COMPLETE INFORMATION CLEANING VALIDATION

1. CLEANING VALIDATION
Presented by
G.Vinay jain
M.Pharmacy 1st year 2nd sem
Department of Pharmaceutical analysis and QA
Malla reddy college of pharmacy

2. Validation
The process of providing documented evidences
which provides a high degree of assurance that
specific process, method, will consistently produce a
result with pre – determine specification and
acceptance criteria
Types of validation
 Analytical method validation
 Process validation
 Software validation
 Cleaning validation

3. Types of validation
Analytical validation Process validation

4. Software validation Cleaning validation

6. Cleaning validation : It is an documented evidence
which provide high degree of assurance that an
approved cleaning procedure will provide equipment
that is suitable for processing of pharmaceutical
products or API
Importantance
 Heart of pharmaceutical activity
 Related to safety and purity of the products
 Level of cleaniness is achieved by clean
procedure which depends on its validation
Cleaning method if performed
confidently, method produced reproducible results

7. Cleaning validation plan
• Cleaning validation plan must define
the following
What is to be validated
How it is to be validated
Who is to validate it
Who is to approve the validation
When it must be revalidated

8. Cleaning technique
Aqueous
cleaning
Solvent
cleaning
Manual cleaning
Ultrasonic
cleaning
Extraction
Vapour
degreasing
Ultrasonic
cleaning

9. Ultrasonic cleaning
• Ultrasound creates waves of
compression and expansion in
the liquid. In the expansion
phase, the molecules are
pulled apart rapidly, causing
the formation of microscopic
vapour bubbles.
• Subsequently, these cavitation
bubbles implodes releasing
tremendous energy. Extreme
temperature (~5000°C),
combined with high velocity
jets provides the cleaning
action.

10. Vapour degreasing Extraction

11. LEVEL OF CLEANING
 The equipment usage (dedicated use or not)
 The stage of manufacture (early , intermediate or
final)
 The nature of potential contaminants (toxicity ,
solubility etc )
Each of the above three bullets must
be evaluate based on the next product.

12. LEVELS ATTRIBUTES CLEANING VALIDATION
LEVEL - 0 Batch to batch cleaning in an identical
process (same intermediate and same
API ) . Change in the early stage of
another process
Not required
LEVEL - 1 Changeover between intermediate of
one product to final intermediate of
another product. Changes in early steps
to intermediate of another product
( API to intermediate )
Required but not necessary
LEVEL - 2 Changeover from one API to another
API. Changeover any intermediate to
any API. Changeover from early step to
final step of same product
Essential

13. • Level of cleaning differ from each
other in the following aspects
Level – 0 Level – 1 Level – 2
RISK Lowest Moderate Highest
ACCEPTANCE
LIMIT
Highest Moderate Lowest
DEGREE OF
CLEANING
Less extensive More extensive Much extensive
VERIFICATION
OF CLEANING
Visual
inspection
Not required Analytical testing
required

14. ELEMENTS OF CLEANING VALIDATION
 Establishment of acceptance criteria
 Product , equipment , facilities to be clean
 Cleaning agents
 Cleaning procedure
 Cleaning mechanism
 Sampling
 Analytical methods
 Establishment of limits
 Documentation
 Validation report

15. • Acceptance criteria
CHEMICAL DETERMINATION
• Limiting the level on toxicity data
• Pharmacological dose method
NMT 1/1000 of residue present in the next
product run in equipment
• Limiting the level of product appear in another
product
upto 0.1% of unknown material may be present
in the product being tested
PHYSICAL DETERMINATION
visual examination of equipment
MICROBIOLOGICAL DETERMINATION

16. Types of cleaning agents
• Detergents

17. – Surfactants
• Anionic and Non-ionic: used as components for
detergent
• Cationic and amphoteric: used in the formulations of
disinfectants for their microcidal e effect
– Complexing agents – complexing with minerals and
inorganic components
– Sequestering agent – EDTA
– Anti foaming agents:- mineral oil , vegetable oli
– Oxidizing agents –H2O2
– Corrosion inhibitors - Silicates

18. Cleaning validation process
It mainly include 4 stages
Stage 1 :-
Determine the most appropriate cleaning
procedure for the equipment
Develop and validate the sampling and chosen
analytical method for the compound being cleaned
Evaluate equipment surface and determine

19. Stage 2 :-
Develop a cleaning validation protocol
for the product and equipment being
cleaned
Stage 3 :-
Generate interim(time) cleaning
validation report on a clean by clean
basis
Stage 4 :-
Generate a cleaning validation report
detailing the acceptability of cleaning
procedure for the product and equipment

20. Cleaning mechanism
• Mechanism totally depends on selection of
cleaning agents and type of residue to be cleaned
• Method involved in cleaning of residue are
Dissolution
Saponification
Wetting agents
Emulsifying agents
Dissolution
mechanism involved is solubility
of residue in cleaning agents.
eg:- SLS , chelating agents etc

21. • Saponification
• mechanism involved is breakage
• of ester bond in fat residue to
• form fatty acid and glycerol which
• is soluble in water.
• eg ;- NAOH, KOH etc
• Wetting agents
• mechanism involved is lower the
• surface tension of cleaning solution
• so that it can easily penetrate in to
• residue
• eg ;- surfactants

22. Sampling methods
• Equipment should normally be cleaned as soon
as possible after use
• This may be especially important for operation
with topical products, suspensions where the
drying residue will directly effect the efficiency of a
cleaning procedure
Two methods of sampling
1.Swab 2.Rinse
Swabbing method
This method of sampling is the
most commonly used and involved taking an inert
material (eg:-cotton wool) on the end of the
probe(referred as swab) and rubbing it methodically
across the surface

23. The swab are added with dilution solvent and these
solvent were analysed by suitable analytical
instruments for the presence of residue of previous
products
Advantages Disadvantages
Dissolve and physically remove
sample
Adaptable to wide variety of
surfaces
May allow sampling of a defined
area
Applicable to active, microbial and
cleaning agent residue
An invasive technique that may
introduce fibre
Complex and hard to reach areas
difficult

24. • Rinse sampling
A measured area of a cleaned surface is rinsed or
solvent washed and solvent is collect and test for
traces of contaminants
Advantage Disadvantage
Allow the sampling of large surface
area
Allows the sampling of unique
(poros) surfaces
Applicable for actives, cleaning
agents and excipients
Limited information about actual
surface cleanliness in some cases
Inability to detect location of
residue
Usually use for rising an entire
piece of equipment

25. Analytical method
• The analytical method should be validated before
the cleaning validation is performed
• The method chosen should detect residuals or
contaminates specific for the substance being
assayed
• Validation of analytical method should include
precision
linearity
accuracy
limit of detection
limit of quantitation
ruggedness
robustness
• Method selected should be specific and sensitive

26. Specific and Non-specific methods
• A specific method detects unique compounds in the
presence of potential contaminants.
eg;- HPLC
• Non-specific methods are those methods that detect
any compound that produces a certain response
eg;- pH and conductivity.
• Others
1. Thin layer chromatography (TLC): TLC is widely used
for the qualitative determination of surfactants.
2. Atomic absorption spectroscopy (AAS): AAS is used
for the determination of inorganic contaminants.
3. Bioluminescence: It is useful for biologicals

27. Establishing acceptable limit
• The acceptance limit established for contaminant
levels in the sample should be practical ,
achievable and verifiable
• NMT 10 ppm of any product will appear in other
product
• NMT 0.1% therapeutic dose of any product will
appear in the maximum daily dose of the following
product
• No quantity of residue should be visible on the
equipment after cleaning procedure are
performed
• For certain allergenic ingredients the limit should
be below the limit of detection

28. DOCUMENTATION
– The cleaning process should be
documented in an SOP
– Documentation should be in such a way
that the following Information is readily
available:
– The area or piece of equipment cleaned
– The person who carried out the cleaning
– When the cleaning was carried out
– The SOP defining the cleaning process
– The product, which was previously
processed on the equipment being
cleaned

29. VALIDATION REPORT
A validation report is necessary to present
the results and conclusions and secure approval of the
study.
The report should include the following,
 Summary of procedures used to clean , sample and
test.
 Physical and analytical test results or references.
 Conclusions regarding the acceptability of the results.
 Revalidation practices if applicable.
 Approval of conclusions.
 Review any deviations for the protocol that occurred

30. Revalidation
Revalidation of the cleaning process is to be done if
 Cleaning procedure is changed
 Raw material are changed
 Change in formulation
 New detergents
 Modification of equipment
Cleaning process validation should be checked at
regular intervals

31. CONCLUSION
• Clean environment and clean operations is the
heart of pharmaceutical activities.
• Four basic requirements of cGMP are safety,
identity, strength and purity which can be
achieved by cleaning process and its proper
validation

32. References
 S.W. Harder, ‘The validation of cleaning
processes’, pharmaceutical technology.(1984)
 James Agalloco, ‘Points to consider in the
validation of equipment cleaning procedures’,
Journal of parenteral science and technology.
(October 20
 Richard J.Forsyth; Equipment Hold Time for Cleaning
Validation: Time to come cleans for a dirty little secret;
Pharma Times Vol 40 No 6, June 2008; Page No: 15-
18.
 Manohar A. Potdar: pharmaceutical quality assurance:
cleaning validation: page no: 8.22 – 8.28 08)