Principles of Cleaning Validation in Pharma (Annex 15)

In short: Cleaning validation proves that a cleaning procedure reliably removes product, cleaning-agent and microbial residues from product-contact equipment to a level that is safe for the next product. This explainer is for QA, production and QC staff and summarises the principles in EU GMP Annex 15, section 10 (2015). Carry-over limits should come from health-based exposure limits (HBEL), and a visually clean surface alone is never enough.

See also: SOP on cleaning validation and Cleaning validation protocol format.

What cleaning validation is for

Equipment shared between products can carry residues from one batch into the next. Cleaning validation gives documented evidence that the approved cleaning procedure removes these residues consistently, so that cross-contamination does not reach a level that could harm a patient or affect product quality. It applies to all product-contact equipment, and to cleaning agents and microbial or endotoxin contamination as well as the previous product.

The main principles

1. Treat cleaning as a lifecycle, not a one-time exercise

Validation is the middle step. A cleaning process is designed and developed first, then validated with a protocol, and afterwards kept under control through routine monitoring, change control and periodic review. Annex 15 asks for a justified number of cleaning runs based on risk assessment (clause 10.13). It also accepts, where a programme takes time to complete, verification after each batch until enough data exist to conclude the equipment is clean (clause 10.3).

2. Identify what can vary, then challenge the worst case

Look at the factors that affect cleaning performance, such as the operator, rinse times and the level of detail in the procedure. Where such variables exist, validate under worst-case conditions (clause 10.5). Where products are grouped, give a scientific rationale for the worst-case product. Annex 15 names solubility, cleanability, toxicity and potency as possible criteria (clause 10.10). Also assess the impact each time a new product is introduced. Where similar equipment is grouped, justify the unit chosen for the study (clause 10.1).

3. Set limits from health-based exposure limits

Carry-over limits should rest on a toxicological evaluation, documented in a risk assessment with its references (clause 10.6). Practically, this means deriving a Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) for the previous product under the EMA guideline on health-based exposure limits, then converting it into a maximum carry-over and a surface or rinse limit. Also set limits for cleaning agents, and consider the cumulative effect across the whole equipment train.

Older rules of thumb, such as 10 ppm in the next product or 1/1000 of the normal therapeutic dose, are historical criteria. The FDA’s 1993 inspection guide mentions them as examples of limits that firms have used, not as set requirements. They may still be calculated as secondary checks, but they do not replace a health-based limit. Under an HBEL-based (PDE/ADE) policy, 10 ppm and 1/1000 of the dose are secondary (legacy or alert) criteria only: the HBEL-derived limit is the primary acceptance limit, and any existing historical limit is kept only if it is equal to or stricter than the HBEL-derived limit.

Some products need a different approach. Therapeutic macromolecules and peptides can degrade or denature under extreme pH or heat and lose activity, so a toxicological evaluation may not apply (clause 10.6.1). If a specific residue cannot be tested, a representative parameter such as total organic carbon (TOC) or conductivity may be chosen (clause 10.6.2).

4. A visual check is necessary but not sufficient

Visual cleanliness is an important part of acceptance criteria but is not generally acceptable as the only criterion. Repeatedly cleaning and retesting until the residue results pass is not acceptable (clause 10.2).

5. Define dirty and clean hold times

The time between manufacture and cleaning (dirty hold time) and between cleaning and next use (clean hold time) both affect how well residues come off and whether microorganisms grow. Annex 15 expects both to be taken into account in defining hold times (clause 10.8). For campaign manufacture, consider how hard the equipment is to clean at the end of a campaign and base the study on the maximum campaign length, in time or number of batches (clause 10.9).

6. Sample properly and prove recovery

Sampling is by swab, rinse or other suitable means. The sampling material and method must not influence the result, and recovery must be shown from every product-contact material sampled, with each method used (clause 10.12). Protocols must state the sampling locations, why they were chosen, and the acceptance criteria (clause 10.11). Analytical methods need to be validated, with a suitable detection and quantification limit where necessary (section 9.1).

7. Consider automation, manual cleaning and microbial risk

For automated cleaning, validate the stated normal operating range of utilities and equipment (clause 10.4). Manual cleaning varies more, so its effectiveness should be confirmed at a justified frequency (clause 10.15). Microbial and endotoxin risk should also be considered when writing protocols (clause 10.7).

8. Use dedicated equipment when cleaning cannot work

If cleaning is ineffective or unsuitable for certain equipment, use dedicated equipment or other appropriate measures for each product (clause 10.14).

Where cleaning validation fits at a glance

Indian context

In India, the revised Schedule M to the Drugs Rules, 1945 was notified as G.S.R. 922(E) on 28 December 2023, and CDSCO documents refer to it as the current GMP schedule for manufacturers. Indian sites should read the cleaning-validation and cross-contamination expectations in the revised schedule alongside the guidelines above. Verify the wording against the current version of the revised Schedule M as notified in G.S.R. 922(E), 28 December 2023, and any later amendments, since this article does not quote its clauses.

Frequently asked questions

Is cleaning validation needed between batches of the same product?

Annex 15 does not tie validation to batches. The FDA inspection guide says that cleaning between batches of the same product may only need to reach a visibly clean standard. Your site should justify the approach, including for campaign manufacture.

How many runs are needed?

Annex 15 says an appropriate number, based on risk assessment, must meet the acceptance criteria. Three consecutive successful runs is a common practice but is not stated in Annex 15.

Can I use TOC instead of a specific method?

Annex 15 accepts representative parameters such as TOC where testing for a specific residue is not feasible. Justify the choice and validate the method.

Is a swab or a rinse better?

They answer different questions. The FDA guide prefers direct surface sampling, while rinse samples cover larger or non-dismantlable areas. Many sites use both.

References

1. European Commission, EudraLex Volume 4, Annex 15: Qualification and Validation (Ares(2015)1380025, 30 March 2015; deadline for coming into operation 1 October 2015), sections 9 and 10.
2. European Medicines Agency, Guideline 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 (2014).
3. US FDA, Guide to Inspections: Validation of Cleaning Processes (7/93).
4. PIC/S, PI 046-1, Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (1 July 2018).
5. CDSCO, Drugs Rules, 1945, revised Schedule M, G.S.R. 922(E), 28 December 2023. Refer to the current official text for the exact clauses on cleaning validation and cross-contamination.