Special Mixes

On February 19, 2015 the FDA issued a guidance stating that special mixes can no longer be manufactured. These mixes refer to those that are specially formulated by a physician for general use and not associated with a named patient. To comply, the Allergen Products Manufacturers’ Association (APMA) has agreed to cease all production of these special mixes. Click here for the full guidance document.

We at ALK are committed to helping physicians maintain a continuity of care, as well as to providing technical support to alleviate any hassle or uncertainty associated with this discontinuation of special mix manufacturing. This technical memo is intended to provide general instructions for making a special mix within a physician’s office, as well as to provide alternative approaches toward maintaining a high standard of patient care in light of the new FDA guidelines. Please do not hesitate to contact Scientific Services, should you have additional questions or concerns (science@alk.net; ALK Special Mix Hotline (855)782-9323).

Prescription Formulations - Equal and Unequal Parts

ALK-manufactured special mixes have an associated prescription formulation, in which all information necessary for compounding can be found. Formulating a special mix is very similar to mixing a patient treatment vial; it is important to pay close attention to all components being included to ensure an appropriate extract mix composition and concentration. Chart 1 shows an example of an equal parts special mix prescription formulation. In an equal parts mix, all components are present in the same volume.

In the example (Chart 1), four components are used to generate a 10 mL vial of glycerinated, 1:10 w/v mold extract. As denoted, the four components are included at equal strengths (1:10 w/v) and equal parts (component %). Since this is an equal parts special mix, the volume of each extract to be added would be calculated as follows:

For the above example, 2.5 mL of each mold extract will be combined into a 10 mL sterile empty vial to generate the desired 10 mL volume of special mix, which can then be used for patient testing and treatment.

When mix components are not present in equal volumes, these special mixes are referred to as unequal parts mixes. Below is an example of an unequal parts special mix prescription formulation (Chart 2).

In the below example (Chart 2), six components are used to generate a 30 mL vial of 10,000 PNU/mL Center-AL extract. As denoted, the six components are included at equal strengths (10,000 PNU/mL) and unequal parts (component %, 10-30%). Since this is an unequal parts special mix, the volume of each extract to be added would be calculated as follows:

Similarly, the above prescription formulation (Chart 2) could be represented in parts, rather than as a percentage. Using this scenario, Ragweed would be 3 parts, Pigweed, Lambs Quarters and Russian Thistle would be 1 part each, and Sagebrush and Mugwort would be 2 parts each. This mix totals 10 parts. The volume of each extract to be added would be calculated as follows:

For the example shown in Chart 2, using either approach, 9 mL of Ragweed, 3 mL of Pigweed, Lambs Quarters and Russian Thistle, and 6 mL of Sagebrush and Mugwort extract will be combined into a 30 mL sterile empty vial to generate the desired 30 mL volume of special mix. Once combined, this special mix can be used for patient testing and treatment.

Special Mix Potency Labeling

Special mixes should be labeled according to the potency of the components that are contained within the mix (i.e., 1:10 w/v, 1:20 w/v, 1:40 w/v, 10,000 PNU/mL, 20,000 PNU/mL, 40,000 PNU/mL). This designation applies when all extracts contained within a special mix are formulated in the same manner (e.g., all extracts are 1:10 w/v, resulting special mix is labeled as 1:10 w/v). This potency labeling is not consistent, however, if various extract formulations are used to generate a special mix (e.g., 1:20 w/v extracts are combined with 1:10 w/v extracts). In these circumstances, a special mix should be labeled with a 1:1 designation, denoting that various potencies were utilized.

Special Mix Expiration Dating

The expiration date for a special mix should not exceed the expiration date assigned to the earliest expiring component contained within the mix. For example, the expiration date for a mix containing an aqueous Ragweed extract (expiring 12/16) and a glycerinated Sagebrush extract (expiring 12/18) would be 12/16. The inclusion of glycerinated extracts with aqueous extracts does not extend aqueous dating.

Special Mixes and USP 797

All safety and sterility recommendations put forth in the USP 797 allergenic extract compounding guidelines apply to the formulation of special mixes [1, 2]. While proficiency testing is not required, annual vial fill tests should be completed to ensure appropriate mixing technique. Please contact your local Allergy Consultant or ALK Scientific Services for vendor recommendations. Sterility testing is not required for special mixes formulated in a physician office setting.

Catalog Mixes

ALK offers many catalog mixes of molds, grasses, weeds and trees. Most of these mixes are equal parts mixes, unless otherwise denoted. Due to the high degree of cross-reactivity that exists among similar species, catalog mixes may be a viable substitute for current special mix formulations [3, 4]. Please refer to the ALK Product Catalog for available mixes and contact your local Allergy Consultant or ALK Scientific Services for questions related to cross-reactivity.

Mixes versus Individual Species

Individual species extracts can be utilized in place of mixes to formulate patient treatment vials, in many circumstances. This can be facilitated by careful analysis of cross-reactivity among species and a thorough understanding of allergen significance. The use of individual species negates the potential for introducing superfluous allergens to a patient who is not sensitized to all mix components, a controversial issue that has yet to be evaluated extensively in clinical research [1]. Furthermore, with multi-component mixes, therapeutic dosing is difficult to achieve, due to significant dilution of the individual extracts. ALK Scientific Services can evaluate current mixing protocols and formulate dosing strategy recommendations based off of individual components, rather than special mixes.

ALK Commitment

ALK is committed to helping physicians and their support staff. Please do not hesitate to contact Scientific Services (science@alk.net; Special Mix Hotline (855)782-9323) should you have additional questions or concerns regarding special mixes.

References:
1. Cox, L., et al., Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol, 2011. 127(1 Suppl): p. S1-55.
2. Lin, S.Y., et al., Impact of newly revised sterile medication compounding guidelines USP {797} on allergy vial preparation. Otolaryngol Head Neck Surg, 2008. 139(1): p. 5-6.
3. Weber, R.W., Cross-reactivity of pollen allergens: impact on allergen immunotherapy. Ann Allergy Asthma Immunol, 2007. 99(3): p. 203-11; quiz 212-3, 231.
4. Portnoy, J.M. and D. Jara, Mold allergy revisited. Ann Allergy Asthma Immunol, 2015. 114(2): p. 83-89.

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