Nitrites in Excipients → Nitrosamines in Drug Products: What Matters Now (and Why Croscarmellose Sodium Helps)

Executive summary

• Nitrosamines form when nitrosating species (often from nitrite) meet nitrosatable amines under conducive conditions (acid, heat, humidity). Trace nitrites in excipients are now a recognized driver in finished products. The FDA (Sept 2024 final) explicitly cites nitrite in excipients at ppm levels as a root cause and asks manufacturers to risk-assess and control across the lifecycle. 

• EMA’s Q&A (Rev. 22) directs MAHs to consider excipient nitrites and recommends testing raw materials (including excipients) when indicated by the risk assessment. 

• Data landscape: cross-supplier variability is real; the Lhasa “Nitrites in Excipients” database and follow on work show non-zero nitrite is common and varies widely by excipient type and supplier. 

• Formulation leverage: modeling shows that switching excipient type and/or supplier can cut modeled nitrosamines dramatically (≈ -59% to -89%) without touching the API often by replacing high-nitrite components. 

• Croscarmellose sodium (CCS): a no amine superdisintegrant that typically carries lower nitrite vs. crospovidone; several industry sources recommend switching to CCS in nitrosation sensitive formulations. 

1) Why this matters (regulatory reality in 2025)

Since 2018, multiple drug classes have faced nitrosamine issues. Regulators responded with concrete expectations: do a risk assessment, confirm by testing where indicated, and implement controls. The FDA’s final 2024 guidance highlights nitrite in excipients as a routine source, notes variability across lots and suppliers, and urges supplier qualification alongside formulation controls. EMA’s Q&A likewise calls out nitrites in many common excipients and supports testing excipients/other materials if the RA points there. 

2) The chemistry in one page (no hand waving)

• Mechanism: Under acidic conditions, nitrite produces nitrosating species (e.g., NO⁺/N₂O₃) that nitrosate secondary/tertiary amines to form N-nitrosamines. Heat and moisture can accelerate pathways during processing or storage. 

• Formulation reality: If your API (or degradants) presents a nitrosatable amine and your formulation contains even trace nitrite (from water, excipients, equipment, or packaging), you have a pathway. The FDA explicitly ties NDSRIs in drug products to residual nitrite in excipients. 

  
  

3) Where excipient nitrites come from

Natural origin excipients (cellulose, starches, lactose) can carry nitrates/nitrites from water/biological feedstocks; processes (e.g., drying, air/NOx exposure) and in plant water treatment can contribute. A classic review already flagged ppm level nitrates/nitrites as common reactive impurities in many excipients long before today’s heightened focus. 

4) The data landscape (and why supplier choice matters)

• Lhasa database & industry papers: Across hundreds of entries, nitrite is prevalent and spread is wide both between excipient types and between suppliers of the same excipient, reinforcing the value of supplier qualification and incoming verification. 

• Concrete ranges frequently cited: Lactose mean ≈ 0.54 ppm, MCC ≈ 0.70 ppm, while crospovidone is often several ppm; these comparative summaries are repeated in supplier/industry communications that reference Boetzel/Lhasa. Bottom line: your nitrite budget is the composition weighted sum across all excipients high % fillers dominate, but a low % high nitrite disintegrant can still be decisive. 

• Supplier variability: White paper analyses of Lhasa data show >10× spread in median nitrite between suppliers for the same excipient; FDA also warns that nitrite varies across lots and suppliers, so procurement strategy matters. 

5) Measurement: what “low” and “not detected” actually mean

Yesterday’s screens (~0.1 ppm) missed meaningful differences. Today, ion chromatography (IC) with selective post column (Griess-type) derivatization or IC-MS achieves low ppb LOD/LOQ in tough excipient matrices enabling decisions that actually map to risk. Pharmaceutical Technology (Sept 2024) describes an IC + one step post column method selective to nitrite with ppb level performance across multiple polymeric excipients. Lhasa/IPEC collaborative notes IC based methods as the most common high-sensitivity approach in the consortium. 

Takeaway for QC: “ND” is method bounded. Always pair an ND claim with LOD/LOQ and method; for nitrosamine risk decisions, ppb-level LOD is the bar. 

6) Formulation leverage: switch types/suppliers before you add complexity

A peer reviewed modeling study (Pharmaceutics 2023) shows that changing one excipient supplier can cut modeled nitrosamines by ~59%, while changing the three critical excipients (type/suppliers) can reach ~89% reduction often enough to drop below AI without antioxidants or API changes. This aligns with industry experience: choose low nitrite excipients and qualify low nitrite suppliers, then verify in stability. 

7) Why croscarmellose sodium (CCS) is a smart default superdisintegrant

• Chemistry: CCS is a cross linked carboxymethylcellulose (polysaccharide) with no amine functionality; its relevance is nitrite impurity only, not amine contribution.

• Comparative nitrite profile: Industry analyses referencing Lhasa indicate CCS tends to be low nitrite, while crospovidone often sits higher; a major supplier’s white paper explicitly recommends replacing crospovidone with CCS (reported ~15× lower mean nitrite) for nitrosation sensitive APIs. 

• What this means in practice: If your API can nitrosate, CCS helps reduce the nitrite side of the equation without adding new amines often an easy formulation win.

8) Practical playbook (procurement • QC • regulatory)

Procurement / Tech-ops

• Ask every excipient supplier for lot wise nitrite COAs that state method + LOD/LOQ (aim: ppb level). Maintain an approved supplier list by nitrite distribution. 

• Where performance allows, prefer CCS over crospovidone for nitrosation-sensitive programs. 

Quality Control

• For high risk products, implement incoming nitrite checks using IC + selective derivatization (or orthogonal IC-MS) until supplier/process capability is proven. 

Regulatory

• In your nitrosamine risk assessment, explicitly trace the excipient nitrite budget and document how low nitrite choices (and CCS) cut formation potential; this language tracks directly with FDA/EMA expectations on risk, confirm, control. 

9) Pehel Specialities : our CCS, your easiest win

• Result: Pehel Specialities Croscarmellose Sodium shows Nitrites Not Detected at an LOD of 0.01 ppm (10 ppb) using ion chromatography with selective post column derivatization, validated in the CCS matrix.

• Why it matters: At typical use levels (≈1-5% w/w), ND @ 10 ppb translates to single digit ng of nitrite per tablet immaterial versus most filler contributions and significantly below typical high-nitrite superdisintegrants. Pair this with low-nitrite fillers/suppliers and you’re often under AI without formulation gymnastics.

• What you get: Lot wise COAs (method + LOD/LOQ), regulatory note to file snippets that plug into your CTD, and support for supplier qualification packages.

Pushback we welcome: “ND isn’t zero.” True ND is method bounded. That’s why we disclose LOD/LOQ and methodology and target ppb-level detection aligned with current industry best practice. 

10) FAQs

Q1. Does CCS itself form nitrosamines?

No; no amine functional group. Risk is only from nitrite impurity. (Our CCS is ND @ 0.01 ppm.)

Q2. Do regulators actually care about excipient nitrites?

Yes. FDA names nitrite in excipients as a root cause and calls for control; EMA recommends testing excipients if the risk assessment indicates. 

Q3. What analytics are acceptable?

IC + selective post column derivatization (Griess-type) or IC-MS with ppb- evel performance; pair every ND claim with LOD/LOQ + method. 

Q4. Is switching disintegrant enough?

Often a big step. Modeling shows supplier/type changes across a few critical excipients can reach 59% to 89%reduction. Combine CCS with low-nitrite fillers and verify in stability. 

References & further reading

• FDA (Final Guidance, Sept 2024): Control of Nitrosamine Impurities in Human Drugs -root causes include nitrite in excipients, supplier variability, and lifecycle control. 

• EMA (Rev. 22 Q&A): excipient nitrites are common; testing excipients is recommended where the RA indicates; LoQ guidance for analytical methods. 

• Boetzel et al., J Pharm Sci (2023): A Nitrite Excipient Database - central Lhasa dataset on nitrite in common excipients; broad variability by type/supplier. 

• Berardi et al., Pharmaceutics (2023): Modeling the Impact of Excipients Selection on Nitrosamine Formation -supplier/type switches deliver −59% to −89% modeled reductions. 

• DFE Pharma (White Paper): mitigation strategies; crospovidone → CCS recommendation (CCS reported ≈15× lower mean nitrite). 

• PharmTech (Sept 2024): Determining Low PPB Levels of Nitrite in Polymeric Excipients - practical IC + post-column method achieving ppb-level detection. 

• Wu et al., AAPS PharmSciTech (2011): reactive impurities in excipients; ppm-level nitrates/nitrites common.