TRAINING MODULE

CLEANING VALIDATION
 OBJECTIVES
• To avoid contamination of the following
pharmaceutical product in the subsequently
manufactured products
• To design and carry out cleaning in a way that
contamination is reduced to an acceptable level
• To have a documented evidence that an approved
cleaning procedure will provide ‘clean’ equipment
• To confirm a reliable cleaning procedure so that the
analytical monitoring may be omitted or reduced
to a minimum in the routine phase
 Principle
•The cleaning validation is to verify the effectiveness of the cleaning
procedure for removal of product residues, degradation products,
preservatives, excipients, and/or cleaning agents as well as the control of
potential microbial contaminants. In a addition one would need to ensure
there is risk associated with cross-contamination of active ingredients.
•Cleaning procedures must strictly follow carefully established and validated
methods
•Appropriate cleaning procedures must be developed for all product-contact
equipment used in the production process. Consideration should also be given
to non-contact parts into which product may migrate (e.g., seals, flanges, mixing
shaft, fans of ovens, heating elements, etc.).
• Cleaning procedures for products and processes which are very similar do
not need to be individually validated. This could be dependent on what is
common, equipment and surface area, or an environment involving all product-
contact equipment.
 Principle
• It is considered acceptable to select a representative range of similar products and
processes. The physical similarities of the products, the formulation, the manner
and quantity of use by the consumer, the nature of other product previously
manufactured, the size of batch in comparison to previously manufactured
product are critical issues that justify a validation program

• A single validation study under consideration of the worst case can then be carried
out which takes account of the relevant criteria.
 Cleaning Validation Process
• Validation is achieved by demonstrating at least
three times that the cleaning process removes
residues down to acceptable levels. Testing for
acceptable residues includes:
• Residue identification
• Residue detection method selection
• Sampling method selection
• Setting residue acceptance criteria
• Methods validation and recovery studies
• Writing a procedure and training operators
 Validation of Cleaning Processes
• In a multi-product facility, the effort of validating the cleaning of a specific piece of
equipment which has been exposed to several products and the cost of permanently
dedicating the equipment to a single product should be considered

• Equipment cleaning validation may be performed concurrently with actual

production steps during process development and clinical manufacturing.
Validation programs should be continued through full scale commercial
production.
• It is not considered acceptable to test-until-clean. This concept involves cleaning,
sampling, and testing with repetition of this sequence until an acceptable residue
limit is attained

• Raw materials sourced from different suppliers may have different physical
properties and impurity profiles. When applicable such differences should be
considered when designing cleaning procedures, as the materials may behave
differently.
 Validation of Cleaning Process
• The procedures are detailed enough to cover all
the cleaning parameters such as:
• i) the concentration of the cleaning agents,
• ii) the temperature of the cleaning solutions and
water rinses,
• iii) the time of the cycle step e.g. cycle step
counter, volume and flow rate of water rinses;
• iv) the mechanism used to deliver the cleaning
agent such as soaking or scrubbing for manual
cleaning or cycle parameters for automated
cycles
 Validation Of Cleaning Processes
• If automated procedures are utilized (Clean-In-Place: CIP), consideration should be
given to monitoring the critical control points and the parameters with appropriate
sensors and alarm points to ensure the process is highly controlled. Critical equipment
and monitoring devices should be calibrated

• During a campaign (production of several batches of the same product), cleaning

between batches may be reduced. The number of lots of the same product which
could be manufactured before a complete/ full cleaning is done should be determine

• Validation of cleaning processes should be based on a worst-case scenario including:

i) Challenge of the cleaning process to show that the challenge soil can be recovered in
sufficient quantity or demonstrate log removal to ensure that the cleaning process
is indeed removing the soil to the required level, and
ii) The use of reduced cleaning parameters such as overloading of contaminants, over
drying of equipment surfaces, minimal concentration of cleaning agents, and/or
minimum contact time of detergents
 Validation Of Cleaning Processes
• At least three (3) consecutive applications of the
cleaning procedure should be performed and shown
to be successful in order to prove that the method is
validated. Equipment which is similar in design and
function may be grouped and a worst case
established for validation.
 Regulatory Reference
1. Schedule M
2 PIC/S PI 006: Recommendations on Validation Master Plan,
Installation and Operational Qualification, Non-Sterile
Process Validation, Cleaning Validation-2007
3. FDA: Guide to Inspections Validation of Cleaning Processes
(1993)
4. EU-GMP-Guideline, Annex 15 Qualification and validation
5. Health Canada-Cleaning Validation Guideline-(GUI-0028)
6. Other GMP
 Validation Procedure
• Validation of cleaning processes should be based on a
worst-case scenario including:
• i) Challenge of the cleaning process to show that the
challenge soil can be recovered in sufficient quantity
or demonstrate log removal to ensure that the
cleaning process is indeed removing the soil to the
required level, and ii) The use of reduced cleaning
parameters such as overloading of contaminants,
over drying of equipment surfaces, minimal
concentration of cleaning agents, and/or minimum
contact time of detergents
 CV procedure
• At least three (3) consecutive applications of
the cleaning procedure should be performed
and shown to be successful in order to prove
that the method is validated. Equipment
which is similar in design and function may be
grouped and a worst case established for
validation
 CV Procedure
• Development of CV Protocol
• Verification of Cleaning SOPS
• Development of Product Matrix (Grouping)
with MACO
• Product Contact equipment Train
• Surface Area Calculation of product contact
surfaces
 Worst Case Product Selection
• Solubility of API in water/Suitable solvent (if
water insoluble then it is the worst case)
• Toxicological Information –LD-50
(Low LD-50 value is high toxic)
• Dose Potency details. (lowest strength shall
be considered)
• Highly difficult to clean - products reported
during development
 The Approach For setting limits
• The approach for setting limits can be:
• i) product specific cleaning validation for all products;
• ii) grouping into product families and choosing a worst
case product;
iii) grouping by properties (e.g., solubility, allergenicity,
potency, toxicity or formulation ingredients known to
be difficult to clean);
iv) setting limits on not allowing more than a certain
fraction of carryover;
v) different safety factors for different dosage forms.
 LIMITS
• No residue is visible on the equipment after
cleaning procedures are performed. Carry over of
product residues should meet defined criteria for
example the most stringent of the following
criteria:
• i) NMT 0.1% of the minimum daily therapeutic
dose of any product to appear in the maximum
daily dose of the following product;(next product)
• ii) NMT 10 ppm of any product to appear in
another product.
 Additional Approach

• ADE Based Limit

• NOEL (Toxicological Based) Limit

• Among all these the least one Limit

considered as Residual Limit for Cleaning
Validation.
 10 ppm Criteria

MAC10ppm= 10ppm(0.00001 mg/mg) X MBS

MAC10ppm X TA
MACO mg/swab=
SSA
MACO Maximum Allowable Carryover in mg/swab
MBS Minimum Batch Size of Next Product B in mg
TA Swab Test Area of 25 sq. cm
SSA Shared Surface Area of Equipments of Product A and Product B in sq.cm
 Dose Based Criteria
MACO SRDD X MBS X SF X TA
mg/swab= LRDD X SSA

Maximum Allowable Carryover in

MACO
mg/swab
Smallest Recommended Daily
SRDD
Dose of Previous Product A in mg
Minimum Batch Size of Next
MBS
Product B in mg
Saftey Factor for Oral Products
SF
(0.001)
TA Swab Test Area of 25 sq. cm
Largest Recommended Daily Dose
LRDD
of Next product B in mg
Shared Surface Area of
SSA Equipments of Product A and
Product B in sq.cm
 ADE Based Criteria

MACO ADE X MBS X TA

mg/swab= LRDD X SSA

MACO Maximum Allowable Carryover in mg/swab

ADE Acceptable Daily Exposure of Previous Product (A) in mg/day
MBS Minimum Batch Size of Next Product B in mg
TA Swab Test Area of 25 sq. cm
LRDD Largest Recommended Daily Dose of Next product B in mg
Shared Surface Area of Equipments of Product A and Product B
SSA
in sq.cm
 NOEL BASED MACO
NOEL X MBS X SF X TA
MACO mg/swab=
LRDD X SSA

LD50 X Av.Body Weight

NOEL =
2000 (Empirical Constant)

MACO Maximum Allowable Carryover in mg/swab

NOEL No Observed Effect Level of Previous Product A in mg
MBS Minimum Batch Size of Next Product B in mg
SF Saftey Factor for Oral Products (0.001)
TA Swab Test Area of 25 sq. cm
LRDD Largest Recommended Daily Dose of Next product B in mg
SSA Shared Surface Area of Equipments of Product A and Product B in sq.cm
Comparison of MACO Limits
 Analytical Methods for CV

• The analytical methods should be validated before the Cleaning

Validation Study is carried out.

• The analytical methods used to detect residuals or contaminants

should be specific for the substance to be assayed and provide a
sensitivity that reflects the level of cleanliness determined to be
acceptable by the company.

• The analytical methods should be challenged in combination with the

sampling methods used, to show that the contaminants can be
recovered from the equipment surface and to show the level of
recovery as well as the consistency of recovery. This is necessary
before any conclusions can be made based on the sample results. A
negative result may also be the result of poor sampling technique
 Sampling Techniques
• Samples should be drawn according to the Cleaning
Validation Protocol.

• There are two methods of sampling that are

considered to be acceptable, direct surface sampling
(swab method) and indirect sampling (use of rinse
solutions).
• A combination of the two methods is generally the
most desirable, particularly in circumstances where
accessibility of equipment parts can mitigate against
direct surface sampling.
 SWAB SAMPLING

• A. Direct Surface Sampling

• (i) The suitability of the material to be used for
sampling and of the sampling medium should
be determined. The ability to recover samples
accurately may be affected by the choice of
sampling material. It is important to ensure
that the sampling medium and solvent are
satisfactory and can be readily used.
 Rinse Samples

• (i) Rinse samples allow sampling of a large surface

area. In addition, inaccessible areas of equipment
that cannot be routinely disassembled can be
evaluated. However, consideration should be
given to the solubility of the contaminant.

• (ii) A direct measurement of the product residue

or contaminant in the relevant solvent should be
made when rinse samples are used to validate the
cleaning process.
 MICROBIOLOGICAL ASPECTS

• The existence of conditions favorable to reproduction of micro-

organisms (e.g. moisture, temperature, crevices and rough surfaces)
and the time of storage should be considered. The aim should be to
prevent excessive microbial contamination.

• The period and when appropriate, conditions of storage of

equipment before cleaning and the time between cleaning and
equipment reuse, should form part of the validation of cleaning
procedures. This is to provide confidence that routine cleaning and
storage of equipment does not allow microbial proliferation.

• In general, equipment should be stored dry, and under no

circumstances should stagnant water be allowed to remain in
equipment subsequent to cleaning operations.
 DEHT and CEHT
• DEHT- Dirty Equipment Hold Time Study
• CEHT-Cleaned Equipment Hold Time Study
• Thanks