Methods for Measuring Consumption of Amino Acid N-Carboxyanhydrides during Manufacture of Glatiramer Acetate

A method of manufacturing glatiramer acetate, the method comprising:

• (a) polymerizing in a reaction mixture individual N-carboxy anhydrides (NCAs) of L-alanine (Ala), benzyl-protected L-glutamic acid (Glu), trifluoroacetic acid (TFA)-protected L-lysine (Lys), and L-tyrosine (Tyr) to generate a batch of protected copolymer;
• (b) measuring the amount of two, three, or all four of the individual NCAs in the reaction mixture at two or more time points during the polymerization reaction;
• (c) determining the rates of depletion of two, three, or all four of the individual NCAs in the reaction mixture using the at least two or more measurements;
• and
• (d) processing at least a portion of the batch of the protected copolymer to generate glatiramer acetate only if one or more of the following criteria (i)-(v) is determined to have been met in step (c):
• (i) the rate of depletion of NCA-Ala is greater than the rate of depletion of NCA-Glu, NCA-Lys, and/or NCA-Tyr (Ala>Glu, Lys and/or Tyr);
• (ii) rate of depletion of Tyr is less than the rate of depletion of NCA-Ala, NCA-Glu, and/or NCA-Lys (Tyr<Ala, Glu, and/or Lys);
• (iii) the rates of depletion of NCA-Glu and NCA-Lys are less than the rate of depletion of NCA-Ala (Ala>(Glu, Lys));
• (iv) the rates of depletion of NCA-Glu and NCA-Lys are greater than the rate of depletion of NCA-Tyr ((Glu, Lys)>Tyr);
• and
• (v) the rates of depletion of NCA-Glu and NCA-Lys are less than rate of depletion of NCA-Ala and greater than the rate of depletion of NCA-Tyr (Ala>(Glu, Lys)>Tyr).