Back to Basics: A Quick Guide to Cleaning Validation

How the Cleaning Validation Emerged:

The inception of cleaning method validation can be linked to a notable incident ‘The Thalidomide Tragedy’ that underscored regulatory oversight, recognizing the critical importance of preventing cross-contamination and the risks associated with inadequate cleaning practices in pharmaceutical manufacturing. This incident laid the foundation for the development of systematic validation procedures as a part of GMP to prevent cross-contamination and ensure the safety of drug products.

What is Cleaning Validation?

Cleaning validation can be defined as the documented process of obtaining evidence that a cleaning procedure consistently and effectively removes residues of the previously manufactured product, cleaning agents, and microbial contaminants from equipment surfaces to predetermined levels.

Cleaning validation is a critical aspect that assures that the cleaning processes in place are effective and robust, preventing any risk of cross-contamination and ensuring the integrity of subsequent drug products.

When Cleaning Validation Should Be Done?

Federal regulations do not specify exactly how often cleaning validation should be done, FDA expects equipment cleaning at the necessary frequency to prevent drug adulteration and enforces Section 211.67a states that;

“Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized?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.”

As per the review published?in the International Journal of Pharmaceutical Erudition enumerates five more instances when cleaning validation should be done:

• When there is a critical change in equipment cleaning procedures;
• When there is a critical change in drug formulation;
• When there is a significant change in the equipment;
• When there is a change in a cleaning process; and
• When there is a change in a cleaning agent.

What are the types of Sampling Methods?

There are two types of sampling methods generally used in cleaning validation.

1. Direct sampling for cleaning validation?is also known as the swab method, where a residue material is systematically rubbed across a surface to be analyzed for the presence of residue.
2. Indirect sampling for cleaning validation?is often referred to as rinse sampling, where a solvent like water is rinsed in a specific area of clean surface and tested for traces of contaminants,

What is MACO (Maximum Allowable Carryover)?

The amount of residue allowed on equipment and/or a process train after cleaning is referred to as a maximum allowable carry-over limit.

How to calculate MACO limits (or the Acceptance Criterion)?

Cleaning validation studies require setting residue acceptance limits for potential residues to control the cross-contamination of any previously manufactured products that may ‘carryover’ into the next manufactured product also called as.

There are 4 options to set the MACO limits:

1. Based on the 10ppm criterion (or General limit)
2. Based on the Therapeutic dose criterion
3. Based on Toxicological data
4. Based on Health Based Exposure Limits (HBELs)

These limits are based on purity, safety, efficacy, stability, and contamination effects on the next product produced with the same surface or equipment.

The FDA in guidance document states that residue limits should be logical, practical, achievable, and verifiable.

Limits are typically set to support visual, chemical, and microbiological residues by taking into consideration the batch size, dosing, toxicology, and surface area of the equipment;

?? The first industry-proposed approach for cleaning limits for pharmaceuticals was developed by Fourman and Mullen at Eli Lilly (Fourman and Mullen, 1993),

Based on 10ppm criteria:

As per this, no more than 10ppm of the previous product shall appear in the next product.

MACO = 10ppm x mBSnext

mBS: Minimum batch size of next product

?? The value of 10ppm comes from an article written by Gary Fourman and Dr. Michael Mullen.

Based on Therapeutic Dose:

No more than 1/1000 of the lowest therapeutic dose of the previous product will appear in the maximum daily dose of the next product.

Based on Toxicological Data:

This method is used where a therapeutic dose is not known (e.g. for intermediates and detergents), and toxicity data in animals is used to calculate MACO.

Calculate the Acceptable Daily Intake (ADI) or No Observed Effect Level (NOEL) value using the following equation;

Acceptable Daily Intake (ADI) is the no observed effect level

The MACO value can be calculated from the above-obtained equations;

According to one of the European Medicines Agency (EMA)?Question and Answer?documents, the use of LD50 to determine Health-Based Exposure Limits (HBEL) for drug products is an inadequate point of departure. Hence, this approach is no longer useful for the calculation of acceptance criteria in drug products.

Based on Health Based Exposure Limit Criteria:

10 ppm criteria and therapeutic dose criteria are without any scientific rationale and LD50 is very stringent according to EMA Q&A documents, the use of LD50 for drug products is an inadequate point of departure.

The health-based method is based on the assumption that the residue of the previous product should not exceed a level that poses a negligible risk to the health of the patient.?

This method is the most scientific and comprehensive, as it considers the toxicity, pharmacological activity, safety margin, and exposure of the residues and the products. It requires a detailed risk assessment and a derivation of a permissible daily exposure (PDE) or an acceptable daily exposure (ADE) based on toxicological data and clinical studies.

Permitted Daily Exposure (PDE):

The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed to or below this dose every day for a lifetime.

Appendices 3 of the ICH Q3C provides the following formula to calculate the PDE.

If no NOAEL is obtained, LOAEL (Low Observed Adverse Effect Level) may be used.

Alternative approaches to the NOAEL such as the reference dose may also be used.

If several critical effects have been identified resulting in the calculation of more than one PDE value, usually, by default the lowest PDE value will be used.

Calculation of MACO based on PDE:

Final MACO value: The lowest calculated MACO value should be selected from the above options.

Calculation of Swab Limit:

Once you obtained the MACO value (from the methods described above), it can be converted into surface area limit (SAL) using the following equation;

Calculate residue/swab;

Calculate residue recovered by swab sampling;

Calculation of Rinse Limit:

Analytical Procedures for Cleaning Validation:

The selection of an analytical method for measuring residues is closely related to the chemical nature of target residues and to the analytical limits established for those residues. Chemical nature includes whether the target residue is organic or inorganic, is soluble in water or other solvents, its degree of polarity, and its stability in the cleaning environment.

HPLC should be the preferred choice for analysis because of its specificity, and sensitivity and is a versatile technique that can be configured with different detectors such as ultraviolet detectors, refractive index detectors, conductivity detectors, and ELSD (evaporative light-scattering detection) detectors.

TOC is considered non-specific and may be used where indicated and justified. TOC analysis involves oxidation of organic compounds and measurement of carbon dioxide by either infrared spectrometry or conductance. TOC works on the assumption that all of the measured carbon is due to target species.

Non-specific methods should only be used where specific methods cannot be employed and their use can be justified, for example, based on the outcome of risk assessment.

Recovery Studies:

A recovery study is performed to assess the efficiency of the cleaning procedure in removing residues from equipment surfaces.

The study involves intentionally contaminating a defined area of product contact surfaces with a known concentration of residue.

The contaminated area is then carefully swabbed using an established cleaning procedure and then analyzed to calculate the recovered amount of residue from the contaminated surface.

A Systematic Approach to Perform Recovery Study:

Identify direct product contact surfaces that are critical for preventing cross-contamination and Select surfaces that are hard to clean effectively.

Prepare a known concentrated stock solution of the potential contaminant in suitable extraction diluents (usually methanol is the first choice due to its volatile nature and most of the organic contaminants have solubility in methanol).

Spike known amount of residue on the pre-defined area of the identified product contact surface (usually recovery plates/coupons are used with identical material of construction (MOC) to the product surfaces, and the pre-defined area is based on assessment and it can be 2 x 2 inch2 or 4 x 4 inch2 ?or even greater than this).

Swab the contaminated area using the established swabbing procedure, a typical swabbing procedure includes,

• Pre-wetting of swab sticks with water or other appropriate solvent.
• Before sampling, remove the excess solvent from the pre-wetted swab by squeezing it against the wall of the container (vial or test tube).
• Swab the surface with sufficient pressure to collect residues (usually 6 vertical and 6 horizontal strokes are applied).

Extract the swab in a suitable solvent to transfer the recovered residue from the swab.

Analyze the recovered residue using an appropriate analytical method.

Calculate the %recovery by using the formula;

Acceptance criteria: Usually < 50% recovery is not acceptable and the limit can be between 70% to 110% or 50% to 110% based on the MOC of the surface.

Recovery factor can be calculated for respective surfaces from their mean recovery value;

Reference guidance documents:

• FDA reference document as ‘Guide to inspections validation of cleaning processes’.
• FDA Cleaning Validation Guideline from?CFR 211.67?
• FDA?CFR 211??– Current Good Manufacturing Practice for Finished Pharmaceuticals?
• FDA?Questions & Answers?on Current Good Manufacturing Practices—Equipment
• EMA Cleaning Guidance
• EMA Cleaning Validation Guideline?on setting HBELs
• EMA QnA?on the implementation of the setting HBELs guideline
• ISPE?Cleaning Validation Guide- Risk MaPP
• WHO?Cleaning Guidance
• Health Canada: Cleaning validation guide
• TGA Australia: Presentation on Cleaning Validation
• APIC “Guidance on Aspects of Cleaning Validation in API Plants” (2014)
• PDA TR 29 “Points to Consider for Cleaning Validation” (2009)