Cleaning Validation Acceptance Criteria: MACO, PDE, TDD, LD₅₀, Swab and Rinse Limits

October 3, 2026 by Pharmaguidances

Cleaning Validation Acceptance Criteria: MACO, PDE, TDD, LD₅₀, Swab and Rinse Limits

Cleaning validation is a critical element of pharmaceutical GMP because inadequate cleaning can result in product carryover, cross-contamination, contamination by cleaning agents, and potential risks to product quality and patient safety.

One of the most important parts of a cleaning validation program is establishing scientifically justified acceptance criteria. These criteria define the maximum amount of residue that may remain on equipment after cleaning without creating an unacceptable risk to the next product manufactured.

A key concept is Maximum Allowable Carryover (MACO). MACO represents the acceptable amount of residue from a previous product that may be carried over into the next product.

The supplied technical text describes several approaches for establishing acceptance criteria:

Health-based data using ADE/PDE
Therapeutic Daily Dose (TDD)
LD₅₀-based calculations
General concentration or ppm limits
Swab acceptance limits
Rinse acceptance limits

The source states that MACO should be based on ADE or PDE when such health-based data are available.

For readers working in the United States, Europe, and other regulated pharmaceutical markets, it is important to understand that acceptance limits should be scientifically justified and supported by appropriate toxicological, pharmacological, process, and analytical information.

1. What Is Cleaning Validation Acceptance Criteria?

Cleaning validation acceptance criteria are predefined limits used to determine whether a cleaning process has successfully removed residues from pharmaceutical manufacturing equipment.

Depending on the product and process, the criteria may address:

Previous product/API residue
Cleaning-agent residue
Potential microbial contamination
Other process contaminants
Visual cleanliness
Swab-test results
Rinse-test results
Health-based exposure limits
Maximum Allowable Carryover (MACO)

FDA’s GMP framework requires equipment to be cleaned and maintained at appropriate intervals to prevent contamination that could affect the safety, identity, strength, quality or purity of drug products. FDA also expects firms to validate cleaning procedures and establish scientifically supported acceptance limits.

2. What Is MACO?

MACO = Maximum Allowable Carryover = MACO is the maximum acceptable quantity of residue from a previous product that may be transferred to the next product without creating an unacceptable risk.

In practical terms: Previous Product → Cleaning Process → Residual Material → Next Product

The objective of cleaning validation is to demonstrate that the cleaning process consistently reduces the residue to a level below the established acceptance criterion.

The supplied source defines MACO as the acceptable transferred amount from the previous product into the next product.

3. Health-Based Acceptance Criteria Using ADE/PDE

3.1 Why PDE/ADE Is Important

The health-based approach uses toxicological and pharmacological information to establish a scientifically justified exposure limit.

The source recommends using Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE) when this information is available.

The basic principle is: “Determine how much of the previous product could safely be carried over into the next product based on its health-based exposure limit.”

The EMA’s health-based exposure-limit guideline addresses the use of scientifically derived exposure thresholds for assessing cross-contamination risks when different medicinal products are manufactured in shared facilities.

4. PDE Calculation Concept

The supplied text presents PDE as being derived from toxicological data such as:

NOAEL
LOAEL
NOEL
Body weight
Adjustment factors
Uncertainty factors
Modifying factors
Pharmacokinetic considerations

The source presents the general relationship as:

PDE = LOAEL/NOAEL/NOEL × BW / F1 × F2 × F3 × F4 × F5

The exact toxicological derivation must be scientifically justified for the substance and should be performed by appropriately qualified toxicological expertise.

Abbrivations

NOAEL: No Observed Adverse Effect Level.

LOAEL: Lowest Observed Adverse Effect Level.

NOEL: No Observed Effect Level.

BW: Body weight used in the toxicological assessment.

F1–F5: Adjustment factors accounting for relevant uncertainties.

UFc: Composite uncertainty factor addressing considerations such as inter-individual variability, interspecies differences, and duration extrapolation.

MF: Modifying factor for additional uncertainty not otherwise addressed.

PK: Pharmacokinetic considerations.

The supplied text identifies these factors as components used in the health-based exposure assessment.

5. PDE-Based MACO Calculation

Once PDE is established, the supplied source gives the following MACO relationship:

MACO = PDE(previous) × MBS(next) / TDD(next)

Where:

MACO = Maximum Allowable Carryover
PDE(previous) = PDE of the previous product
MBS(next) = Minimum batch size of the next product
TDD(next) = Therapeutic Daily Dose of the next product

The source explains that the calculation determines how much residue from the previous product can be transferred into the next product while remaining within the health-based exposure limit.

6. Worst-Case Product Selection

Cleaning validation programs often involve many products and equipment combinations. Calculating every possible product-to-product changeover may not be practical. A worst-case approach can be used.

The product with the lowest ADE/PDE
The next product with the lowest MBS/TDD ratio

This combination represents a potentially challenging carryover scenario.

Worst-case selection criteria

Multiproduct facility several APIs are manufactured on the same equipment. A worst-case assessment may consider:

Previous product: High potency / low PDE

Next product: Small batch size / low therapeutic daily dose

The cleaning validation strategy can then focus on a scientifically justified worst-case scenario rather than treating every product combination identically.

FDA’s cleaning-validation guidance similarly emphasizes consideration of factors such as potency, toxicity, solubility, and difficulty of cleaning when selecting representative or worst-case materials.

7. Therapeutic Daily Dose-Based MACO

When toxicity data are limited, but the Therapeutic Daily Dose (TDD) is known, a TDD-based approach.

The source gives: MACO = TDD(previous) × MBS(next) / [SF × TDD(next)]

Where:

TDD(previous) = therapeutic daily dose of the previous product
TDD(next) = therapeutic daily dose of the next product
MBS(next) = minimum batch size of the next product
SF = safety factor

A safety factor of 1000 is normally used for calculations based on TDD.

When is this approach considered?

It may be considered when:

Toxicological information is limited
TDD information is available
The changeover involves products where the therapeutic-dose relationship is appropriate

However, in a modern health-based cleaning-validation program, the scientific justification for the selected approach should be documented rather than applying a historical numerical factor automatically.

8. LD₅₀-Based Acceptance Criteria

An LD₅₀-based approach is used when other information such as ADE, PDE, OEL or TDD is unavailable. This may be relevant to certain:

Chemicals
Intermediates
Detergents
Materials with limited toxicological information

NOEL = LD₅₀ × BW / 2000

The resulting NOEL can then be used to establish MACO.

The animal species and route of administration associated with LD₅₀ data are important.

Safety factors mentioned in the source

The supplied material lists ranges of:

Route	Safety Factor Range
Topical	10–100
Oral	100–1,000
Parenteral	1,000–10,000

A factor of 200 is generally employed when manufacturing APIs intended for oral dosage forms.

Important: These values should be treated as source-specific historical methodology and not automatically assumed to be the current regulatory requirement for every product.

9. General ppm-Based Acceptance Criteria

Where appropriate toxicological information is unavailable, or calculated MACO values are considered unsuitable within the source’s framework, a general maximum concentration approach may be considered.

MACO = MAXCONC × MBS

Where:

MAXCONC = maximum permitted concentration of previous-product residue in the next batch
MBS = minimum batch size of the next product

The general limits in the range of 5–500 ppm, with 100 ppm frequently used for APIs depending on the characteristics of the products.

Important regulatory point

A generic ppm limit should not automatically replace a scientifically justified health-based assessment when appropriate toxicological information is available.

The EMA has specifically explained the move toward scientifically derived health-based exposure limits because older fixed approaches such as 10 ppm or 1/1000th of the minimum therapeutic dose did not necessarily account for the actual pharmacological and toxicological characteristics of the substance.

Therefore, for a modern EU GMP cleaning validation strategy, a company should document why the selected acceptance criterion is scientifically appropriate.

10. Threshold of Toxicological Concern (TTC)

The Threshold of Toxicological Concern (TTC) concept for APIs or intermediates where clinical or toxicological information is limited. It identifies three broad categories:

Materials likely to be carcinogenic
Materials likely to be potent or highly toxic
Materials not likely to be carcinogenic, potent or highly toxic

The source associates these categories with ADE values of:

1 µg/day
10 µg/day
100 µg/day

respectively. Because TTC application depends on the substance and the toxicological framework being used, this approach should be applied only with appropriate scientific justification.

11. Swab Acceptance Criteria

Swab sampling is widely used in cleaning validation to assess residue on defined equipment surfaces.

Target Value (mg/cm²) = MACO × 25 cm² / Total Direct-Contact Surface (cm²)

The 25 cm² represents the nominal swabbed area in the source’s example.

Why are swab limits important?

A total MACO limit alone may not adequately control localized contamination.

For example, one small part of an equipment train could contain a disproportionately high residue even though the calculated total carryover remains below MACO.

Therefore, the recommends establishing:

Overall MACO
Individual swab limits
Appropriate sampling locations
Hard-to-clean locations
Recovery factors
Analytical method suitability

The different equipment surfaces may have different recovery characteristics, including stainless steel, glass-lined surfaces, and Teflon.

12. Hard-to-Clean Locations

Cleaning validation should identify areas where residues are most difficult to remove. Examples can include:

Equipment joints
Gaskets
Valves
Dead legs
Transfer lines
Spray balls
Agitator areas
Filters
Seals
Difficult-to-access surfaces

The exact locations depend on equipment design.

FDA’s cleaning-validation information emphasizes consideration of equipment design, material of construction, and the specific substances being cleaned.

Also recommends considering difficult-to-clean areas and, where necessary, dividing an equipment train into sections with separate swab limits.

13. Swab Recovery Studies

A swab result is meaningful only when the sampling method can adequately recover the residue from the surface. Therefore, cleaning validation should consider:

Surface → Residue → Swab → Extraction → Analytical Method → Result

Recovery studies should consider:

Surface material
Analyte
Swab material
Extraction solvent
Extraction procedure
Contact time
Drying conditions
Analytical method

The recovery studies and method validation are necessary when swabbing is used for residue determination.

14. Evaluation of Swab Results

After sampling and analysis, results should be compared against predetermined acceptance criteria.

The document recommends establishing both:

A. Overall MACO Limit

The calculated total carryover from the equipment train must remain within the established MACO.

B. Individual Swab Limit

Individual sample results should also remain within predefined limits.

This prevents a situation where one area is excessively contaminated while the total calculated carryover remains acceptable.

Both MACO and swab limits should be established.

15. Rinse Sampling Acceptance Criteria

Rinse sampling is another important approach for demonstrating equipment cleanliness. It is particularly useful when:

Equipment has large internal surfaces
Direct swabbing is difficult
The equipment can be adequately wetted by the rinse solvent
A representative rinse can be obtained

The supplied text states that equipment qualification should establish that all relevant product-contact surfaces can be reached by the rinsing solvent.

16. Rinse Target Value

Target Value (mg/L) = MACO (mg) / Rinse Volume (L)

This converts the equipment-level MACO into an analytical concentration limit for the rinse sample.

17. Rinse Residue Calculation

The supplied source provides: M = V × (C − Cb)

Where:

M = amount of residue in cleaned equipment, mg
V = volume of final rinse/wash solvent, L
C = concentration of impurity in sample, mg/L
Cb = concentration of impurity in the blank, mg/L

The acceptance requirement is: M < Target Value

The same solvent blank may be used for multiple samples from a run when the same solvent lot is used.

18. Swab vs Rinse Sampling

The selection of swab or rinse sampling should be scientifically justified based on equipment design.

Swab sampling

Useful for:

Direct examination of defined surfaces
Hard-to-clean locations
Equipment such as mixers
Milling equipment
Filters
Accessible surfaces

Rinse sampling

Useful when:

Direct swabbing is difficult
The equipment has extensive internal surfaces
The rinse solvent can reach relevant product-contact surfaces
Surface wetting has been demonstrated

The milling, mixing, and filters are usually suitable for swabbing, while reactor systems are often sampled by rinsing.

19. Visual Cleanliness Is Important — But Not Always Sufficient

Visual inspection remains an important element of cleaning verification.

However, visual inspection alone may not demonstrate that residue is below a scientifically justified quantitative limit.

FDA states that visual examination can detect gross contamination concentrated in small areas, but analytical testing may also be needed to demonstrate that residues have been reduced to acceptable levels.

A recent FDA warning letter illustrates this point: FDA cited a cleaning-validation program that relied exclusively on visual inspection and lacked scientifically determined carryover limits, quantitative residue testing, and direct surface sampling of difficult-to-clean areas.

Therefore: Visually Clean ≠ Automatically Scientifically Demonstrated Clean

20. Cleaning-Agent Residue

Cleaning validation should not focus only on the previous API or product.

Cleaning agents themselves can become contaminants.

Acceptance limits for detergent or cleaning-agent residues should be scientifically justified and documented.

FDA states that there is no universal standard detergent-residue limit; the manufacturer is responsible for establishing acceptance limits and being able to provide the scientific basis for them.

Relevant considerations can include:

Toxicity
Concentration used
Rinseability
Solubility
Equipment material
Product-contact risk
Potential impact on product quality
Analytical detectability

21. Analytical Method Requirements

The analytical method selected for cleaning validation should be suitable for its intended purpose. Important characteristics can include:

Specificity
Accuracy
Precision
Sensitivity
Appropriate quantitation range
Recovery
Robustness
Suitable detection capability

This connects swab acceptance criteria with method validation and recovery studies.

FDA’s API GMP guidance also states that analytical methods used for cleaning-validation purposes should be validated unless an appropriate recognized standard method applies.

22. Cleaning Validation and Health-Based Exposure Limits in Europe

EU GMP expectations, Health-Based Exposure Limits (HBELs) are particularly important.

The EMA guideline provides an approach for deriving scientifically based safe threshold values for individual active substances when different medicinal products are manufactured in shared facilities.

The underlying principle is to assess the toxicological and pharmacological characteristics of the active substance rather than relying solely on arbitrary universal residue limits.

This is particularly relevant for:

Shared manufacturing facilities
Multiple APIs
Highly potent substances
Low-dose products
Products with narrow therapeutic margins
Products with significant toxicological concerns

23. Cleaning Validation Expectations for the U.S. Market

For U.S. pharmaceutical manufacturing, 21 CFR 211.67 establishes GMP requirements concerning equipment cleaning and maintenance.

FDA explains that firms using nondedicated equipment should identify cross-contamination risks and implement appropriate controls, including cleaning and cleaning validation.

FDA’s guidance also emphasizes that cleaning-validation protocols should define:

Equipment
Cleaning procedures
Materials
Acceptance limits
Parameters
Analytical methods
Sampling procedures

and that the validation data should demonstrate consistent achievement of acceptable residue levels.

24. EU and U.S. Approach — Practical Comparison

Topic	U.S. FDA Context	European Context
Cleaning validation	Required as part of GMP controls	Required as part of GMP controls
Cross-contamination	Must be appropriately controlled	Strong emphasis on risk-based prevention
Acceptance limits	Scientifically justified and documented	Health-based exposure limits are important
PDE/HBEL	Useful scientific basis	Major component of cross-contamination risk assessment
Swab sampling	Appropriate where justified	Appropriate based on risk/equipment
Rinse sampling	Appropriate where justified	Appropriate where justified
Visual inspection	Important but not necessarily sufficient	Used with risk-based controls and analytical evidence
Worst-case approach	Used based on risk and equipment/product factors	Risk-based selection expected
Analytical methods	Suitable/validated methods expected	Suitable/validated methods expected

This table is a high-level comparison rather than a statement that the two regulatory systems have identical requirements.

25. Current PIC/S Context

There is also an important current development for pharmaceutical professionals following international GMP expectations.

PIC/S announced in July 2026 that its revised Recommendations on Qualification and Validation (PI 006-4) supersede the previous cleaning-validation recommendations, with entry into force on 1 October 2026.

This is relevant for professionals working with multinational pharmaceutical operations because PIC/S recommendations influence GMP expectations across participating regulatory authorities.

26. Common Mistakes in Cleaning Validation Acceptance Criteria

Mistake 1: Using a fixed ppm limit without justification

A generic ppm limit should not automatically be applied when better health-based information is available.

Mistake 2: Relying only on visual inspection

Visual cleanliness cannot necessarily demonstrate that a residue is below a quantitative health-based limit.

Mistake 3: Ignoring hard-to-clean locations

Sampling should be representative and should consider difficult-to-clean surfaces.

Mistake 4: Ignoring recovery

A low analytical result may be misleading if the sampling method has poor recovery.

Mistake 5: Ignoring cleaning-agent residues

The cleaning process itself can introduce another contamination risk.

Mistake 6: Ignoring equipment design

A cleaning procedure validated on one equipment configuration cannot automatically be assumed to work on a substantially different design or material.

FDA specifically notes that equipment material, design, conditions of use and the substances being cleaned need to be considered.

Mistake 7: Using historical formulas without scientific justification

TDD, LD₅₀ and generic ppm approaches may appear in historical cleaning-validation methodologies, but their applicability should be scientifically justified for the current product and regulatory context.

27. Practical Cleaning Validation Acceptance-Criteria Workflow

A practical workflow can be summarized as:

Step 1 — Identify Previous Product

↓

Step 2 — Identify Next Product

↓

Step 3 — Assess Toxicological/Pharmacological Data

↓

Step 4 — Establish PDE/ADE or Appropriate Health-Based Limit

↓

Step 5 — Calculate MACO

↓

Step 6 — Identify Worst-Case Product/Equipment Combination

↓

Step 7 — Convert MACO Into Swab/Rinse Limits

↓

Step 8 — Select Sampling Locations

↓

Step 9 — Establish Recovery and Analytical Method Suitability

↓

Step 10 — Execute Cleaning Validation

↓

Step 11 — Compare Results With Acceptance Criteria

↓

Step 12 — Evaluate Deviations and Trends

↓

Step 13 — Approve Validation Conclusion

28. Example of a Simplified MACO Calculation

Assume, for illustration only:

PDE of previous product = 0.5 mg/day
Minimum batch size of next product = 100 kg
TDD of next product = 500 mg/day

Using the source’s PDE-based relationship:

MACO = PDE(previous) × MBS(next) / TDD(next)

Therefore:

MACO = 0.5 × 100,000 / 500

MACO = 100 mg

This means that, under the assumptions and units used in the example, the calculated maximum allowable carryover would be 100 mg.

The actual calculation in a GMP environment must use the appropriate units, approved toxicological assessment, batch size, dose information and scientifically justified methodology.

29. Key Acceptance Criteria Checklist

Before approving a cleaning-validation protocol, verify:

Health-based exposure information evaluated
PDE/ADE established where appropriate
MACO scientifically justified
Worst-case product identified
Minimum batch size considered
Therapeutic daily dose considered where applicable
Equipment surface area established
Hard-to-clean areas identified
Swab locations justified
Rinse sampling strategy justified where applicable
Recovery study completed
Analytical method suitable/validated
Cleaning-agent residue considered
Visual inspection criteria established
Microbiological considerations assessed where applicable
Acceptance criteria predefined before execution
Results evaluated against both overall and individual limits where applicable
Deviations investigated
Cleaning process demonstrated to be reproducible

30. Key Takeaways for QA Professionals

The most important principles are:

1. Start with health-based science.
Where appropriate information is available, ADE/PDE/HBEL should form an important basis for residue limits.

2. MACO is an equipment-level carryover concept.
It represents the acceptable amount of previous-product residue transferred into the next product.

3. Product selection matters.
Worst-case selection should consider toxicity/potency, solubility, cleanability, batch size, dose and equipment characteristics.

4. Swab and rinse limits translate MACO into measurable acceptance criteria.

5. Recovery matters.
A sampling method must be capable of recovering residue from the relevant surface.

6. Visual inspection is important but may not be sufficient for quantitative cleaning validation.

7. Cleaning-agent residues should also be addressed.

8. Acceptance criteria must be scientifically justified and documented.

9. Historical approaches such as TDD, LD₅₀ and generic ppm limits should not automatically be treated as universal current regulatory requirements.

10. The cleaning-validation program should remain aligned with the applicable regulatory framework and current GMP expectations.

Frequently Asked Questions

What is the acceptance criterion in cleaning validation?

The acceptance criterion is the predefined maximum level of residue or contamination that may remain after cleaning without creating an unacceptable risk to product quality or patient safety. It may be expressed through MACO, PDE/HBEL-based limits, swab limits, rinse limits or other scientifically justified criteria.

What is MACO in cleaning validation?

MACO means Maximum Allowable Carryover. It is the maximum acceptable amount of residue from a previous product that can be carried over into the next product.

Is 10 ppm still the universal cleaning-validation limit?

No. A fixed 10 ppm criterion should not automatically be treated as a universal modern regulatory requirement. The EMA has described the limitations of historical fixed criteria and emphasizes scientifically derived health-based exposure limits.

What is the preferred basis for MACO?

Where suitable toxicological information is available, a health-based exposure limit such as PDE/ADE/HBEL provides a scientifically relevant basis for establishing residue limits.

What is the difference between swab and rinse sampling?

Swab sampling directly samples a defined surface, making it useful for hard-to-clean and localized areas. Rinse sampling can provide broader equipment coverage when the rinse solvent adequately reaches the relevant product-contact surfaces.

Is visual inspection enough for cleaning validation?

Not necessarily. Visual inspection is useful for detecting visible contamination, but quantitative residue testing may be required to demonstrate that residues meet scientifically established acceptance limits. FDA has specifically identified deficiencies where cleaning validation relied exclusively on visual inspection.

Why are recovery studies required?

Recovery studies demonstrate how effectively the sampling method removes and measures residue from the equipment surface. Without adequate recovery information, the analytical result may not accurately represent the residue actually present.

Conclusion:

Cleaning validation acceptance criteria are the foundation for demonstrating that pharmaceutical manufacturing equipment can be cleaned consistently and effectively.

The cleaning-validation framework describes several methods for establishing limits, including PDE/ADE-based MACO, TDD-based MACO, LD₅₀-based calculations, general ppm limits, swab limits and rinse limits.

For modern pharmaceutical manufacturing, the emphasis should be on scientifically justified, risk-based and health-based acceptance criteria, supported by appropriate toxicological assessment, equipment knowledge, analytical methods, recovery studies and representative sampling.

For companies serving the U.S. and European pharmaceutical markets, cleaning-validation strategies should be aligned with applicable GMP expectations, including FDA requirements and guidance and European health-based exposure-limit principles. FDA requires effective controls to prevent contamination and expects cleaning-validation programs to demonstrate that residues are reduced to acceptable levels. The EMA provides a scientifically based framework for health-based exposure limits in shared facilities.

Ultimately, the key question is not simply: “Is the equipment visually clean?”

It is: “Has the cleaning process been scientifically demonstrated to consistently reduce residues to a safe and predefined acceptance level?”

That is the central principle behind an effective pharmaceutical cleaning-validation program.

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