed pollen products, based on AgE content, but this was never implemented.
4. CBER provides two US standard reagents to manufacturers for their determination of Amb a 1 content, a reference standard and a reference serum. The assay used is a radial immunodiffusion assay (RID).
5. Solid references discussing the relationship between Antigen E U/mL/Amb a 1 U/mL and micrograms of Antigen E U/mL/Amb a 1/mL are being researched.

From this explanation a short discussion ensued:

B: Based upon your email, it seems as if we only need either "Amb a 1 units" or "AgE units" as a unit of measurement term, but not both. Is this your understanding?

J: I would not object to using just one measurement term, as long as there is an explanation of the equivalence of the two in the definition and it would not have an impact on labeling.

B: Which one of the two would you prefer? Do you have a definition for either "Amb a 1 units" or "AgE units"?

J: Dr. S. and I agree with using one term, and our preference would be to use the current scientific name of Amb a 1.

B: Okay, then "Amb a 1 units" it is. We still need a definition that does not define "Amb a 1 units" in terms of either "AgE units" or "BAU".

PS: In the context of this discussion, some other units (either recently added or pending requests were discussed):

BIOEQUIVALENT ALLERGY UNITS/ML (BAU/ML)- biological potency unit assigned to standardized grass pollen and cat allergenic extracts, following in-vitro comparison of the test extract to a FDA CBER reference standard. The FDA CBER reference standard is assigned a specific BAU unitage based on quantitative skin testing.

ALLERGY UNITS/ML (AU/ML) - biological potency unit assigned to standardized mite and short ragweed pollen allergenic extracts, following in-vitro comparison of the test extract to a FDA CBER reference standard. The FDA CBER reference mite standard is assigned a specific AU unitage based on quantitative skin testing. For the short ragweed pollen allergen extract FDA CBER reference mite standard is assigned a specific AU unitage based on specific ragweed allergen content.

WEIGHT TO VOLUME (W/V) - potency unit expressed as a ratio of the weight of allergen source material extracted to the volume of diluting fluid, and adjusted based on subsequent dilutions.

GS: This is not a unit since weight (ahem, mass) and volume could have different units. It would have to be something like mg/L or something like that, which is an existing UCUM unit.

PROTEIN NITROGEN UNIT (PNU) - potency unit based on the micro-Kjeldahl measurement of protein nitrogen in an acid precipitated extract. Compared with other protein determination methods, 1 mg of protein nitrogen typically equals 100,000 PNU.

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2009-07-18 16:58:58: gschadow@pragmaticdata.com edited the issue description

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2009-07-18 17:19:14: gschadow@pragmaticdata.com changed status from new to assigned

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2009-07-18 17:19:14: gschadow@pragmaticdata.com changed owner from * to gschadow*

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2009-07-18 17:19:14: gschadow@pragmaticdata.com

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2009-07-18 20:49:44: gschadow@pragmaticdata.com changed status from assigned to closed

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2009-07-18 20:49:44: gschadow@pragmaticdata.com set resolution to fixed

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2009-07-18 20:49:44: gschadow@pragmaticdata.com commented

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EDITORIAL NOTE: The University of Texas' Structural Database of Allergenic Proteins (SDAP) contains close to 1000 allergens, isoallergens. Comparing the prospect of thousands of such special units for every allergen, one begins to appreciate even the metrologically comlex BAU unit.