Table 1.

Common methods to reduce lactic acid and/or ammonium production in animal cell culture.

Method	References	Effect on Lactic Acid (Lac A) Production	Effect on Ammonium (NH4+) Production	Likely Universally Reduces Lac A and NH4+ Production?	No Change or Decrease in Process Complexity?	Commonly ImplemenTed in cGMP Operations?
Replacement of glucose (gluc), glutamine (gln), or both with alternative sugars and/or amino acids	[1,2,13,14,15,16] (gluc only)	Reduced	NR	No	Yes	No
	[17,18] (gln only)	NR	Reduced	No	Yes	No
	[3,19,20] (gluc only)	Reduced	Increased	No	Yes	No
	[21] (gluc only)	Reduced	Unchanged	No	Yes	No
	[20] (both)	Reduced	Reduced	Possibly	Yes	No
On-line feedback control of glucose and/or glutamine at very low levels using glucose sensor, glutamine sensor, and/or other sensors and concentrated feeds	[22,23,24] (gluc only)	Reduced	Increased	No	No	No
	[23] (gln only)	Reduced	Reduced	No	No	No
	[4,22,23,24,25,26] (both)	Reduced	Reduced	Yes	No	No
	[3,27] (gluc only with other sensors)	Reduced	Increased	No	No	27 at Pfizer
	[28] (both with other sensors)	Reduced	Unchanged	Yes	No	Not in completely full form
Copper supplementation	[12,29,30,31,32]	Reduced	NR	No	Yes	Yes
Reduction in temperature	[33]	Reduced	Unchanged	No	Yes	Yes
	[34]	Reduced	Reduced	No	Yes	Yes
Reduction in pH	[34,35,36]	Reduced	Unchanged	No	Yes	Yes
	[37]	Reduced	Increased	No	Yes	Yes
Selection of clones with lactate consumption phenotype	[10,11,12,27,30,38]	Reduced	Mixed	No	Yes	Yes

NR—not reported