Methods of manufacturing amino acid compositions

1. A method of manufacturing a pharmaceutical grade dry blended preparation (PGDBP) comprising at least four pharmaceutical grade amino acid entities, said method comprising:

forming a combination of at least four pharmaceutical grade amino acid entities and blending the combination at a temperature lower than 40° C. for a time sufficient to achieve a PGDBP having a mass of at least 10 kg, the combination being blended substantially lacking solvent,

wherein:

the PGDBP comprises a level of a contaminant that is less than 0.15% (w/w), and

less than 20%, by weight, of at least one of the pharmaceutical grade amino acid entities transforms from a crystalline state to an amorphous state during blending and wherein at least 50% of the pharmaceutical grade amino acid entities are in a crystalline state during blending.

2. The method of claim 1 , further comprising portioning the PGDBP into a plurality of portions of the PGDBP.

3. The method of claim 1 , wherein the blending is sufficient to achieve blend and content uniformity without generating impurities or inducing blend heterogeneity.

4. The method of claim 1 , further comprising, after blending, selecting or taking a downstream processing step chosen from: dividing the PGDBP into portions, fill-finish, packaging, labeling, shipping, distribution, storage, or release into commerce.

5. The method of claim 1 , wherein the PGDBP is suitable for oral administration.

6. The method of claim 5 , wherein the combination or PGDBP further comprises one or more excipients and/or oral administration components.

7. The method of claim 1 , wherein the PGDBP comprises less than 10% (w/w) of a tastant, a bitterness covering agent, flavorants, a sweetener, odor masking agent, a wetting agent, a stabilizing/thickening agent, or a coloring agent.

8. The method of claim 1 , wherein blending occurs with one, two, or three of the following properties:

i) blending does not effect a transition from a crystalline state to an amorphous state; or

ii) blending comprises blending or mixing in a blender or mixer at a speed of less than 15,000 rpm.

9. The method of claim 1 , wherein the PGDBP comprises:

a) a leucine amino acid entity,

b) an arginine amino acid entity,

c) glutamine amino acid entity; and

d) a N-acetylcysteine (NAC)-entity.

10. The method of claim 1 , wherein the combination being blended substantially lacks water.

11. The method of claim 1 , wherein the amount of a pharmaceutical grade amino acid entity in the PGDBP measured at a sampling point comprises a weight percent, and wherein the amount of the pharmaceutical grade amino acid entity present in the PGDBP as a whole comprises a weight percent.

12. The PGDBP produced by claim 1 .

13. The plurality of portions of a PGDBP produced by claim 2 .

14. A method of manufacturing a plurality of portions of a pharmaceutical grade dry blended preparation (PGDBP) comprising at least four pharmaceutical grade amino acid entities, said method comprising:

blending a combination of at least four pharmaceutical grade amino acid entities at a temperature lower than 40° C. for a time sufficient to achieve a content uniformity standard thereby making a PGDBP, wherein less than 20%, by weight, of at least one of the pharmaceutical grade amino acid entities transforms from a crystalline state to an amorphous state during blending and wherein at least 50% of the pharmaceutical grade amino acid entities are in a crystalline state during blending, and

dividing the PGDBP into a plurality of portions, wherein at least 1% of the plurality of portions are test portions, and wherein the amount of a component present in at least 90% of test portions differs from a reference value by no more than 10%.

15. The method of claim 14 , wherein the amount of the component present in at least 90% of test portions is the percent of the component present in at least 90% of test portions, and wherein the reference value is the percent of the component present in the PGDBP as a whole.