SOP on Cleaning Validation (Example Template)

In short: This is an illustrative example SOP on cleaning validation for QA, production, QC and IPQA staff. Adapt it to your own quality system before use. Current regulatory practice sets carry-over limits from health-based exposure limits (PDE/ADE); the older 10 ppm and 1/1000 dose rules are kept below only as legacy, secondary criteria.

This SOP is a template. Titles, limits, frequencies and annexures must be adapted and approved under your site’s quality system.

See also: Principles of cleaning validation and Cleaning validation protocol format.

1. Objective

To describe a general approach for validating equipment cleaning, so that contamination and cross-contamination of starting materials and products are prevented, as expected under GMP.

2. Scope

This SOP covers the general aspects of cleaning validation. It applies to critical cleaning, such as cleaning between one product and the next, and to product-contact surfaces of equipment used for drug products and APIs at the manufacturing site.

3. Responsibility

4. Definitions

Cleaning validation: documented evidence that the cleaning procedure consistently reduces residues of the previous product, excipients and cleaning agent to a level within predefined, scientifically justified acceptance criteria.

5. Procedure

5.1 Cleaning validation protocol and report

Cleaning validation is described in a formally approved protocol. While preparing it, consider:

• disassembly of the system and pre-cleaning
• cleaning agent, concentration, solution volume and water quality
• time and temperature
• flow rate, pressure and rinsing
• complexity, design and size of the equipment
• operator training

The protocol should include:

• objective, scope and purpose of the study
• people responsible for performing and approving it
• the most sensitive (worst-case) product, with a matrix based on risk assessment
• acceptance criteria
• list of equipment with the product-contact surface area of each (in cm²)
• hard-to-clean locations (tables or drawings), especially for clean-in-place systems
• sampling methods, sampling medium and solvent suitable for the residue

5.2 Sampling

Use direct surface sampling (swab) and, where suitable, indirect sampling (rinse). Rinse sampling covers a large area, including parts that cannot be dismantled, and is useful for cleaning-agent residues. It should be combined with surface sampling, not used alone. Swab and coupon recovery studies must be performed so that samples are shown to be accurately recovered.

Example in-house criteria (not a pharmacopoeial or regulatory requirement): recovery of more than 80% is considered good, more than 50% reasonable, and below 50% questionable. Each site should set and justify its own recovery criteria from its validated sampling study.

5.3 Analytical methods

Validate the analytical methods before the cleaning validation runs. They must be specific for the residue and sensitive enough to detect it at the acceptance limit. Validation should include, as appropriate, precision, linearity, selectivity, LOD, LOQ, recovery by spiking and reproducibility. Specific methods (for example HPLC, UV) are preferred; non-specific methods such as TOC, pH or conductivity may be used with justification.

5.4 Establishing acceptance limits

Limits must be practical, achievable, verifiable and scientifically justified. Residues of the previous product, degradants, and the cleaning agent should be considered. Limits may be expressed as mg/swab, µg/cm² of surface, or concentration in rinse water.

Current approach: health-based exposure limits. The carry-over limit (MACO) is derived from the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) of the previous product, set by a toxicologist. In outline, the maximum allowable carry-over is the PDE of the previous product, scaled by the batch size of the next product and divided by the maximum daily dose of the next product, with the result converted into a surface limit using the shared equipment area. A safety factor and sampling and recovery allowances may be applied as per site procedure. This follows the EMA guideline on setting health-based exposure limits for risk identification in shared facilities (2014) and its Q&A, EU GMP Annex 15 (2015) and PIC/S guidance.

Also keep in mind: the limit for visibly clean surfaces (no visible residue) remains a mandatory additional check. For highly potent or low-dose products it is not enough alone.

Legacy, secondary criteria. Older practice used two other criteria, and some sites still calculate them for comparison or for products without toxicological data:

• Not more than 10 ppm of the previous product in the next product.
• Not more than 1/1000 (0.1%) of the normal therapeutic daily dose of the previous product in the maximum daily dose of the next product. This dose-based criterion was traditionally used for conventional oral solid dosage forms of products without high potency or special toxicity concerns. It is not suitable for highly potent, cytotoxic, hormonal, sensitising or otherwise highly hazardous products. Under EMA and PIC/S expectations, the health-based exposure limit (PDE/ADE) is the primary approach; this dose-based criterion is a legacy or secondary check only.

Older texts say the most stringent of the criteria should be used. Under the health-based approach, the PDE-derived limit is the starting point; a stricter legacy value may still be adopted by the site if it is lower. Do not use dose-based or ppm limits for highly hazardous materials (for example cytotoxic, hormonal, sensitising or highly potent) where a toxicological limit is expected.

5.5 Revalidation

Revalidate in these situations:

1. Equipment change
2. Change in cleaning equipment
3. Change in cleaning agent
4. Change in cleaning procedure
5. Introduction of a new product
6. Periodically, as defined by the site (an older version of this SOP said once in three years). Any fixed interval, such as three years, is an in-house interval set by the site from its own study and trend data; it is not a regulatory or pharmacopoeial requirement. It is applied alongside ongoing lifecycle verification of the cleaning process.

5.6 Worst-case selection

Document the rationale for each worst case. A matrix approach based on risk assessment is typical.

• Solubility: the least soluble product (in water or the cleaning solvent) is harder to clean and can represent the easier ones.
• Toxicity: the product with the lowest PDE (older texts used lowest LD50) is taken as the worst case. PDE is preferred as LD50 is not a health-based exposure limit.
• Strength: for multiple strengths, validate the highest strength. For combination products, consider the ingredient that is least soluble, highest in concentration or most toxic.
• Batch size and surface area: the next product with the smallest batch size and the largest shared equipment surface gives the strictest limit, because batch size is in the numerator and shared surface area in the denominator of the MACO calculation.
• Maximum daily dose: the next product with the highest daily dose gives the strictest limit.
• Equipment: if the same equipment exists in several sizes with the same cleaning procedure, validating the largest size is adequate. Identical units with the same design, material and cleaning procedure can be represented by one.

Review worst-case choices periodically against new products and new equipment. If the worst case changes, issue a new validation report.

6. Abbreviations

7. Annexures

• Annexure I: Flow chart of cleaning validation procedure
• Annexure II: Surface area sheet
• Annexure III: Sampling points
• Annexure IV: Cleaning validation protocol
• Annexure V: Cleaning validation report

Frequently asked questions

Is the 10 ppm criterion still acceptable?

It is a historical rule. Regulators now expect carry-over limits to be justified by health-based exposure limits (PDE/ADE). Treat 10 ppm as a secondary check at most.

What is the difference between PDE and ADE?

Both are daily exposure levels considered safe for lifelong exposure. PDE is the term used in the EMA guideline; ADE is used in some other documents. Both are derived by a qualified toxicologist.

Is visual cleanliness enough?

No. It is a required check, but residues must also be shown below the calculated limit with a validated analytical method.

When is revalidation needed?

After changes to equipment, cleaning agent or procedure, on introduction of a new worst-case product, and as per the site’s periodic review plan.

References

1. European Commission, EudraLex Volume 4, EU GMP Annex 15: Qualification and Validation (effective 1 October 2015), section 10: Cleaning Validation.
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 (adopted November 2014; effective June 2015).
3. European Medicines Agency, Questions and answers on implementation of risk-based prevention of cross-contamination in production and the Guideline on setting health-based exposure limits, EMA/CHMP/CVMP/SWP/246844/2018 (2018).
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. WHO Technical Report Series No. 1033 (2021), Annex 2: Points to consider on the different approaches – including HBEL – to establish carryover limits in cleaning validation for identification of contamination risks when manufacturing in shared facilities.