Visual Clean Is Important — but When Is It Enough?

A surface that looks clean is genuine information. The question a cleaning validation programme has to answer is different: is the residue below a limit derived from toxicological and dose-based reasoning? Enforcement letters from 2024 to 2026 never attacked visual inspection as a technique. They attacked programmes in which visual inspection carried the entire release decision.

Visual in the validated lifecycle

Cleaning validation is a release activity, not housekeeping. The citation heading FDA used against Wuhu Nuowei Chemistry in 2025 says it plainly — "cleaning equipment and its release for use in manufacture of API" — and the regulatory expectations converge on the same point from three directions.

EU GMP Annex 15 holds that a visual check for cleanliness is an important part of acceptance criteria but is not generally acceptable as the sole criterion. FDA's 1998 cleaning validation inspection guide states that relying only on visual examination would not be scientifically sound. PIC/S PI 006-4, in force since 1 October 2026, puts the acceptance criterion for visual inspection as simply "visually clean" (7.8.2) — and then, one paragraph later, states that visual inspection will likely not be appropriate for lower-HBEL products or where visual thresholds are nearer to the required safety limit (7.8.3).

The same document anchors the extent of any cleaning programme to a toxicological risk assessment based on HBEL values (7.3.1), requires evidence for dirty hold time, clean hold time and maximum campaign length (7.3.9, 7.3.11), and prohibits testing until clean (7.3.12). Visual inspection therefore has a defined place in the lifecycle — as one element inside a limits-based system, not as the system itself.

What the enforcement record shows (2024–2026)

Five letters read together describe a consistent pattern, and in none of them is the technique itself the problem.

Wuhu Nuowei Chemistry Co., Ltd. — Warning Letter 320-25-38, dated 4 February 2025, inspection 2–6 September 2024. FDA found that the cleaning protocol for a manufacturing tank "does not include acceptance criteria for carryover residues. Instead, you relied on visual inspection to determine cleanliness of your equipment and could not provide any analytical or microbiological data to support the efficacy of your cleaning procedures." The firm's corrective response supplied an updated protocol with microbiological data; FDA judged it inadequate because analytical testing of potential carryover residues was still not considered, and noted that no cleaning procedures were provided at all for other equipment in the train.

Aspen Biopharma Labs Private Limited — Warning Letter 320-25-50, dated 5 March 2025, inspection 16–21 September 2024. Investigators found manufacturing equipment labelled "Cleaned" containing liquid with a floating substance or residue on product-contact surfaces. The site lacked cleaning validation studies demonstrating adequacy, despite having already identified the need for them in an internal deviation report. The failure here is the sharpest form of the problem: if visible residue can coexist with a "Cleaned" status tag, the site can no longer distinguish clean from dirty equipment at the point of use.

Chemco Corporation — Warning Letter 320-26-60, dated 7 April 2026, inspection 11–22 August 2025. FDA observed white residue inside Tank #68 — equipment the quality unit had verified as clean according to the tank cleaning logbook. The firm stated during the inspection that it had not conducted cleaning validation studies for non-dedicated equipment. Its proposed analytical verification method was judged inadequate, and FDA requested a comprehensive independent retrospective cleaning-effectiveness assessment.

Dabur India Limited — Warning Letter 320-26-105, dated 24 July 2026, inspection 12–16 January 2026. FDA stated that the cleaning validation programme for a non-dedicated unit and line "relied exclusively on the visual inspection of (b)(4) to determine adequate cleaning. Your cleaning validation program lacked scientifically determined maximum allowable carryover limits, quantitative residue testing, or direct surface sampling of difficult-to-clean areas." No cleaning validation had been performed for that line although at least (b)(4) different OTC drug products were manufactured on it. The firm committed to validated analytical methods, carryover limits, direct surface swab sampling and revalidation; FDA found the response inadequate for want of interim cross-contamination controls during remediation, statistically insufficient sampling, and no retrospective review of U.S.-market products within expiry.

Granules India Limited — Warning Letter 320-25-48, dated 26 February 2025, inspection 26 August to 6 September 2024. Swabs taken after HEPA filters detected residues of multiple previously manufactured drug products and too-numerous-to-count microbial contamination, with no documented cleaning procedures for the duct sections concerned. FDA's language here is the most quotable statement of the principle: "Cross-contamination is not uniform, and testing of limited reserve samples alone cannot ensure products are contaminant-free. While MACO is helpful in validated cleaning scenarios, it cannot apply where cleaning has not been performed, or exposure is inconsistent." FDA also found the batch-size denominators in the firm's MACO calculations inconsistent with the size of the relevant vessels, and the limits not adequately justified.

The common thread is not visual inspection. It is the absence of a number to inspect against — and, in three of the five cases, a corrective response that argued risk from limited sampling rather than rebuilding the cleaning control itself.

The quantitative anchor (HBEL/MACO)

The numerical anchor arrives by a defined route. EMA's guideline on health-based exposure limits (EMA/CHMP/CVMP/SWP/169430/2012) was adopted on 20 November 2014 with effect from 1 June 2015, followed by the EMA Q&A of 19 April 2018, which in turn underpins PIC/S PI 053-1 and PI 052-1, in force since 1 June 2020. ASTM E3219-25, the Standard Guide for Derivation of Health-Based Exposure Limits (DOI 10.1520/E3219-25, Committee E55 / Subcommittee E55.14, 33 pages), sets out a five-step derivation sequence: hazard characterization; critical effect(s) with dose–response; point(s) of departure; PoD-specific adjustment factors; and calculation and justification of the HBEL.

That value, converted through dose, batch size and shared surface area, produces the maximum allowable carryover limit against which a cleaning process can be validated and a swab or rinse result interpreted. The Granules letter shows what happens when MACO is used without that foundation: a number can be written down without being justified, with denominators that do not match the vessels it is meant to protect. Visual inspection cannot repair that gap, because it is a different kind of measurement. A visual result is qualitative; a carryover limit is a number. Where the programme contains no number — no MACO, no residue method, no defined sampling points — there is nothing against which an observation can be checked, no process capability to establish, and no way to distinguish a comfortable pass from a marginal one.

Qualifying visual inspection

Visual inspection becomes defensible when it is qualified as a method in its own right. ASTM E3263-22e1, the Standard Practice for Qualification of Visual Inspection of Pharmaceutical Manufacturing Equipment and Medical Devices for Residues, defines the conditions: a statistically valid visual detection limit, inspector qualification, an acceptable hazard analysis, a validated and repeatable cleaning process, and — in section 4.5 — "a suitable safety margin between the VRL and MSSR."

Those requirements answer four operational questions every programme should be able to evidence:

• What can an inspector actually see? The visual residue limit must be determined experimentally, not assumed, and expressed as a number.
• Who is looking, and how? Inspector qualification, defined lighting, defined viewing angles and access to the surface — the conditions under which the result holds. Aspen Biopharma Labs shows the consequence of skipping this: a status tag with no verification step behind it.
• How much margin is there? The gap between the visual residue limit and the maximum safe surface residue determines whether visual inspection can carry a release decision. PIC/S PI 006-4 7.8.3 states that visual inspection will likely not be appropriate for lower-HBEL products or where visual thresholds approach the safety limit.
• What happens when the margin disappears? PI 006-4 7.13.2 requires that products whose maximum allowable carry-over limits fall below the limit of visual detection, incorporating a safety factor, be subject to cleaning verification after every change-over. Visual inspection remains useful; it simply no longer stands alone.

Complementary analytical evidence matters in the same way that sampling location does. PI 006-4 7.9.2 states that swab sampling is generally more effective than rinse sampling and should be used if feasible. EU GMP Annex 15 sections 10.6.1 and 10.6.2 accept non-specific methods such as TOC and conductivity where specific residue testing is not feasible — notably for biologics, which degrade and denature under pH extremes and heat. Non-specificity is permissible; unattributed non-specificity is not, since a sum of carbon says nothing about which substance is present until it is anchored to a worst-case compound.

A practical decision path

For each shared equipment item and product family, the sequence that survives inspection looks like this:

• Establish the limit first. Derive or adopt the HBEL, convert it to a MACO using justified dose, batch-size and surface-area inputs, and record the basis. FDA's objection in the Granules and Dabur letters was to unjustified numbers as much as to absent ones.
• Then decide what measurement answers the question. Specific residue testing where feasible; a validated non-specific method where it is not; swab sampling of the hardest-to-clean and hardest-to-inspect locations, chosen and justified rather than convenient.
• Then decide whether visual inspection adds value or carries the decision. If the visual residue limit sits comfortably below the carry-over limit with a documented margin, visual inspection can support release, provided inspectors are qualified and viewing conditions are defined. If the margin is thin or inverted, visual inspection is a supplementary check and analytical verification after every change-over applies.
• Link changes back to the rationale. A new product, a higher potency, a lower-solubility soil, a new equipment item or a longer hold time all ask the same question: does the cleaning validation rationale still hold? Neither Wuhu Nuowei nor Aspen Biopharma Labs could show that it did.
• Close the loop on the interim state. When a gap is found, the period between discovery and remediation needs written controls, and the assessment must reach product already in distribution — not only future manufacture. Both Dabur India and Wuhu Nuowei were faulted for exactly this omission.

Fazit

Visual inspection is not the weak point of cleaning validation; unanchored visual inspection is. The 2024–2026 enforcement record shows a stable pattern: firms that used visual inspection as one qualified element inside a limits-based system were not the ones cited — the ones cited had a visual observation standing in for an acceptance criterion, and in three cases a "Cleaned" label with nothing quantified behind it. The practical test is short. Name the limit, name the method that measures against it, name the qualified person who looks and the conditions under which the result means something, and name the margin between what the eye can detect and what toxicology will tolerate. Where all four can be named, visual inspection is enough — as part of a programme. Where any one cannot, it is a convention rather than a control.

Sources

• US FDA Warning Letter 320-26-105, Dabur India Limited, MARCS-CMS 728828 (24 July 2026) — https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/dabur-india-limited-728828-07242026
• US FDA Warning Letter 320-25-38, Wuhu Nuowei Chemistry Co., Ltd., MARCS-CMS 697727 (4 February 2025) — https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/wuhu-nuowei-chemistry-co-ltd-697727-02042025
• US FDA Warning Letter 320-25-50, Aspen Biopharma Labs Private Limited, MARCS-CMS 698665 (5 March 2025) — https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/aspen-biopharma-labs-private-limited-698665-03052025
• US FDA Warning Letter 320-26-60, Chemco Corporation, MARCS-CMS 721592 (7 April 2026) — https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/chemco-corporation-721592-04072026
• US FDA Warning Letter 320-25-48, Granules India Limited, MARCS-CMS 697115 (26 February 2025)
• ASTM E3263-22e1, Standard Practice for Qualification of Visual Inspection of Pharmaceutical Manufacturing Equipment and Medical Devices for Residues — https://store.astm.org/e3263-22e01.html
• ASTM E3219-25, Standard Guide for Derivation of Health-Based Exposure Limits (HBELs), DOI 10.1520/E3219-25 — https://store.astm.org/e3219-25.html
• PIC/S PI 006-4, Recommendations on Qualification and Validation (in force 1 October 2026) — https://picscheme.org/docview/11277
• EU GMP Annex 15, Qualification and Validation — sections 10.6.1 and 10.6.2 as cited in the STERIS in-line UV work
• US FDA, Guide to Inspections of Validation of Cleaning Processes (1998) — https://www.fda.gov/media/71023/download
• EMA guideline on setting health-based exposure limits, EMA/CHMP/CVMP/SWP/169430/2012 (adopted 20 November 2014, effective 1 June 2015); EMA Q&A EMA/CHMP/CVMP/SWP/246844/2018