Afzaal Ahmed

Manager QA & Validation

24/09/2024 1
 1 What is Cleaning Validation?
 2 Scope
 3 Why Validate Cleaning Procedures?
 4 Common Elements of Cleaning Validation
 5 Sampling Techniques
 6 Establishment of Limits
 7 Approaches of cleaning Validation
 8 Methods of Calculations
 9 Final Rinse Sample Typical Acceptance Criteria
 10 Careful Use of Safety Factors
 11 Change Control & Revalidation
 12 Example of CV & Risk Assessment

Cleaning Validation 24/09/2024 2

The process of providing documented evidence that
the cleaning methods employed within a facility
consistently controls potential carryover of product
(including intermediates and impurities), cleaning
agents and extraneous material into subsequent
product to a level which is below predetermined
levels.”

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 It addresses the validation of cleaning procedures
of equipment used in manufacturing of
pharmaceutical products.
 Normally cleaning validation would be applicable
for critical cleaning such as cleaning between
manufacturing of one product and another, of
surfaces that come into contact with products.
 Cleaning validation is done to remove the
contaminants associated with previous products,
residues of cleaning agents, Microbial
contaminations.

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• Regulatory Requirement
 “Equipment and utensils shall be cleaned, maintained
and sanitized at appropriate intervals to prevent
contamination that would alter the safety, identity,
strength, quality or purity of the drug product.” FDA

 “Particular attention should be accorded to the

validation of … cleaning procedures” (WHO)
 “Cleaning validation should be performed in order to
confirm the effectiveness of a cleaning procedure”
(PIC/S)

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• To prevent possible contamination
and cross-contamination

• It is a prime customer requirement

since it ensures the purity and safety
of the product.

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• It also assures the quality of the process
through an internal control and
compliance.
• To ensure that the output is consistent
first time & every time.
• Less time hosting government agencies,
more time manufacturing.

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*Procedure on how validation will be performed should be in place.
*The maximum period that equipment may be left dirty before being
cleaned as well as the establishment of the time that should
elapse after cleaning and before use should be defined.
*The levels of microorganisms (bioburden) should be defined.
*What sampling procedures to be used?
*The data on recovery studies (efficiency of the recovery of the
sampling technique should be established);
For example, a recovery of >80% is considered good, >50%
= reasonable and <50% questionable.

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• *Analytical Methods should be sensitive and
specific and must be validated before the
cleaning validation is performed. It is the key
requirement.

• *The cleaning agent should be carefully

selected and approved.

• *The cleaning personnel should be reliable,

trained and should be effectively supervised.

• *Acceptance criteria should be set

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o Direct Surface Sampling (Swab Method)

o Rinse Sampling

o Placebo Sampling

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Swabbing technique involves the use
of a swabbing material, often
saturated with solvent, to physically
sample the surfaces. The preferred
sampling method and the one
considered as the most acceptable by
regulatory authorities is the swabbing
method.
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Cleaning Validation 24/09/2024 12
Placebo sampling can be used to detect residues on
equipment through the processing of a placebo batch
subsequent to the cleaning process. It is appropriate for
active residue, cleaning agent, particulates and microbial
testing. Placebos are used primarily to demonstrate the
lack of carryover to the next product.

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• The limit-setting approach can:
- be product-specific
- group products into families and choose
a worst case product

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Worst Case Rating :

i. Solubility in subjected solvent

ii. Maximum Toxicity
iii. Minimum Therapeutic Dose
iv. Difficult to Clean
v. Lowest Limit based on therapeutic dose / toxic
data, batch sizes, surface areas, etc
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• The acceptance criteria established for
contaminant levels in the sample should be
practical, achievable and verifiable.
• The rationale for the residue limits established
should be logical, and based on the knowledge of
the materials involved.
• Limits may be expressed as a concentration in a
subsequent product (ppm), limit per surface area
(mcg/cm2), or in rinse water as ppm.

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• The sensitivity of the analytical methods
should be defined to enable reasonable
limits to be set.
• The rationale for selecting limits for
carry-over of product residues should
meet defined criteria.

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The Five most commonly used Approaches are:
1. Visually clean no residue visible on equipment after
cleaning.
2. No more than 10 ppm of one product will appear
in another product.
As per 10ppm
MAC = 10ppm*Batch Size

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 3. Dose Criterion Method:
No more than 0.1% of the normal therapeutic dose
of one product will appear in the maximum daily
dose of a subsequent product, identify worst case
scenario.

MAC = (Min. daily dose of active in Product A) x Batch Size of Product B

(Max. daily dose of Product B) x Safety Factor

 4. Therapeutic PDE Value

NOEL= LD50*(5*10-4)*50Kg

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5.Toxicological PDE Value:
Toxicological PDE=Reference Dose or NOEL*Body Weight/F1*
F2* F3* F4* F5

MAC =Toxicological PDE*BS/Maximum Daily Dose

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 Approach 2 (Dose Criterion)
No more than 0.1% of the normal therapeutic dose of one product will
appear in the maximum daily dose of a subsequent product.

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EXAMPLE (Dose Criterion) Safety factor for different dosage forms

Lowest Dose of Product A = 500mg Dosage Form Safety Factor

Maximum Daily Dose of Product B = 5gm Parenteral Products 1000 – 10000

Safety Factor = 1000 Oral Dosage Forms 100 – 1000

(tablets, Capsules etc.)
Batch Size = 50Kg
Total Surface Area of the Equipment = 10,000Topical
cm2Products 10 – 100

Swab Area = 100 cm2 and a swab recovery of 100% are assumed
Swab Sample Volume = 20ml
So
MAC = 500mg / 1000 x 50Kg/5gm Or 500mg / 1000 x 50 x 1000gm / 5gm =
5000mg

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 Surface Residue mcg/cm2 = MAC/Total Surface Area =
5000mg/10,000 cm2= 0.5mg/cm2 OR 500 mcg/cm2
 Residue on Swab (mcg) = Surface Residue mcg/ cm2 x
Area Swabbed (cm2) = 500 mcg/cm2 x 100cm2 =
50,000mcg
 Residue Level in Swab Sample (ppm) = Residue on Swab
(mcg) x Dilution Volume (ml) = 50,000mcg / 20ml =
2500ppm

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 Approach 3 (10ppm Criterion)

No more than 10 ppm of one product will appear in another product.

Batch Size = 50Kg

Total Surface Area of the Equipment = 10,000 cm2

Swab Area = 100 cm2 and a swab recovery of 100% are assumed

Swab Sample Volume = 20ml

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MAC (mg) = RxS

Where ;
 R = 10mg of active ingredient of product A in 1 Kg of Product B i.e 10ppm

 S = Batch Size of Product B in Kg

MAC (mg) = 10mg/Kg x 50Kg = 500mg

 Surface Residue mcg/cm2 = MAC/Total Surface Area = 500mg/10,000 cm2=
0.05mg/cm2 OR 50 mcg/cm2

 Residue on Swab (mcg) = Surface Residue mcg/ cm2 x Area Swabbed (cm2)
= 50 mcg/cm2 x 100cm2 = 5000mcg

 Residue Level in Swab Sample (ppm) = Residue on Swab (mcg) x Dilution

Volume (ml) = 5000mcg / 20ml = 250ppm

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 Rinse Sample
Target Value (mg/Liter) = MAC (mg) / Volume of
Rinse (Liters)
The residue in the sample is determined by a suitable analytical method and the
residue in the whole equipment is calculated according to the following equation:

M = V x (C – Cb)
Where
M = Amount of residue in the cleaned equipment in mg.
V = Volume of Rinse Sample (Liters)
C = Concentration of Residue found in Rinse sample (mg/liter)
Cb = Concentration of Residue found in blank Rinsing Fluid (mg/liter)

Requirement: M < Target Value

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Example:
Let 250mg be the MAC calculated by using 10ppm criterion and 2 liter is the rinsing fluid
then

Target Value (mg/liter) = 250 mg / 2 liter = 125mg/liter

if 5mg/liter is the residue observed in rinsing sample & 0 mg/liter in the blank then

M = 2 x (5 – 0) = 2 liter x 5 mg / liter = 10mg

As the M < Target value so the final rinsing meets the cleaning validation
requirements.

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Appearance Clear, colorless, odorless & tasteless
liquid free from foreign particles.
pH 5.0 - 7.0
Conductivity NMT 4.3 µS/cm @ 20±1˚C
TOC < 2.0 ppm
Bioburden NMT 100 CFU/ml
Product Residue Varies, typically non-detect

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 Using the 1/1,000th approach, a low risk drug such as Aspirin
can have much lower limits than some drugs that are much
riskier. This doesn’t seem science-based and certainly not
logical at all.

 Pharmaceutical industries must consider the safety data of their

product which they have established during the pharmacological
and toxicological studies prior to marketing for establishing
science-based limits.

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Revalidation of the cleaning process is to be done if:
• Cleaning Procedure is changed.
• Raw Materials are changed.
• Change in formulation.
• Change in detergents.
• Modification of Equipment.

Cleaning process validation should be checked at regular

intervals.

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 CV Protocol (Qualifying Dirty Equipment Hold
Time) – Example of Employing Risk-Based
Approach
 Employ any of the Tools for Risk Assessment,
i.e., FMEA
 Identify the Risk (the Residue Will be Dried on the
Equipment Surfaces and will be Hard to Clean,
Especially with a Manual Cleaning Method)
 Propose the Mitigation Strategy and Evaluate the
Risk Score Before and after Successful Mitigation
Strategy Execution.
 Document This Exercise in the CV Protocol.

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Mitigation Strategy –
 Develop a Very Detailed Step-by-Step SOP/Work
Instruction for the Manual Cleaning, with
Requirement for Testing & Retraining,
 Train the Operators and Document the training.
Score the Risk as Low Theoretically if Your CV
Study is Successful with the SOP ,Trained
Operator Conducting the Manual Cleaning for
Typically Three (3) CV Batches.
If the CV Study Meets the Acceptance Criteria,
You Have Successfully Used the Risk-
Based Approach.

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