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.
- 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).
- If this policy is finalized, USP will no longer include reporting threshold in PF proposals for drug substance and drug product monographs.
- 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.
- 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 EG@usp.org.
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) |
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