PRESENTATION ON

CLEANING VALIDATION

ByKusum ShresthaM Pharm 1st year

Kathmandu UniversityBatch 2011

INTRODUCTION Pharmaceutical products and active

pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by microorganisms, or by other materials (e.g. air borne particles, dust, raw materials).

In many cases, same equipment may be used for processing different products.

So adequate cleaning procedures are essential.

INTRODUCTION Cleaning Validation is a documented evidence that

an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products or APIs.

Objective of Cleaning Validation is the confirmation of a reliable cleaning procedure so that analytical monitoring may be omitted or reduced to a minimum in a routine phase.

Implies to validation of cleaning procedures for removal of contaminants associated with the previous products, residues of cleaning agents as well as the control of potential microbial contaminants.

GENERAL CONSIDERATIONS Normally only cleaning procedures for product contact

surfaces of the equipment need to be validated. But consideration should be given to non-contact parts into which product may migrate. For e.g. seals, fan of the oven etc

At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

Cleaning procedures for products and processes which are very similar do not need to be individually validated.

A single validation study under consideration of “worst case” can be carried out.

GENERAL CONSIDERATIONS 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.

Re-validation should be considered under following circumstances: Re-validation in cases of changes in equipment,

product or processes. Periodic Re-validation at defined intervals

DOCUMENTATIONCleaning validation protocol must include following: Objective of the validation process Responsibilities for performing and approving the validation study Description of the equipments used Cleaning procedures to be used for each product, process and

equipment Sampling procedures Clearly defined sampling locations Data on recovery studies where appropriate Acceptance criteria, including the rationale for setting the specific

limits. Analytical methods including the limit of detection and limit of

quantitation of those methods. Other product, processes, and equipment for which planned

validation is valid according to a “bracketing” concept When Re-validation will be required

DOCUMENTATION Cleaning validation protocol should be

formally approved by the Plant Management. Quality Assurance should be involved in

approval of protocols and reports. A final validation report should be prepared

stating if the cleaning process has been validated successfully.

The cleaning process should be documented in an SOP.

DOCUMENTATION Records should be kept of cleaning performed

in such a way that 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

SAMPLING Samples should be drawn according to the

cleaning validation protocol There are two methods of sampling that are

considered to be acceptable1. Direct surface sampling (Swab method)

2. Indirect sampling (Use of Rinse solutions)

ESTABLISHMENT OF LIMITS The pharmaceutical company’s rationale for

selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.

ESTABLISHMENT OF LIMITS Limit calculation for API residue can be

conducted by three ways: DOSE CRITERIA: No more than 0.1% of the

normal therapeutic dose of any product will appear in the maximum daily dose of the following product

PPM CRITERIA: No more than 10 ppm of any product will appear in another product

VISUAL CRITERIA: No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible

ESTABLISHMENT OF LIMITSSELECTION OF THE ACCEPTANCE

CRITERIA The most stringent criterion amongst above

three criteria will be considered as the acceptance criterion.

DOSE CRITERIACalculation of the maximum allowable residue

Where, MAR = Maximum Allowable Residue LHTDp = Lowest Human therapeutic dose of the previous

product BSS = Batch Size of the Subsequent Product

IFS = Intake Frequency of the Subsequent product

MDS = Mass of the dosage form of the subsequent product

MAR = 0.1% x LHTDp (mg) x BSS

(g) IFS x MDS (g)

10 PPM CRITERIACalculation of Maximum Allowable Residue

Where, MAR = Maximum Allowable Residue BSS = Batch Size of the Subsequent Product

MAR = 10 ppm (mg/kg) x BSS

(kg)

VISUAL CRITERIA Concentration above which majority of the

APIs are visible to the naked eye is to be determined first

Fourman and Mullen specified the visual limit of detection for most active pharmaceutical ingredients with 100 µg/25 cm2 i.e 4 µg/cm2

Spiking studies should be carried out to determine the visible limit

HOW TO CONDUCT SPIKING STUDIES Dilution series of the affected API are made in

solvent as volatile as possible and defined volumes applied on the marked test surface which corresponds to the sample surfaces (e.g. 25 cm2).

volatile solvent is then allowed to dry Person involved in the cleaning process, issuance

of line clearance are allowed to check for the cleanliness of the test surface

Record the readings of all the observers Identify the concentration above which all the

observers identified the test surface as dirty to determine the dividing line between visually clean and visually dirty.

HOW TO CONDUCT SPIKING STUDIES

Solution 1

Solution 2

Solution 3

Solution 4

Applied quantity of API

200 µg 150 µg 100 µg 50 µg

Test area 25 cm2 25 cm2 25 cm2 25 cm2

Volume applied 100 µl 100 µl 100 µl 100 µl

Concentration of test solution

2 mg/ml 1.5 mg/ml

1 mg/ml

0.5 mg/ml

CALCULATION OF CLEANING AGENT RESIDUES The efficiency of the cleaning procedures for

the removal of detergent residues should be evaluated.

Acceptable limit should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected.

The acceptance criteria can be formulated as: “The largest daily dose of the subsequent

product may contain as a maximum the acceptable daily quantity of the cleaning agent used”.

CALCULATION OF MAXIMUM ACCEPTABLE RESIDUEAcceptable Daily Intake (ADI)

Maximum Acceptable Carry Over (MAC)

Where,

SF = Safety factor

BSs = Batch size of the subsequent product

D = Daily dose of the subsequent product

ADI (mg) = 5 x 10-4 x LD50 [mg/kg] x 70 kg

SF

MAC (mg) = ADI (mg) x BSs (g)D (g)

HOW TO IDENTIFY WORST CASE PRODUCTS “Worst case” products refers to the most

critical products A single validation study under consideration

of the “worst case” can be carried out which drastically reduces the scope of cleaning validation

Worst case products can be considered for the validation, and not each individual product. This practice is termed “Bracketing”

BRACKETING OF PRODUCTSFIRST STEPProducts are categorized into several risk

groups on the basis of Risk factor “solubility”: product contains a poorly

soluble active pharmaceutical ingredient Risk factor “ Pharmacology” : product contains a

highly potent active pharmaceutical ingredient Risk factor “Formulation” : product contains

formulation components that are difficult to remove such as dyes, flavours etc

EXAMPLEProduct Solubility

Risk group

Pharmacology Risk group

Formulation Risk group

No risk

Limiting Criterion

API is practically insoluble

Therapeutic dose is < 100 mg

Product contains dye, flavours etc

None of the Limiting Criteria apply

A X - - -

B - X - -

C X - X -

D - - - X

E X X - -

BRACKETING OF PRODUCTSSECOND STEPThe critical or worst case products is each risk

groups must be identified. The following selection criteria may be used for this: Active pharmaceutical Ingredient content: product

has the highest active pharmaceutical content (%) in the category

Solubility: The API contained in this product has the lowest solubility in the category

Therapeutic dose: The API contained in this product has the lowest therapeutic dose in the category

EXAMPLE Solubility Risk group:

Worst case in this group are: Product A and Product E

Product Content of API

Solubility

Therapeutic dose

Worst case

A 50% Practically insoluble

500 mg Content of API, solubility

C 20% Practically insoluble

200 mg -

E 5% Practically insoluble

10 mg Solubility, therapeutic dose

EXAMPLE Pharmacology Risk group:

Worst case in this group is Product E

Product Content of API

Solubility Therapeutic dose

Worst case

B 25% soluble 50 mg -

E 5% Practically insoluble

10 mg Solubility, therapeutic dose

BRACKETING OF PRODUCTS The result of the bracketing shows that

Product A and Product E represent the worst case, taking into account the relevant criteria.

Hence the cleaning validation is carried out only for these critical markers.

If the cleaning procedure has been validated for the worst case products, this validation also applies for all other less critical products to be cleaned using the same procedure.

CONCLUSION Cleaning validation is broad topic and is

a continuous process. Criticality of effective cleaning needs to

be understood Reliable cleaning procedures need to be

developed to ensure that the product which we make to cure the disease of the patient is not creating other health related issues besides from curing the concerned disease.

THANK YOU

REFERENCES Anita Maas, Barbara Piether, Thomas

Piether, GMP Manual Good Manufacturing Practice and Implementation; November 2006, Version 1.1

Health products and Food branch inspectorate, Good Manufacturing Practices- Cleaning Validation Guidelines, Health Canada,2000.

http://pharmaceuticalvalidation.blogspot.com/2010/12/visually-clean-and-visual-limits.html