Cleaning Validation Pillars “part 1”

1. Pre-Requisites to Begin Cleaning Validation
1.1. Cleaning Validation Strategy and Protocols are approved.
1.2. Equipment used for most of the products should be identified
1.3. SOP for Equipment Cleaning has been established (draft)
1.4. Sampling and Analytical Methods are validated
1.5. A list of CPPs and CQAs is available
1.6. Drug toxicity data is available
1.7. Product contact surface area is calculated
1.8. Training is given to the personnel involved in cleaning validation activity
1.9. Drug characteristics are evaluated for cleaning difficulty

2. Cleaning Validation Process Flowchart

3. Critical Process Parameters (CPPs) for Cleaning procedure
3.1. Temperature of detergent solution
3.2. Pressure
3.3. Contact time
3.4. Concentration of the cleaning agent
3.5. Surface Roughness (More roughness means more difficult to clean)
3.6. Flow rate
3.7. Proper mixing RPMs
3.8. Dirty Hold Time for Equipment
3.9. Clean Hold Time for Equipment

4. Critical Quality Attributes (CQAs) For Cleaning procedure
4.1. Product residue
4.2. Cleaning agent residue
4.3. Required concentration of cleaning agent
4.4. Microbial residue
4.5. Drain ability
4.6. Conductivity
4.7. Number of rinses
4.8. Time for cleaning

5. Notes
5.1. A risk-based approach would help identify the risks associated with:
5.1.1. Concerned residue
5.1.2. Priority of selecting sampling locations
5.1.3. Determining and justifying product/equipment groups
5.1.4. Defining acceptance criteria
5.1.5. A sequence of protocol execution
5.1.6. Product change-over SOPs
5.2. Selection of Analytical Methods and Their Validation
5.2.1. Specific
5.2.2. Non-Specific
5.3. The selection of these methods requires a science- and risk-based approach. Inappropriate evaluation and selecting any of these methods may invite regulatory objections.

Specific Methods Non-Specific Methods
Gives us the exact quantification of the target residue Related to the target residue but doesn’t provide its direct measurement or quantification
Recommended during cleaning validation Recommended after cleaning validation OR also complement specific methods during cleaning validation
Can detect interference in substances other than residue like cleaning agents Itself can falsify the measurement of the target residue because of the presence of other substances
Examples: HPLC, RP-HPLC with UV, Ion Chromatography Examples: pH,

6. Sampling Methods for Cleaning Validation
6.1. Direct Surface Sampling (Swab Sampling)
6.1.1. Direct surface sampling (swab sampling) is the most preferred sampling method for hard-to-reach but reasonably accessible areas of the equipment.
6.1.2. A sterile swab made of cotton is attached to a compatible stick just like earbuds.
6.1.3. The challenge is to use the solvent along with the swab comfortably without interfering with the analytical test. Swabs may contain certain adhesives that can alter the results.
6.1.4. These swabs are stored and dipped in a buffer like a phosphate solution or as appropriate to soak the cotton. During sampling, swabs are removed and then applied gently on the equipment surface in one vertical and one horizontal direction without rubbing.

6.2. Rinse Sampling
6.2.1. Unlike swab sampling, rinse sampling has the advantage of covering a large surface area of the equipment in a particular instance, including systems that are hard to disassemble frequently.
• The required amount of cleaning solvent with the help of a suitable spray ball preferably with 360° coverage used to rinse the equipment.
• Rinsed samples are then collected from sample points located near drain lines for physical and microbiological inspection.
6.2.2. One of the major disadvantages of rinse samples is when rinsed, the residue may incompletely solubilize in the rinse solvent like WFI or PW and remain clogged to the equipment surface. In this case, just checking downstream water for compendial requirements is illogical and hence unacceptable.
6.2.3. Instead, the system should be in place to identify the direct measurement of the residue in the rinse sample such as Infrared sensors or visual inspection, etc.

7. Ways of Cleaning
7.1. Cleaning can be performed in 3 different ways using cleaning agents such as purified water, WFI (Water for Injection), or chemical solvents.
• Cleaning In Place (CIP)
– CIP Skid to Clean the Equipment
– Automated CIP of the Equipment
• Cleaning Out of Place (COP)
– Washers like Tray Washers, Dish Washers, etc.
– Sub-systems of equipment hard to approach in CIP
• Manual Cleaning
– Components that are difficult to clean during COP and hence cleaned using tools such as Cleaning Brushes, Scrubbers, etc.

8. Types of Cleaning
8.1. As per the common understanding among pharma professionals, there are two types of cleaning.
➢ Batch To Batch
• Cleaning of the process equipment in between two batches for ongoing manufacturing campaign of the same product.
➢ Product to Product
• Cleaning of the process equipment in between the two different products i.e. after finishing the previous product campaign and before initiating a new product campaign.

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