Cleaning Validation

Ref: APIC guidelines

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 Introduction & Definition

❖ Pharmaceuticals manufacturers must demonstrate during validation that

the cleaning procedure routinely employed for a piece of equipment limits
potential carryover to an acceptable level. The limits established must be
calculated based on sound scientific rational.

❖ Cleaning validation is the methodology used to assure that a cleaning

process removes chemical and microbial residues of the active, inactive or
detergent ingredients of the product manufactured in a piece of
equipment, the cleaning aids utilized in the cleaning process and the
microbial attributes below predetermined acceptance level.

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 Acceptance criteria’s

➢ Acceptance criteria using health-based data -1

HBELprevious x MBSnext x PF
MACO = ---------------------------------------------
TDDnext x SF

HEBL= Health-Based Exposure Limit (mg/day) of the previous

compound.

HEBL = ADE or PDE

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 Acceptance criteria’s

➢ Manufacturers should also understand potential variations in Active

Pharmaceutical Ingredient (API) and drug products that could occur during
commercialization and scale-up activities. They need to make every
effort to understand the source, degree, and impact of the variation

POD x BW
ADE = ------------------------
UFc x MF x PK

POD x BW
PDE = ------------------------------
F1 x F2 x F3 x F4 x F5

POD= Point of departure

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 Acceptance criteria’s

❑ In cases where no other data is available and only LD50 data is available the HBEL
can be based upon LD50 data. Calculate NOEL according to the following equation
and use the result for the establishment of HBEL

LD50 x BW
NOEL = ------------
2000

❑ The TTC principles can be applied in case limited or no toxicity data is available:
(1)Compounds that are likely to be carcinogenic (ADE/PDE: 1 μg/day).
(2)Compounds that are likely to be potent or highly toxic (ADE/PDE: 10 μg/day)
(3)Compounds that are not likely to be potent, highly toxic or carcinogenic. (ADE/PDE:
100 μg/day).

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 Acceptance criteria’s

➢ Acceptance criteria using a General Limit -2

MACO = MAXCONCprevious x MBSnext

E.g. for a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS),
and for a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS).

➢ Acceptance criteria using Therapeutic daily dose-3

TDDprevious x MBSnext
MACO = --------------------------------------
SF x TDDnext

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 Swab calculation

❖ Swab Limits calculation

MACO [µg]
Target value [µg/dm2 ] = -------------------------
Total surface [dm2 ]

▪ During equipment qualification and cleaning validation hard to clean parts

can be determined. Rather than declaring the hard to clean part as the worst
case swab limit for the whole equipment train, it could be separated. It should
be noted that different types of surfaces (e.g. stainless steel, glass lined,
Teflon) may show different recoveries during swabbing. In those cases, it may
be beneficial to divide the equipment train in several parts and combine the
results in a table.

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 Evaluation & Acceptance criteria

❖ Evaluation & Acceptance criteria:

➢ When all surfaces have been sampled and the samples have been analyzed,
the results are compared to the acceptance criteria.

➢ Companies may find it easier to evaluate against the MACO. However, it is

advisable to have a policy for swab limit as well.

➢ Especially because analytical methods are validated within a certain range

for swab results. Another reason is that some pieces could be very
contaminated, and it is not good practice to clean certain pieces very
thoroughly in order to let others be dirty. Thus, limits for MACO and swabs
should be set.

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 Rinse & Acceptance criteria

➢ Rinse cleaning and calculation:

Target value (mg/L) = MACO (mg) / Volume of rinse or Boil

➢ The choice of the rinse solvent should be established during cleaning validation,
taking into account solubility of the contaminations, and reactivity of the rinse
solvent towards the contaminants (saponification, hydrolyses, etc).

➢ Method validation is needed. In a worst-case approach, the amount of the residue in

the equipment can be assumed to be equal to the amount determined by analysis of
the rinse sample. This can be supported by rinse studies that show a strong decay of
a residue in a piece of equipment or recovery studies of the rinse cycle.

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 CLV considerations

❖ Cleaning validation considerations between batches of different product lines:

❖ The level of cleaning required depends on the stage of manufacture. If the following
product is an early stage in the API chain, in general lower levels are required than if it is
an intermediate or final stage. The progression of levels is outlined in High risk, however
an individual risk assessment for each potential product changeover scenario has to be
performed to decide which level is applicable.
❖ This risk assessment should address the following topics:
• Easiness of cleaning
• Toxicological / pharmacological activity of the previous product, its side products or
degradants
• Maximum daily dose of the following product
• Microbiological growth
• Batch size of the following product
• Solubility, experience, difficult to remove previous product
• Chemical interactions
• Campaign lengths should be evaluated and determined as part of the risk assessment.

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 Cleaning Verification

❖ Cleaning verification:
Cleaning verification The cleaning verification can be made by:
• visual inspection or
• visual inspection and analytical verification (e.g., swabbing and/or rinsing)
Visual inspection:
➢ After cleaning procedures are performed, equipment should be dried to allow the
visual inspection. No residue should then be visible. Visual inspection should be
performed using the best known capabilities.
❑ During visual inspection the following situations should be considered:
➢ Discoloured surfaces, worn or torn parts;
➢ Solid residues (for final product equipment used downstream of last filtration, the
residues should be evaluated also by passing the final washing through a rough filter
media (e.g. a lint-free cloth)); Visual inspection is usually applied in LOW RISK where
no cleaning validation is required.
❖ Analytical verification:
➢ Analytical verification should be performed with scientifically sound methods. The
analytical methods should be validated before use in cleaning validation, unless they
are compendial methods. 11
 Cleaning Validation

❑ Cleaning validation:
➢ The cleaning validation involves a series of stages over the lifecycle of the
product and cleaning process:
➢ cleaning process design,
➢ cleaning process qualification and
➢ continued cleaning process verification.
➢ Details on the work to be performed and acceptance criteria should be
defined in a protocol.
➢ The cleaning procedure can be prepared per equipment or set of equipment
and should include detail enough to reduce operator’s variability.
➢ The strategy should be defined and taken in consideration in the cleaning
validation activities.
➢ The validation consists in successive applications of the cleaning procedure
complying with the acceptance criteria defined, in a minimum of 3
successful applications.

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 Cleaning Validation

➢ The success of the applications should be consecutive unless the

cause of failure is clearly identified as not related to the process or
procedure.

➢ At this stage analytical methods should be validated and suitable to

quantify at the acceptance criterion level.

➢ The limit of detection must be lower than or equal to the acceptance

criterion level.

➢ Blanks must be evaluated to ensure that there is no significant

interference with the recovery of the analyte.

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 Cleaning Validation

➢ In dedicated facilities, validation of cleaning procedures is not normally required but a

risk assessment should be performed to make sure that there is no potential for
degradation and or microbial contamination that may adversely impact the quality of
the product.
➢ For both dedicated and multi-product facilities, the frequency with which the cleaning
procedure should be performed should be validated to assess risks related to potential
degradation a microbiological contamination.
❖ Dirty Hold Times and Clean Hold Times:
➢ The period and when appropriate, conditions of storage of equipment before cleaning,
commonly referred to as The Dirty Hold Time (DHT) and the time between cleaning
and equipment re-use, prior to additional cleaning, commonly referred to as The Clean
Hold Time (CHT), should form part of the validation of cleaning procedures.
➢ This is to provide confidence that routine cleaning, drying and storage of equipment
does not allow potential for buildup of degradation products that may not be removed
by the standard cleaning procedure and does not allow potential for microbial
contamination of equipment and to ensure that these potential risks are properly
assessed and controlled.

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 Cleaning Validation Protocol

❖ Microbiological acceptance criteria in biopharma /API manufacturing:

It is expected to have microbial samples taken during the cleaning validation. To determine the
acceptance criteria for microbiological samples (bioburden and endotoxin), the following
approaches may be used: • Leverage of product / process limits at the different process stages
• Compendia (EP, JP, US, etc.) based acceptance criteria, in which case that the EMA 158/01 ‘Note
for Guidance on Quality of Water for Pharmaceutical Use’ could be used as a basis to set an
appropriate limit.
❖ Cleaning validation Protocol contents:
1. Background
2. Purpose
3. Scope
4. Responsibility
5. Sampling procedure (Rinse & Swab)
6. Testing procedure
7. Acceptance criteria
8. Training
9. Deviations
10. Revalidation
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Any questions? please

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Kumar Veeramalla
+91 9949116763

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