It Provides the information about the Cleaning Process in the Industry.

1. Cleaning validation
Presented by:-Ram Kumar
M.Pharmacy (1st semester)
Department of pharmaceutical analysis
ISF College Of Pharmacy, Moga, Punjab

2. Contents
• Introduction
• Objective
• Possible contaminants
• Levels of cleaning
• Analytical method used in cleaning process
• Validation of analytical methods
• Validation of cleaning process
• Acceptance criteria

3. Cleaning validation
• It is a documented evidence that assures us that a
cleaning process removes residues of API of
manufactured product from a piece of equipments,
cleaning aids utilized in the cleaning process and the
microbial attributes
• By cleaning all the residues are removed to a
predetermined level

4. Objective
• The objective of cleaning validation is to prove that
the equipment is properly cleaned of products,
detergents and microbial residues to an acceptable
level,to prevent contamination and cross
contamination.

5. Possible contaminants
• Product residue
• Cleaning agent residue
• Airborne matter
• Lubricant, ancillary method
• Decomposition residue
• Bacteria, mould, pyrogens

6. Levels of cleaning
• Level 1 cleaning: It is used only between steps in the
same manufacturing process
• Level 2 cleaning: It is used when cleaning between
steps in the same manufacturing process. Level 2
cleaning would be used if step B was to be performed
immediately after step A for the same product line.

7. Levels of cleaning
• Level 3 cleaning: It would be performed when
cleaning after an intermediate or final product step or
one product in preparation of an intermediate step of
another product.
• Level 4 cleaning: It would be used after final product
is ready.

8. Analytical methods used in cleaning
• Analytical methods used for cleaning validation
should be validated before the cleaning validation is
performed
• The detection limit for each analytical method should
be sufficiently sensitive to detect the established
acceptable level of residual or contaminants.
• Some of the analytical methods used for cleaning
validation are as follows

9. Analytical methods
• HPLC
• HPTLC
• GC
• UV spectroscopy
• Ph
• Conductivity
• Elisa
• These methods can be used alone or in combination
depending upon the need.

10. Analytical method validation
Parameters for analytical method validation:-
a) Linearity and range
b) Specificity
c) Precision
d) Accuracy
e) LOD
f) LOQ
g) Robustness
h) System suitability

11. Analytical method validation
• Linearity and Range:-The range of an analytical
procedure is the interval between the upper and
lower levels of analyte (including these levels) that
have been demonstrated to be determined with a
suitable level of precision, accuracy, and linearity.
• For establishment of linearity, minimum 5
concentrations are recommended.
• Linearity results should be established by
appropriate statistical methods.

12. • The Range of the procedure is validated by verifying
that the analytical procedure provides acceptable
precision, accuracy, and linearity when applied to
samples containing analyte at the extremes of the
range as well as within the range.

13. Analytical method validation
• Precision:-The precision of an analytical procedure
expresses the closeness of agreement (degree of
scatter)between a series of measurements obtained
from multiple sampling of the same homogeneous
sample under the prescribed conditions.
• Precision may be considered at three levels:-
a. Repeatability
b. Intermediate precision
c. Reproducibility

14. Analytical method validation
• Accuracy:- it is defined as the nearness between the
True value/Reference value and the experimentally
observed value.
• Accuracy should be assessed by using o minimum
of 9 concentration over a minimum of 3
concentration levels covering the specified range.

15. Analytical method validation
Limit of Detection:-It is the lowest amount of analyte
in a sample which can be detected but not necessarily
quantitated.
Limit of Quantitation:- It is the lowest amount of
analyte in a sample which can be quantitatively
determined with suitable precision and accuracy.

16. Analytical method validation
• Robustness:-The robustness of an analytical
procedure is a measure of its capacity to remain
unaffected by small, but deliberate variations in
method parameters and provides an indication of its
reliability during normal usage.
• If measurements are susceptible to variations in
analytical conditions, the analytical conditions should
be suitably controlled or a precautionary statement
should be included in the procedure, such as:-
1. Use solution within 24 hours
2. Maintain temperature below 25 degree

17. Analytical method validation
• Specificity:- The ability to detect the analyte in the
presence of interfering substances (typically
impurities, degradants, matrix)is called as specificity.
• Suitable identification tests should be able to
discriminate between compounds of closely related
structures which are likely to be present.

18. Analytical method validation
• System suitability:-System suitability testing is an
integral part of many analytical procedures. The tests
are based on the concept that the equipment,
electronics, analytical operations and samples to be
analyzed constitute an integral system that can be
evaluated as such.

19. Cleaning process validation

20. Cleaning process validation
• Cleaning process validation should be performed in
order to confirm the effectiveness of a cleaning
procedure
Parameters of cleaning validation:-
• Equipment
• Personal
• Microbiological consideration
• Documentation
• Sampling
• Acceptance criteria

21. Cleaning process validation
• It is usually not considered acceptable to test-untill-clean.
This concept involves cleaning, sampling and testing with
repetition of this sequence untill an acceptable residue
limit is attained .
Equipments:-any equipment used for processing should be
specifically designed to facilitate cleanability and permit
visual inspection and whenever possible, the equipment
should be made of smooth surface of non-reactive
materials.
Personal:- it is difficult to validate a manual cleaning
procedure,Therefore operator carrying out manual
cleaning procedures should be adequately trained,
monitored, and periodically assessed.

22. Cleaning process validation
Microbial consideration:- equipment should be dried
before storage and under no circumstances should
stagnant water be allowed to remain in equipment
subsequent to cleaning operations
• The aim should be to prevent excessive microbial
contamination.

23. Cleaning process validation
Documentation :-Detailed cleaning procedure should
be documented in SOPs
Cleaning validation protocol should include:-
• Objective of cleaning validation
• Responsibilities for performing and approving the
validation study
• Description of the equipment to be used
• The interval b/w the end of production and the
beginning of the cleaning procedure
• Sampling procedure

24. Cleaning process validation
• Detail cleaning procedures to be used for each
product , each manufacturing system or each piece of
equipment
• The number of cleaning cycles to be performed
consecutively
• Clearly defined sampling locations
• A final validation report should be prepared .The
conclusion of this report should state that cleaning
process has been validated successfully

25. • The report should be approved by the plant
manager
Sampling
Method of sampling:-There are two methods of
sampling
1. Swabbing method
2. Rinse sampling
swabbing method:-this method of sampling is the most
commonly used and involve taking an inert material
(Such as cotton wool) on the end of probe and rubbing
it methodically across the surface

26. Sampling
• Then these swabs are added to diluted solvents and
these solvents and these solvents are than analysed by
suitable analytical instruments to check the presence
of residues of previous products
• Multiple swabs can be taken to improve surface
recovery
• An area of 10 cm by 10 cm and located in the most
problematic region of the apparatus is scrutinized

27. sampling
Rinse sampling :- In this method ,a measured area of
clean surface is rinsed or washed with solvent and the
solvent is collected and tested for traces of
contaminants.
• Rinse sampling method should be used along with
other sampling methods such as surface sampling
• This method can be used for large surface area and
inaccessible areas of equipment that can not be
routinely disassembled

28. Acceptance criteria
Chemical determination:-
1. Nmt 0.1% of the normal therapeutic dose of any
product will appear in the maximum daily dose of
subsequent product
2. Nmt 10 ppm of any product will appear in another
product
3. For certain allergic ingredient ,penicillin,
cephalosporin, steroid and cytotoxic , the limit
should be below the limit of detection

29. Acceptance criteria
Physical determination:- No quantity of residue should
be visible on the equipment after cleaning procedure
are performed
Microbial contaminant:-
Total aerobic count
1. Bacterial count:-NMT 20 CFU
2. Molds :- NMT 02 CFU

30. References
• Kumar Satinder, Shashikant, & Prashar Bharat: “A Review on Concept of Cleaning
Validation in Pharmaceutical Industry.” International Research Journal of Pharmacy,
2012; Vol. 3(7): 17-19.
• www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=211
• www. hsa.gov.sg .
• Babita Lodhi, Poonam Padamwar, & Arif Patel: “Cleaning Validation for the
Pharmaceuticals, Biopharmaceuticals, Cosmetic and Neutraceutical
Industries.”Journal of Innovations in Pharmaceuticals and Biological Sciences,
2014; Vol 1(1): 27-38.
• Kumar V.S., Sanjeev T., & Sharma P.K.,: “Overview of Cleaning Validation in
Pharmaceutical Manufacturing unit.” International Journal of Advanced Research in
Pharmaceutical & Bio Sciences, 2012; Vol.2(2): 154-164.
• P.V. Waghmare, A.S.Chinchole, B.N.Poul, & O.G.Bhusnure: “A Brief Review on
Cleaning Validation and its Significance in Pharmaceutical Industry.” an
International Journal of Pharmaceutical Sciences, 2013; Vol 4(4): 165-192
• Dipak k. Sarker, A Quality Systems and Control For Pharmaceuticals, p. no.- 39-41
10/13/2015