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)