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Reporting Threshold in USP-NF Monographs: Proposed Policy Change for Public Comment

Type of Posting: General Announcement
Posting Date: 13–Aug–2019; updated Notice posted 07–Nov–2019
Comment Deadline:  12–Nov–2019

An update to this Notice was posted on November 7, 2019 and can be found here.

As part of our commitment to ongoing monograph modernization, USP is updating organic impurities testing for articles subject to USP–NF standards. Our approach applies the ICH Q3A/B-based limits for identification and reporting of organic impurities and degradation products in drug substances and drug products. Currently, USP drug substance and drug product monographs’ impurities tests with specifications for total impurities or total degradation products will in many cases include a reporting threshold consistent with the ICH guidelines.

In addition to setting criteria for a peak to be included in the total impurities, the reporting threshold also aligns with the approach to verify the system sensitivity. Monographs with recently modernized or new impurity procedures are expected to contain a sensitivity solution at a concentration corresponding to the reporting threshold, and a signal-to-noise requirement as a part of system suitability requirements. This approach is used for both drug substance and drug product monographs.

Beginning in 2016, the U.S. Food and Drug Administration (FDA) provided comments requesting that reporting thresholds not be included in drug product monographs. Since compendial monographs are not intended to identify every impurity and degradation product, the FDA is concerned that the inclusion of reporting thresholds could result in very toxic impurities not being identified or reported. The FDA commented that reporting thresholds for drug products vary based on product-specific factors and should be addressed as an application assessment issue.  FDA uses ICH reporting thresholds as guidelines and deviates from them as needed based on application specific considerations.  

FDA has recently notified USP that the same public health and safety concerns regarding the inclusion of reporting thresholds would also be applicable to drug substance monographs. Since a drug substance may be used in different products with different maximum daily doses, ICH Q3A limits (including reporting threshold) will vary due to product specific factors and should also be addressed as an application assessment issue. 

To address the FDA’s recommendation, USP is proposing the following policy change pertaining to inclusion of reporting thresholds in drug substance and drug product monographs which is presented here for a 90-day public comment period.  

  1. For the impacted monograph proposals, the Expert Committees will have an option of deleting the proposed reporting threshold at the ballot, without republishing the proposal in Pharmacopeial Forum (PF).
  2. If this policy is finalized, USP will no longer include reporting threshold in PF proposals for drug substance and drug product monographs. 
  3. USP will continue including a sensitivity solution and signal-to-noise requirement in monographs, to ensure that the sensitivity of the equipment is sufficient to reliably integrate any impurities that are included for calculating the total impurities result. 
  4. For monographs that are already official, USP will not solely revise these monographs to remove the reporting threshold as a result of this policy change. However, as these monographs are identified for revision as part of the ongoing revision process, USP will remove the reporting threshold at that time.

After the 90-day public comments period, USP will review the comments and post an updated Compendial Notice. Until the policy is finalized, USP will continue including reporting thresholds in the drug substance and drug product monograph proposals being submitted for publication in PF

Stakeholders are encouraged to contact USP and provide their comments and recommendations. The lists of drug product and drug substance monograph proposals impacted by FDA comments is included at the end of this Notice.

Should you have any questions or comments, please contact Elena Gonikberg, Ph.D., Principal Scientific Liaison, at

List of impacted drug product monographs

PF 44(1) [Jan.–Feb.] 2018 to PF 45(3) [May–June] 2019

Monograph title PF issue
Albuterol Inhalation Aerosol PF 44(1)
Atomoxetine Capsules PF 44(1)
Carbidopa and Levodopa Orally Disintegrating Tablets PF 44(1)
Desvenlafaxine Extended-Release Tablets PF 44(1)
Pramipexole Dihydrochloride Tablets PF 44(1)
Primidone Tablets PF 44(1)
Terbutaline Sulfate Injection PF 44(1)
Sertraline hydrochloride Tablets PF 44(1)
Cefepime for Injection PF 44(2)
Clindamycin Hydrochloride Capsules PF 44(2)
Clindamycin Injection PF 44(2)
Clindamycin Phosphate Topical Solution PF 44(2)
Clobetasol Propionate Ointment PF 44(2)
Dacarbazine for Injection PF 44(2)
Escitalopram Oral Solution PF 44(2)
Minoxidil Tablets PF 44(2)
Pyridostigmine Bromide Extended-Release Tablets PF 44(2)
Sodium Phenylbutyrate Oral Powder PF 44(2)
Sodium Phenylbutyrate Tablets PF 44(2)
Testosterone Cypionate Injection PF 44(2)
Benztropine Mesylate Injection PF 44(3)
Benztropine Mesylate Tablets PF 44(3)
Clonazepam Tablets PF 44(3)
Cromolyn Sodium Oral Solution PF 44(3)
Norethindrone Acetate and Ethinyl Estradiol Tablets PF 44(3)
Fluconazole Tablets PF 44(3)
Galantamine Extended-Release Capsules PF 44(3)
Galantamine Oral Solution PF 44(3)
Galantamine Tablets PF 44(3)
Hydrocortisone Acetate Cream PF 44(3)
Hydroxychloroquine Sulfate Tablets PF 44(3)
Nitroglycerin Injection PF 44(3)
Sitagliptin and Metformin Hydrochloride Tablets PF 44(3)
Sitagliptin and Metformin Hydrochloride Extended-Release Tablets PF 44(3)
Triamcinolone Acetonide Injectable Suspension PF 44(3)
Triamcinolone Acetonide Lotion PF 44(3)
Bimatoprost Ophthalmic Solution PF 44(4)
Brimonidine Tartrate Ophthalmic Solution PF 44(4)
Bupropion Hydrochloride Extended-Release Tablets PF 44(4)
Bupropion Hydrochloride Tablets PF 44(4)
Clarithromycin Extended-Release Tablets PF 44(4)
Clindamycin Phosphate Gel PF 44(4)
Clindamycin Phosphate Vaginal Cream PF 44(4)
Quinapril Tablets PF 44(4)
Tizanidine Capsules PF 44(4)
Methylprednisolone Sodium Succinate for Injection PF 44(4)
Atovaquone and Proguanil Hydrochloride Tablets PF 44(5)
Baclofen Injection PF 44(5)
Clozapine Tablets PF 44(5)
Quinine Sulfate Capsules PF 44(5)
Repaglinide and Metformin Hydrochloride Tablets PF 44(5)
Triamcinolone Acetonide Cream PF 44(5)
Triamcinolone Acetonide Dental Paste PF 44(5)
Hydrocortisone Cream PF 44(6)
Hydrocortisone Ointment PF 44(6)
Hydrocortisone Tablets PF 44(6)
Norgestimate and Ethinyl Estradiol Tablets PF 44(6)
Prednisolone Acetate Ophthalmic Suspension PF 44(6)
Venlafaxine Extended-Release Tablets PF 44(6)
Diazepam Injection PF 45(2)
Diazepam Tablets PF 45(2)
Granisetron Hydrochloride Injection PF 45(2)
Granisetron Hydrochloride Tablets PF 45(2)
Selegiline Hydrochloride Capsules PF 45(2)
Lacosamide Injection PF 45(3)
Lacosamide Oral Solution PF 45(3)
Lacosamide Tablets PF 45(3)
Nadolol Tablets PF 45(3)
Prednisone Tablets PF 45(3)
Sorafenib Tablets PF 45(3)
Sulfasalazine Delayed-Release Tablets PF 45(3)
Sulfasalazine Tablets PF 45(3)
Trihexyphenidyl Hydrochloride Oral Solution PF 45(3)

List of impacted drug substance monographs

PF 45(3) [May–June] 2019

Monograph title PF issue
Ceftazidime PF 45(3)
Formoterol Fumarate PF 45(3)
Guanfacine Hydrochloride PF 45(3)
Labetalol Hydrochloride PF 45(3)
Lacosamide PF 45(3)
Mupirocin Calcium PF 45(3)
Nadolol PF 45(3)
Phenobarbital Sodium PF 45(3)
Phentermine Hydrochloride PF 45(3)
Pindolol PF 45(3)
Rabeprazole Sodium PF 45(3)
Tetrahydrozoline Hydrochloride PF 45(3)
Tranexamic Acid PF 45(3)