Metformin Hydrochloride API: Specification, Nitrosamine Limits and Supplier Documents

Buyers make two separate decisions: qualify the source, then approve each lot. A quote can support one without the other.

Source qualification asks whether a supplier's site, process and change-control system can be trusted for repeat supply. Lot approval asks whether one batch meets the specification on its Certificate of Analysis (COA). A quote supports qualification only if it names the documents behind it. It supports lot approval only if the results belong to a named lot. The checklist below tests the quote. The monograph and NDMA sections supply the numbers. The documents section covers qualification.

A usable metformin API quote checklist has twelve lines, and each one has a pass test and a reject test. Run the checklist against the written quote, not a brochure.

The USP monograph for metformin hydrochloride requires an assay of not less than (NLT) 98.0% and not more than (NMT) 102.0%, calculated on the dried basis. Assay ranges differ by pharmacopeia and edition. Older USP editions set 98.5% to 101.0%, so a quote must name both.

USP general chapter <1469> Nitrosamine Impurities has been official since December 1, 2021.

Identification and assay

Dried basis means the result is corrected for the water and volatiles lost on drying. Loss on drying (LOD) is the weight lost when a sample is dried, so the assay and LOD figures must be read together. Ask the COA to state which pharmacopeial identification test was run and which edition it follows.

The monograph lists three reference standards: USP Metformin Hydrochloride RS, USP Metformin Related Compound A RS and USP Melamine RS. A COA that cites the monograph should name the reference standard it used.

Impurities and loss on drying

Take the related-substance limits and the LOD limit from the current USP-NF text, and require the COA to print the limit beside each result. The dried-basis assay depends on LOD, so ask for both from the same lot.

Our guide to how to read a COA's test results covers related substances and residual solvents under ICH Q3C (the International Council for Harmonisation guideline on residual solvents).

FDA's acceptable intake for NDMA is 96 ng/day. That is 0.038 ppm for immediate-release (IR) metformin at a 2,550 mg maximum daily dose and 0.048 ppm for extended-release (ER) at 2,000 mg. In the EU, a frequently authorized maximum daily dose is 3,000 mg, which gives 0.032 ppm (Keire et al., 2022). All three are drug-product limits derived from dose.

The conversion formula

The metformin NDMA limit in ppm equals the acceptable intake in nanograms (ng) divided by the maximum daily dose in milligrams (mg). Acceptable intake is the daily NDMA amount the regulator allows, here 96 ng. Maximum daily dose is the highest daily amount of metformin hydrochloride the product's labeling permits. One ng per mg is one part per million (ppm).

FDA's metformin method document (dated June 3, 2020) gives the 96 ng/day figure and the two FDA limits below. The arithmetic is ours. For the same method applied to any nitrosamine, see our guide to turning nitrosamine intake limits into ppm specs.

Metformin ER vs IR NDMA limit

The ER limit is higher than the IR limit because the ER maximum daily dose is lower.

FDA's June 11, 2020 update named five companies recalling ER metformin. The page, last updated January 6, 2021, states that FDA testing had not shown NDMA in IR products.

How the EU's 3,000 mg dose basis gives a lower limit

In the EU, a frequently authorized maximum daily dose for metformin is 3,000 mg. Dividing the same 96 ng/day by 3,000 mg gives 0.032 ppm, or 32 ppb, as set out by authors from FDA, EMA, EDQM and other regulatory laboratories in International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines (AAPS Journal, 2022). A larger denominator gives a smaller ppm. For a lot sold into a market that uses that basis, specify to 0.032 ppm.

For example, a reading of 0.034 ppm sits below FDA's 0.038 and 0.048 but above 0.032.

What NDMA result and method to request

Metformin API nitrosamine testing should be reported on four points: matrix, method, quantitation limit and lot.

• Matrix: the result must say whether API or finished product was tested. FDA's method covers both (Purpose, page 2). A finished-product result does not describe an API lot.
• Method: a named method type, such as LC-MS/MS, GC-MS/MS or high-resolution MS (HRMS). FDA's published metformin methods use liquid chromatography with HRMS.
• Quantitation limit (LOQ): stated, and below the limit you are held to. FDA's method reports an NDMA LOQ of 0.01 ppm (Conclusions table, page 1), about 26% of 0.038 ppm (our division). A COA with an LOQ of 0.05 ppm exceeds all three limits, so "<0.05 ppm" proves nothing.
• Lot: the lot number the result belongs to.

Method choice matters. In 2020, FDA found that a private laboratory's method had over-reported NDMA in US metformin tablets (Keire et al., 2022). A published comparison of LC-MS and LC-MS/MS methods also studied NDMA quantification in metformin tablets in the presence of dimethylformamide, which can interfere with the reading. FDA's primary LC-HRMS screen reports an NDMA quantitation limit of 0.03 ppm, and FDA states that positive results can be confirmed with a second, orthogonal method (Background, page 1).

Ask whether the lab confirmed any result near the limit the same way. Compare the quantitation limit with the limit you are held to: 0.03 ppm leaves little headroom under 0.038 ppm and almost none under 0.032 ppm (our division: 0.03 ÷ 0.032 ≈ 94%).

Regulators found NDMA mainly in finished tablets, not in the API. In a joint regulatory-laboratory study, 213 of 215 metformin API lots had no measurable NDMA, while 156 of 875 finished-dose samples (17.8%) exceeded the acceptable intake (Keire et al., 2022). The authors note that the samples were not a comprehensive market survey.

Two formation routes are reported. In one, dimethylamine (DMA) left in the API reacts with nitrite from excipients such as povidone and hypromellose, and NDMA fell below detection in one study when lower-nitrite excipients were used (Keire et al., 2022; Schlingemann et al., 2022). In the other, trace atmospheric nitrogen dioxide reacts with DMA during processing (Fukuda et al., 2023). Regulators note that the role of DMA levels is still under study.

So the API supplier's job is narrower than "NDMA-free": control and report DMA, and warn you before a change shifts it. DMA in API lots ranged from below 10 ppm to almost 500 ppm in one regulator's testing, so ask for the DMA limit, the lot result and a change-control commitment (Keire et al., 2022). A change of route, solvent or site can shift DMA. That is our inference.

FDA's testing and recalls brought nitrosamine control into metformin sourcing. On December 6, 2019, EMA reported NDMA in a small number of metformin medicines outside the EU (EMA). FDA posted its first laboratory results on February 3, 2020 and named five ER recalls on June 11, 2020, and its page lists further ER recalls through November 4, 2020 (FDA). FDA's guidance Control of Nitrosamine Impurities in Human Drugs (Revision 2, September 2024) sets out how manufacturers assess and control nitrosamine risk.

Request the DMF reference or letter of authorization, the CEP, GMP evidence, the change-control procedure and the nitrosamine risk assessment. Each is only as good as its match to the quote.

• DMF (Drug Master File) or letter of authorization: pass if it names your product, the supplier's site and the DMF number.
• CEP (Certificate of Suitability): pass if the number, holder and site match the quote and the certificate is valid.
• GMP evidence: pass if it covers the exact site on the quote. ICH Q7 GMP expectations for API suppliers explain what to check.
• Change control: pass if the supplier commits to notify you before a route, solvent or site change.
• Nitrosamine risk assessment: reject if it only asserts "no nitrosamine risk."

For what each document proves, see what WHO-GMP, DMF and CEP tell a buyer.

Send your request for quotation (RFQ) with the product or CAS number (1115-70-4), quantity, destination, grade or purity, documents needed, payment terms and Incoterms. Add the pharmacopeia and edition, and the DMA and NDMA results you require.

Price, minimum order quantity, capacity and lead time are confirmed product by product at quotation. Buyers should state the documents and test results they require in the RFQ. We answer DMF, CEP and US registration status for metformin in each RFQ response. We support sample and evaluation quantities for qualified B2B buyers, with quantity, price and documents confirmed per product. COA, specification and SDS/MSDS are shared where applicable. For what each contains, see COA and SDS contents.

A quote that cannot show its edition, its limits and its method is not ready for approval.

To put your requirement into a quote, email sunil@aarisepharma.com, message +91 9899783330 on WhatsApp, or send an RFQ through our contact page.