Low Lactose ERP - Review Book

3. Are the definitions specified in the SMPR used and applied appropriately in the method? If no, please indicate how the terms are used.

RSDR was not correctly defined in the validation but the data still met the SMPR requirement.

RSDR data was collected as per decade duplicate analyses of 9 different samples on 9 different days with individual duplicate values measured on different days. The protocol lists these analyses are done at the same location on the same instruments/equipment but with two analysts. I read this as intermediate precision. However, RSDR is typically attained in the process after First Action Status is granted, so the resulting MLV can be used for this SMPR requirement.

As a note: data for RSDr (repeatability) was also collected in a second approach of deco-duplicate analyses of 9 samples on the same day (correct).

Both approaches estimated RSDr as 9.3% and 7.9%, both below the RSDr requirement of 10%

The remaining definitions were met. Notably reported lactose levels account for monohydrate forms.

4. Does the method, as written, contain all appropriate precautions and warnings related to the method's reagents, components, instrumentation, or method steps that may be hazardous? If no, please suggest wording or option(s). III. Review of Supporting Information 1. Are the definitions specified in the SMPR used and applied appropriately in the supporting documentation (manuscripts, method studies, etc...)? If not, please explain the differences and if the method is impacted by the difference. 2. Is there information demonstrating that the method meets the SMPR Method Performance Requirements using the Reference Materials stated in the SMPR? If not, then specify what is missing and how this impacts demonstration of performance of the method.

This condition is met. I especially approve of the Safety Table 5 which presents safety concerns in a clear an actionable fashion.

The method abstract states sugars are extracted from both solutions using an aqueous-ethanol solution; however the method protocol only states water is used. The ethanol must be confirmed since ethanol is needed to denature enzymes present in the sample, a criteria listed in the SMPR. This could impact the method.

RSDr issues are described above but data still meets SMPR requirements.

Authors stated the SMPR CRM of SRM 2383a was not available. An SRM substitute, the SRM1869a from the SPIFAN II SLV kit was used after approval of the lactose content given in the reference certificate for NIST SRM1869 with that measured with the present method. Also used were two MUVA Kempten CRMs (UHT milk at 0.006% lactose and sodium casseinate (0.0024% lactose). All results were acceptable.