CLEANING VALIDATION
Presented by
G.Vinay jain
M.Pharmacy 1st year 2nd sem
Department of Pharmaceutical analysis and QA
Malla reddy college of pharmacy
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
Types of validation Analytical validation Process validation
Software validation Cleaning validation
CLEANING
VALIDATION
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
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
Cleaning technique
Aqueouscleaning
Solvent cleaning
Manual cleaning
Ultrasonic cleaning
Extraction
Vapour degreasing
Ultrasonic cleaning
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.
Vapour degreasing Extraction
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.
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
• 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
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
• Acceptance criteriaCHEMICAL 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
Types of cleaning agents
• Detergents
– 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
Cleaning validation process
It mainly include 4 stagesStage 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
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
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
• 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
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
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 sampleAdaptable to wide variety of surfacesMay allow sampling of a defined areaApplicable to active, microbial and cleaning agent residue
An invasive technique that may introduce fibreComplex and hard to reach areas difficult
• 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
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
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
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
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
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
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
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
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)