1What cleaning validation is.
EU GMP Annex 15 defines cleaning validation as “documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in the equipment below the scientifically set maximum allowable carryover level”. Cleaning verification is different: “the gathering of evidence through chemical analysis after each batch/campaign” that residues are below that level.¹
FDA’s inspection guide of July 1993 explains why regulators care. Its concern was historically penicillin and potent steroid or hormone cross-
2What the US regulation requires.
21 CFR 211.67(a) requires equipment and utensils to be cleaned, maintained and, as appropriate, sanitised or sterilised “at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements”. Paragraph (b) requires written cleaning procedures, covering responsibility, schedules, methods in sufficient detail, removal of previous batch identification, protection of clean equipment and inspection for cleanliness immediately before use, and paragraph (c) requires records.³ The regulation does not use the word validation, but FDA is clear: “Firms must validate that cleaning procedures are adequate to ensure that cross-contamination does not occur.”⁴
The 1993 guide sets out what investigators expect: written cleaning procedures; a written general procedure on how cleaning is validated, saying who performs and approves the work, the acceptance criteria and when revalidation is needed; protocols written in advance, covering sampling and analytical methods and their sensitivity; and a final report approved by management stating whether the process is valid.²
FDA does not set acceptance limits. The firm’s rationale should be “logical”, and limits “practical, achievable, and verifiable”. The guide records limits mentioned by industry, such as 10 ppm, 1/1000 of the normal therapeutic dose and no visible residue. Between batches of the same product, equipment need only be “visibly clean”, and those between-batch processes “do not require validation”. Testing and retesting until a result passes “should not be utilized and is acceptable only in rare cases”. The guide covers chemical residues only.²
3What FDA’s questions and answers add.
FDA’s questions and answers on equipment, current as of November 2022, fill in detail.⁴
- Equipment should be “as clean as can be reasonably achieved to a residue limit that is documented to be safe, causes no product quality concerns, and leaves no visible residues”. Limits need not chase the most sensitive detection method.
- Rinse samples alone are not acceptable; surface residue should also be measured directly where feasible.
- Total organic carbon can be used if the contaminant is substantially organic and oxidisable, and recovery studies are necessary.
- Validation should reflect routine use: no pre-cleaning, batches not significantly smaller than full scale, and sampling of equipment stored uncleaned for longer than validated.
- Dedicated equipment for potent compounds is not specifically required, but cleaning must be validated to prevent cross-
contamination. - After validation, equipment need not be tested after every cleaning, though manual cleaning may be an exception, and a risk-based residue-monitoring programme is recommended.
4What EU GMP Annex 15 requires.
Annex 15, in operation since 1 October 2015, gives cleaning validation its own section.¹
| Topic | Requirement | Clause |
|---|---|---|
| Scope | All product contact equipment; grouping of similar equipment must be justified | 10.1 |
| Visual check | Important, but “not generally acceptable” as the only criterion; repeated cleaning and retesting is not acceptable | 10.2 |
| Worst case | Variable factors such as operators and rinse times assessed, with worst cases as the basis; a worst-case product needs a scientific rationale | 10.5, 10.10 |
| Limits | Based on a toxicological evaluation, justified in a risk assessment; limits for cleaning agents; cumulative effect across the equipment train | 10.6 |
| Sampling | Swabbing, rinsing or other means; recovery shown from all product contact materials with all methods | 10.12 |
| Holds and campaigns | Dirty and clean hold times; maximum campaign length | 10.8, 10.9 |
| Repetitions | An appropriate number of runs, based on risk assessment | 10.13 |
Annex 15 also allows total organic carbon or conductivity where specific residues cannot be tested, accepts that a toxicological evaluation may not apply to therapeutic macromolecules and peptides that degrade, and may require verification after each batch for investigational products.¹ The toxicological basis comes from EMA’s guideline on health-based exposure limits, first published on 24 November 2014, which recommends “a scientifically based safe threshold value for individual active substances”.⁵ MACO and HBEL cleaning limits shows how those limits are calculated.
5FDA and EU GMP compared.
The two largely agree, with differences of emphasis.²⁴¹
| Question | FDA | EU GMP |
|---|---|---|
| Basis of limits | Scientifically justifiable, documented to be safe | Toxicological evaluation, justified in a risk assessment |
| Visual inspection | Enough between batches of the same product | Important, but not the only criterion |
| Rinse samples | Not enough alone | Allowed, with recovery shown |
| Retesting until clean | Only in rare cases | Not acceptable |
For active substances, ICH Q7 section 12.7 adds that residue limits should be “practical, achievable, verifiable and based on the most deleterious residue”, that recovery should be established, and that procedures should be monitored after validation.⁶
6How it runs in Seal.
In Seal, the cleaning validation blueprint connects the product and equipment matrix to versioned limit calculations, worst-case rationale, cleaning instructions, dirty and clean hold clocks, swab and rinse samples and laboratory results. Each limit keeps its toxicological or pharmacological input, dose basis, batch sizes, surface area and safety factors. The production step checks the selected equipment’s clean state before use, an exceeded hold blocks normal use, and a change to a toxicological input, procedure or surface area shows the calculations, studies and campaigns in scope.
Neil can review cleaning validation evidence, mapping results to equipment locations, recovery assumptions and protocol limits; it does not derive a safety limit or release equipment from an incomplete package. In electronic logbooks, cleaning, inspection and planned use stay separate facts, so ‘cleaned’ is not read as ‘ready’.
References
- 1EudraLex Volume 4, Annex 15: Qualification and Validation, European Commission, 30 March 2015, in operation since 1 October 2015. https:/
/ health. ec. europa. eu/ system/ files/ 2016- 11/ 2015- 10_ annex15_ 0. pdf (read 6 November 2026) - 2Guide to Inspections: Validation of Cleaning Processes, FDA, July 1993. https:/
/ www. fda. gov/ inspections- compliance- enforcement- and- criminal- investigations/ inspection- guides/ validation- cleaning- processes- 793 (read 6 November 2026) - 321 CFR 211.67, Equipment cleaning and maintenance, eCFR. https:/
/ www. ecfr. gov/ current/ title- 21/ section- 211. 67 (read 6 November 2026) - 4Questions and Answers on Current Good Manufacturing Practice Requirements: Equipment, FDA, content current as of 16 November 2022. https:/
/ www. fda. gov/ drugs/ guidances- drugs/ questions- and- answers- current- good- manufacturing- practice- requirements- equipment (read 6 November 2026) - 5Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, EMA/
CHMP/ CVMP/ SWP/ 169430/ 2012, European Medicines Agency, 24 November 2014. https:/ / www. ema. europa. eu/ en/ setting- health- based- exposure- limits- use- risk- identification- manufacture- different- medicinal- products- shared- facilities- scientific- guideline (read 6 November 2026) - 6ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Step 4, ICH, 10 November 2000. https:/
/ database. ich. org/ sites/ default/ files/ Q7%20Guideline. pdf (read 6 November 2026)
AQuestions and answers
What is the difference between cleaning validation and cleaning verification?
Validation shows in advance that an approved procedure reliably cleans to the set limit, so routine cleans need not each be tested. Verification tests after a specific batch or campaign that residues are below the limit. Verification after each batch may be needed while a validation programme is completed, or for investigational products.
How many cleaning runs are needed to validate a cleaning process?
Neither FDA nor EU GMP fixes a number. Annex 15 says the procedure should be performed an appropriate number of times, based on a risk assessment, and meet the acceptance criteria. FDA expects a final report that states whether the cleaning process is valid, with data supporting the conclusion that residues have been reduced to an acceptable level.
Is a visual inspection enough to show equipment is clean?
Not for validation between different products. Annex 15 calls the visual check important but generally not acceptable as the only criterion. FDA accepts visibly clean equipment between batches of the same product, and 21 CFR 211.67 requires inspection for cleanliness immediately before use.
Can total organic carbon be used for cleaning validation?
Yes, if most of the contaminating material is organic and oxidisable under the test conditions. Any carbon found is attributed to the target compound, background carbon should be kept low, and recovery studies are still required. Annex 15 accepts TOC or conductivity where specific residues cannot be tested.
Does dedicated equipment need cleaning validation?
In the US, not when it is cleaned only between batches of the same product: FDA’s 1993 guide says the equipment then need only be visibly clean, and that cleaning does not require validation. It must still be cleaned under 21 CFR 211.67, which FDA says covers dedicated and multipurpose equipment, with cleaning agent residues removed. EU GMP Annex 15 asks for cleaning validation for all product contact equipment and makes no exception for dedicated equipment.