Cleaning Validation

&
Cross-contamination

Ubonrat Sinraksa

15/08/2016
Prerequisites have to be
fulfilled before cleaning validation studies
Prerequisites have to be fulfilled
before cleaning validation studies
1.Processes :
- Potential contaminate to be consider
for CV.
- Analytical method
- Acceptance criteria
2.Use equipment and cleaning method:
- Sampling method
- Critical sports
- Frequency of revalidation or on going
verification.
Prerequisites have to be fulfilled
before cleaning validation studies
3.Product type and application :
- Special requirement regarding
potential contaminants to be consider.
- Cross contamination issue.

Answers:
Who (Responsibility) , What (Equipment),
When(Schedule), Where(Facilities),Why
(GMP) and How (Procedure)
Grouping
1.Complex integration “Processing Line”
grouped according to function, Process
steps , Contamination profiles.
2.Similar Equipment : Mobile tank with out
the need to validate each tank individually.
3.Different equipment ( e.g. Various small
parts) can be group if they are all cleaned
manually with the same method.
The manufacturer should have a
cleaning policy and an appropriate
procedure for cleaning validation;
covering :
1.Surface that come into contact with the
product.
2.Cleaning after product change over.
3.Between batches in campaigns.
(PIC/S: Generally in case of batch-to-batch
production it is not necessary to clean after
each batch . However, cleaning intervals and
methods should be determined)
4.Bracketing products for cleaning
validation.
(-Products contain substances with similar
properties such as solubility)
- The same substance in different strengths
: The most concentrated form.)
5.Periodic evaluation and revalidation.
Re-validation should be
considered under the following
circumstances:
 Re-validation in case of changes to
equipment , products or process.
 Periodic re-validation at defined intervals.

Manual methods should be reassessed at

more frequent intervals than CIP systems.
Several questions should be
addressed when evaluating the
cleaning process:
1.At what point does a piece of equipment
or system become clean?
2.What does visually clean mean?
3.Does the equipment need to be scrubbed
by hand?
4.What is accomplished by hand scrubbing
rather than just a solvent wash?
5.How variable are manual cleaning
processes from batch to batch and product
6.What is the most appropriate solvent or
detergent?
7.Are different cleaning processes required
for different products in contact with a
piece of equipment?
8.How many times need a cleaning process
be applied to ensure adequate cleaning of
each piece of equipment?
Questions ?
1.Raw materials sourced from different
suppliers should do cleaning validation?

2.The cleaning validation protocol and

report should be approved by whom?
(A. Plant Manager B. QA Manager )
Answers
1.PIC/S : Raw materials sourced from different
suppliers may have physical properties and
impurity profiles. Such differences should be
considered when designing cleaning procedures, as
the materials may be have differently.

2.PIC/S: The cleaning validation protocol should be

formally approved by the plant management, to
ensure that aspects relating to the work defined in
the protocol, for example personnel resources, are
known and accepted by management.
Quality Assurance should be involved in the
approval of protocols and reports.
Cleaning Agent
Cleaning Agent (WHO)
 The choice of the cleaning agent should be
documented and approved by quality unit
and should be scientifically justified on the
basis of, e.g.
o - the solubility of the materials to be
removed
o - the design and construction of
equipment and surface materials to be
cleaned.
◦ The safety of cleaning agent
◦ The ease of removal and detection
◦ The minimum temperature and
volume of cleaning agent and rinse
solution
◦ The manufacturer’s recommendations
Sampling Method & Recovery rate
Sampling method
1.Direct method = direct surface sampling
“Swab”
2.Indirect method=Rinse samples

Recovery rate :
WHO: There should be evidence that samples are
accurately recovered .

For example, a recovery of > 80% is considered

good,
> 50% reasonable, < 50 % questionable
 Example for

Establishing acceptant limits

Establishing acceptant limits

The three most commonly used criteria are:

1.Visually clean = No residue should be visible
on equipment after clean.
2.No more than 10 ppm of one product will
appear in another product.( basis for heavy
metals in starting materials)
3.No more than 0.1% of the normal therapeutic
dose of one product will appear in the
maximum daily dose of subsequent product.
Establishing acceptant limits

4.The bio-burden not more than 100 cfu/ml

for the rinse water and 10 cfu/25 cm2 for
the swab.
5.Endotoxin not more than 0.25 EU/ml
Justification of acceptance criteria
1.Base on toxicity data. (LD50,acceptable
daily intake , threshold of toxicological
concern including safety factors )

2.Based on product quality aspects (Where

residues present a potential hazard to the
product quality)

3.Any other risk based scientific rational.

Example for risk assessment
procedure
1.Prepare a list of all potential contaminations
for a certain equipment group :
- Product
- By-product ( Degradation products)
- Solvent , Reagent , Buffer , etc.
- Microorganisms (bio-burden),Endotoxin
- The cleaning agent
- Lubricants
- Total ALF, DNA etc.
Example for risk assessment
procedure
2.Substance properties is gathered for all
potential contaminants.
- Toxicity ( e.g.LD50 values, literature
reference etc.)
- Solubility (e.g. in g/L solvent used for
cleaning)
- Absolute amount introduced ( The
highest possible amount shall be considered for
evaluation (worst case))
 Ex. 3.Substance property evaluation key :
L = Low M = Medium H= High
Toxicity Solubility Amount
Value Description Value Description Value Description

L LD50≥2000 L < 10 g/ml L <1/3 of the

mg/kg average
amount
M 500<LD50<2 M 10-100 g/ml M 1/3-2/3 of the
000 average
mg/kg amount
H LD50≤500 H > 100 g/ml H > 2/3 of the
mg/kg average
amount

Amount: The sum of all absolute contaminants amounts is divided by

the number of contaminants.
Amount Calculation
Lf = Vr X Cl Vr = Volume of final rinse remaining in
the equipment
Cl = Contamination of lead substance in
Ls = Msa X At the final rinse
Msa = Average lead substance amount in
the swabs
As X R At = Total equipment surface
As = Swabbing surface
R = Recovery factors
Lt = Ls + Lf

Lf = Residual lead substance detect from the final rinse

Ls = Residual lead substance detect by swabbing
Lt = Total amount of residual lead substance in the equipment
4.Relative rating for toxicity , Solubility ,
Amount

- Cleanability is a function of the solubility

and introduced amount

- Hazard Potential is a function of the

toxicity and introduced amount
Evaluation key for cleanability

L = Low M = Medium H = High

Amount Solubility Cleanability
H L L
H M M
H H H
M L M
M M H
M H H
L L H
L M H
L H H
Evaluation key for hazard potential

L = Low M = Medium H = High

Amount Toxicity Hazard Potential

H H H
H M M
H L L
M H M
M M L
M L L
L H L
L M L
L L L
Evaluation key for the lead substance
Lead substances Cleanability Hazard potential
category
Priority 1 L H
L M
Priority 2
M H
M M
Priority 3 H H
L L
M L
Priority 4
H M
Priority 5 H L
Equipment to prevent
contamination to the
environment
Environment prevention contamination

RABS = Restricted
Access Barrier
system

Isolator
Bag in-Bag out filter (BIBO)
Decontamination autoclave
Killed and neutralization system
Dehydrator
Incinerator
Thank you

For

Attention