Cleaning Validation
Introduction
Cleaning validation is 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 Validation is not monolithic; it requires a comprehensive, science-based approach throughout the product lifecycle.
Cleaning Validation Lifecycle
A lifecycle approach ensures that cleaning validation is maintained throughout the product's entire lifespan, from initial validation to ongoing verification and revalidation when changes occur.
Key Insight: The lifecycle approach integrates cleaning validation into the overall pharmaceutical quality system, ensuring continuous compliance and improvement.
Quality Risk Management Approach
Cleaning Validation is essential to all stages of manufacture, and a Quality Risk Management (QRM) approach should be followed to identify high-risk areas where cleaning validation efforts should be focused.
Preliminary Risk Assessment Factors:
- Nature of the residue
- Equipment design (difficult to clean locations)
- Grouping of products and equipment & validating worst-case combinations
- Solvent or detergent type needed to remove residue
- CIP (Cleaning-in-Place) vs COP (Cleaning-out-of-Place)
- Level of Automation as opposed to manual cleaning process
- Processing times & total number of cycles
Additional Key Factors:
- Maximum length of a campaign and its impact on cleaning effectiveness
- The influence of the time between manufacture & cleaning (DHT - Dirty Hold Time)
- The influence of the time between cleaning and use (CHT - Clean Hold Time)
If cleaning procedures are not capable of cleaning down to an acceptable level, consider the prospect of using dedicated equipment or facilities, or single-use technologies.
Types of Residues
Cleaning Validation should be based on identification & evaluation of potential residues and assigning appropriate acceptable residue limits.
Typical Residues:
| Residue Type | Examples |
|---|---|
| API | Small molecule & macromolecule |
| Excipients | Fillers, binders, lubricants |
| Degradation Products | Breakdown products of APIs or excipients |
| Cleaning Agents | Detergents, solvents |
| Microbiological agents | Bioburden & Endotoxins |
Cleaning Methods Considerations
Cleaning methods depend on available equipment and design considerations:
- Automated vs Manual process (Automation level)
- Equipment design allows for cleaning-in-place (CIP)
- Disassembly required to clean out-of-place (COP)
Critical Cleaning Parameters:
- Detergent type & concentration selection
- Temperature & Pressure of cleaning solution
- Cleaning action (spray, turbulence, etc.)
- Detergent contact & rinse times
- Number of cleaning cycles
Setting Acceptable Limits
Limits are typically set to support three types of cleanliness:
- Visual cleanliness: No visible residues on surfaces
- Microbiological cleanliness: Absence of Bioburden & Endotoxin
- Chemical cleanliness: Effective removal of APIs, Excipients, Detergents
Historical Methodologies:
- 10 ppm criterion
- LD50 (Lethal Dose 50%)
- 0.001 of dose method
Relying exclusively on these historical approaches may obscure true patient risk & presents a compliance gap. Modern approaches should be scientifically justified.
Health-Based Exposure Limits (HBELs)
Cleaning Validation limits must be scientifically justified & based on toxicological evaluation. Health-Based Exposure Limits (HBELs) are determined through Permitted Daily Exposure (PDE).
Represents a substance-specific dose unlikely to cause an adverse effect to individuals if exposed to ≤ PDE dose every day for a lifetime.
PDE Determination:
PDE determination involves NOAEL (No Observed Adverse Effect Level) and several adjustment factors to account for various uncertainties, including weight adjustment for the individual.
PDE determination = (NOAEL * Weight Adjustment ) /( F1 * F2 * F3 * F4 * F5)
Once HBELs are confirmed, they should be used as part of QRM to determine what controls need to be in place and assess if existing control measures are adequate.
Maximum Allowable Carryover (MACO)
PDE values are used in the determination of MACO levels. MACO represents the acceptable transferred amount of preceding product (α) that can be carried over to the next product (β).
MACO = (DPEA * MBSb) / MDDb
Where:
- DPEA = Permitted Daily Exposure Limit of Product A
- MBSb = Max batch size of the next Product (B)
- MDDb = Maximum Daily Dose of the next Product (B)
Sample Acceptance Limit (SAL):
SAL = {(DPEA * MBSb) / MDDb} / {(sample Area * RF) / Cumulative Surface Area}
Where RF represents recovery factors that relate a single sample to total amount of residue.
Alternative Approaches to PDE
Other approaches could be accepted if adequately justified.
Example 1: Therapeutic Macromolecules
These may degrade & denature when exposed to pH/heat extremes → becoming pharmacologically inactive. Therefore, HBELs-based PDE limits of (active & intact) product may not be required.
Example 2: Legacy Products
Other methods (e.g., 10ppm) may result in lower MACO levels than PDE-based ones for legacy products.
Analytical Methods
Selection of analytical method for the detection of residues should consider pharmacopeial or individually developed test methods, specific or non-specific methodology, and capability of detecting (LOD) or quantifying (LOQ) residues.
| Method Type | Examples | Characteristics |
|---|---|---|
| Specific Methods | HPLC, UPLC, Titration | Identify and quantify specific residues |
| Non-Specific Methods | Total Organic Carbon (TOC), pH levels, Conductivity | Detect presence of residues without identification |
Cleaning Validation Studies
Cleaning validation studies involve systematic evaluation of cleaning procedures to ensure they consistently reduce residues to acceptable levels.
Sampling Methods:
Through post-cleaning sampling, we estimate the amount of residue on equipment. Equipment can be sampled through rinse sampling or swabbing.
Sampling locations & method must be selected based on equipment (type & design), residue type, and residue limit.
Swab Sampling:
Used to collect residues directly from surfaces. Preferred technique for easily accessible locations.
Rinse Sampling:
Flushing rinsing solution over surfaces and measuring residues in the rinse solvent. Preferred method for large surfaces, runs of piping, and locations inaccessible to swabbing.
Visual Inspection:
Combination of swab, rinse sampling & visual inspection is typically selected. Visual inspection is an important part of Cleaning Validation/Verification and is supplementary to swab & rinse sampling. It should be performed under appropriate lighting conditions, with borescopes & fiber-optic probes used for hard-to-reach locations.
Recovery Studies
Materials of construction should be taken into account in recovery studies. This involves spiking coupons with known amounts of contaminants to establish recovery factors relating the result of a single sample to total residue amount on equipment.
Similar to swab & rinse recovery studies, the level below which a residue is not visible should be determined (visual detection limit).
DHT, CHT, and Campaign Length
The following should be assessed & validated:
- Maximum length of a campaign
- Time between manufacture & cleaning (DHT - Dirty Hold Time)
- Time between cleaning & use (CHT - Clean Hold Time) ⇒ Ingress of Microbiological load
Cleaning Verifications
Refers to the practice of gathering evidence through measurement with chemical analysis after each batch/campaign to show that the residues of the previous product or cleaning agents have been reduced below the scientifically set MACO level.
Meant to provide assurance that equipment is clean & available for further use in the following cases:
- Cleaning Validation campaign ongoing
- To support re-validations
- In the event of cleaning failures
The Matrix Approach
A science & risk-based approach used to streamline validation, more prevalent in multiproduct facilities.
- Grouping equipment and/or processes
- Validating "worst case" equipment/product combinations
- Assuming easier-to-clean equipment/product combination are adequately represented
- When new product or equipment is introduced → New evaluation is performed to determine whether this constitutes a new worst-case
Common Deficiencies
- Cleaning validation protocols & reports did not include swab locations
- No periodic cleaning verification of manually cleaned equipment
- The threshold at which product was readily visible had not been established
- No PDE data for some of the active pharmaceutical ingredients (APIs)
- Swab recovery studies were not performed for all types of surfaces swabbed
- The volume of rinse solution used was not taken into account in the determination of the acceptance criteria for rinse samples
- The recovery factor identified in swab recovery studies was not applied in the determination and reporting of swab results
- The validated LOD & LOQ were above the residue limit acceptance criteria
- The MACO limit for the product was based on individual pieces of equipment within the equipment train, rather than on the total cumulative surface area, therefore resulting in significantly higher MACO levels
Regulatory Resources
Key Regulatory Documents:
- EudraLex Volume 4, Part1, Annex 15: 'Qualification and Validation'
- EMA/CHMP/CVMP/SWP/169430/2012: 'Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities'
