Cleaning validation strategy & regulations

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CLEANING VALIDATION
STRATEGY & REGULATORY
Requirements

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 What is Cleaning validation
 Purpose of the Cleaning validation
 How to do Cleaning validation
 Compliance with GMP & other Regulatory requirements
CLEANING VALIDATION

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What is Cleaning validation
The process of providing “Documented evidence that the cleaning methods
employed within a facility consistently controls potential carryover of product,
cleaning agents and extraneous material into subsequent product to a level
which is below predetermined acceptance criteria”.
IMPORTANCE :
 Heart of pharmaceutical activity
 Related to safety and purity of the products

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Purpose of Cleaning validation
It is necessary to Validate Cleaning procedures for the following
reasons:
a. It is a customer requirement - it ensures the safety and purity
of the product.
b. It is a regulatory requirement in Active Pharmaceutical
Ingredient & formulation product manufacture.
c. It also assures from an internal control and compliance point
of view the quality of the process.

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How to do Cleaning validation
Cleaning Validation - Requirements
• Development of Cleaning Process
• Assessment for selection of Marker compound
• Determination of Acceptance Criteria
• Validated Analytical methods for detection of marker
compound
• Cleaning Validation Protocol
• Sampling Procedure
• Cleaning Validation Report

Development of Cleaning
process

Possible contaminants
 Product residues
 Cleaning agent residues and breakdown
 Airborne matter
 Lubricants, ancillary material
 Decomposition residues
 Bacteria, mould and pyrogens
Development of cleaning Process

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Cleaning Process
Aqueous
cleaning
Solvent
cleaning
Manual cleaning
Ultrasonic
cleaning
Vapour
degreasing
Ultrasonic
cleaning

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Ultrasonic cleaning
 An ultrasonic cleaning is a process that)
uses Ultrasound (usually from 20–
400 kHz) and an appropriate cleaning
solvent (sometimes ordinary tap water)
to clean items. The ultrasound can be
used with just water, but use of a solvent
appropriate for the item to be cleaned
along with the soiling enhances the
effect.
 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 vapor bubbles.
 Subsequently, these cavitation bubbles
implodes releasing tremendous energy.
Extreme temperature combined with
high velocity jets provides the cleaning
action.

Levels of cleaning (Ref APIC guidline)
The degree or level of cleaning and validation required for
cleaning processes in Active Pharmaceutical Ingredient
(API) & Formulation manufacturing depends largely on:
 The equipment usage (i.e. dedicated equipment or not)
 The stage of manufacture (early, intermediate or final
step)
 The nature of the potential contaminants (toxicity,
solubility etc.)

LEVELS ATTRIBUTES CLEANING VALIDATION
LEVEL - 0 Batch to batch cleaning in an identical
process (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
LEVEL - 2 Changeover from one API to another 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
VERIFICATION
OF CLEANING
Visual inspection Not required Analytical testing
required

When the cleaning process is considered
and developed?

Cleaning Process shall be considered during design
qualification of processing equipment to ensure the
implementation of effective and efficient cleaning
processes of equipment
Document the following requirements:
 Cleaning cycle requirements: including the different types of
utilities (e.g. cold water, WFI, compressed air), selected
cleaning agent including concentrations, operating
temperatures and pressures (flow) of utilities, maximum
duration of the cleaning cycle etc.
 Sampling requirements for qualification and validation
activities.

Assessment for selection of
Marker compound

Assessment for selection of Marker compound
Marker compound:
It is a high contamination risk compound for patient safety
which is identified based on worst case scenario of the products
and governs the cleaning validation activity.
The risk assessment for prioritization and selection of marker
compound for the cleaning validation activity is documented
based on the following criteria:
 Toxicity of active materials
 Solubility of active materials
 Colouring agents
 ‘Difficult to clean’ active materials

Toxicity of Active Materials (Criteria-1):
Active materials with the lowest recommended therapeutic dose and with the
highest toxicity effects, based on Pharmacopeial recommendations are likely to
have high contamination risk to patient safety.
Table: Toxicology Data -Lethal Dose (mg/kg)
S No. Included descriptive terms
Probable oral lethal dose
(mg/kg)
1 Practically nontoxic Slightly toxic >15 000
5 000 - 15 000
2 Moderately toxic 500 - 5 000
3 Very toxic 50 - 500
4 Extremely toxic 5 - 50
5 Supertoxic <5

Solubility of Active Materials (Criteria-2):
A solubility-rating is performed based on the solubilities of the API substances in
water used for cleaning. The United States Pharmacopeia (USP) describes the solubility of
drugs as parts of water required for one part solute. The solubility criteria for materials
soluble in water is listed in below Table
Table-Solubility criteria with respect to water (As per USP-29 NF 24)
Description form
(Solubility definition)
Parts of water required for one
part of solute
Solubility range
(mg/mL)
Very soluble (VS) < 1 > 1000
Freely soluble (FS) from 1 to 10 100 – 1000
Soluble from 10 to 30 33 – 100
Sparingly soluble (SPS) from 30 to 100 10 – 33
Slightly soluble (SS) from 100 to 1000 1 – 10
Very slightly soluble (VSS) from 1000 to 10000 0.1 – 1
Practically insoluble(PI) > 10000 < 0.1

Colouring agents (Criteria-3):
Risk of colouring agents should be assessed based on the
flavour ingredient concentration and colouring
characteristics for darkness, during visual inspection
of product contact parts by using lint free cloth.

Difficult To Clean Active Materials (Criteria-4):
One criterion which can be used is the ability to clean a substance
due to its solubility in water . Based on the solubility, Difficult-
to-clean substances are identified and the difficulty of cleaning
could be rated according to the three categories suggested below,
Category:
Easy
Medium
Difficult

DETERMINATION OF
ACCEPTANCE CRITERIA

Determination of Acceptance criteria
Acceptance Criteria for chemical residue can be determined in
the following ways :
 Visual Inspection (Visually clean)
 MACO limit Based on Therapeutic Daily Dose, NMT 0.1 % of
therapeutic dose
 MACO limit Based on toxicology Data,
 General Limit (10 ppm) criteria

Visually Inspection:
A visual check for cleanliness is an important part of the
acceptance criteria for cleaning validation.
A lint-free cloth will be used to wipe the equipment parts for
visual inspection to verify the effectiveness of the cleaning
process. This will be done after the machine parts have been
cleaned and oven-dried. The visual inspection should not be
done before the machine parts have completely dried as
sometimes a thin layer of water remaining on the surfaces of
the equipment parts might make residues difficult to detect.

MACO limit Based on Therapeutic Daily Dose:
The principle for the requirement is that the standard Therapeutic Daily Dose (TDD) of the
following substance (contaminated. substance, in this case called "next") may be
contaminated by no more than a certain proportion (usually 1/1000 part) of the TDD of the
substance investigated in the cleaning validation (contaminating substance, in this case called
"previous").
Procedure
Establish the limit for Maximum Allowable Carryover (MACO) according to the following
equation.
Min TDDprevious x MBS
MACO = ------------------------------
SF x Max TDDnext
 MACO Maximum Allowable Carryover: acceptable transferred amount from the contaminant product ("previous")
 TDD previous Standard therapeutic dose of the contaminant product (in the same dosage form as TDDnext)
 TDD next Standard therapeutic dose of the daily dose for the next product
 MBS Minimum batch size for the next product(s) (where MACO can end up)
 SF Safety factor (normally 1000 is used in calculations based on TDD)

Example: MACO based on therapeutic dose
Product A will be cleaned out. The product has a standard daily dose of 10 mg and
the batch size is 200 kg. The next product B has standard a daily dose of 250 mg and
the batch size is 50 kg. Both A and B are administrated orally and SF is set to 1000.
Calculate the MACO for A in B!
10 (mg) x 50 000 000 (mg)
MACO = ------------------------------------ = 2 000 (mg)
1000 x 250 (mg)
Result: MACO is 2 g (2000 mg), i.e 2 g of Product A is allolable to carryover into
product B

MACO Limit Based on Toxicological Data:
In cases in which a therapeutic dose is not known (e.g. for intermediates and detergents), toxicity data may
be used for calculating MACO.
Procedure
Calculate the so called NOEL number (No Observable Effect Level) according to the following equation and
use the result for the establishment of MACO.
LD50 (g/kg) x 70 (kg a person)
NOEL = -----------------------------------------
2000
From the NOEL number a MACO can then be calculated according to:
NOEL x MBS
MACO = ------------------------------
SF x TDDnext
 MACO Maximum Allowable Carryover: acceptable transferred amount from theinvestigated product ("previous")
 NOEL No Observed Effect Level
 LD50 Lethal Dose 50 in g/kg animal. The identification of the animal (mouse,rat etc.) and the way of entry (IV, oral etc.) is
important.
 70 kg is the weight of an average adult
 2000 is an empirical constant
 TDD next Largest normal daily dose for the next product
 MBS Minimum batch size for the next product(s) (where MACO can end up)
 SF Safety factor

General Limit (10 ppm) criteria:
A general upper limit for the maximum concentration of a contaminating
substance in a subsequent batch (MAXCONC) is often set to 10 ppm and 10
ppm in APIs is very frequent
Establish MACOppm, based on a general limit, using the following equations.
MACOppm = MAXCONC x MBS
E.g. For a general limit of 10 ppm: MACO = 0.001% of the minimum batch
size (MBS).

Swab & Rinse Limits
Swab Limit per surface:
Limit per Surface (LS) = MACO x swab surface area
--------------------------------------- mg/swab
TSS x swab recovery rate
Rinse Limit for rinse Sample for an equipment
Limit per Rinse Sample (LRS) =
MACO x Surface of the equipment
---------------------------------------------- mg/ml
TSS x Final rinse volume

Validated Analytical methods for
detection of marker compound

Analytical method Validation
 Validate analytical method
The validation of an analytical method should occur in compliance with pre
established acceptance criteria.
 Must be sensitive assay procedure
 HPLC, GC, HPTLC
 TOC
 pH
 conductivity
 UV
Parameters evaluated as apart of acceptance criteria for
analytical method validation are given in the below table:

Cleaning validation protocol
Should include :
 Objective of the validation and identification of the process
 Responsibility for performing and approving validation study
 Description of equipment to be used
 Status of equipment (qualified, calibrated according to the
maintenance program etc.) used in the process to be validated
 Status of utilities (water, gases etc.) needed during the validation
 Responsibilities of personnel in the validation process
 Training of personnel responsible for the process and personnel
operating with the process
 Status of the SOPs concerning the cleaning and other related
activities

Cleaning Validation Protocol
Should include :
 Dirty hold Time & Clean Hold Time (DHT & CHT) Interval between end of
production and cleaning, and commencement of cleaning procedure
 Cleaning procedures to be used
 Any routine monitoring equipment used
 Number of cleaning cycles performed consecutively
 Sampling procedures used and rationale
 Sampling locations (clearly defined) and the defined area size
 Data on recovery studies
 Validated Analytical methods
 Acceptance criteria and rationale
 When revalidation will be required

Sampling Procedure
How to sample
 Swab
 Rinse fluid
 The sample transport and storage conditions
should be defined

Sampling Procedure
Swab samples
 Direct sampling method
 Document swab locations
 The swab are added with dilution solvent and these solvent were analysed
by suitable analytical instruments for the presence of residue of previous
products
 Disadvantages
 inability to access some areas
 assumes uniformity of contamination surface
 must extrapolate sample area to whole surface

Sampling Procedure
Rinse samples
 Basic principle: to be used only to support other sampling methods, however may
be used in …
 Indirect method
 Combine with swabs
 Sample very large surface areas
 Usually use for rising an entire piece of equipment
 A measured area of a cleaned surface is rinsed or solvent washed and solvent is
collect and test for traces of contaminants

Cleaning validation Report
Results and reports
 Cleaning record signed by operator, checked by production and reviewed
by QA
 Analysis results for chemical and Microbial testing
 Final Validation Reports, including conclusions
 Statement if there were any changes to the validation protocol
 Clear statement if the validation results meet the criteria stated in the validation
protocol
 Approval/rejection as described in SOP and/or validation protocol

Good Manufacturing Practices &
other Regulatory requirements
for cleaning validation

Cleaning Validation is Extremely important, specific and are the requirements
established by regulatory agencies such as the US Food and Drug
Administration (FDA), the European Medicinal Evaluation Agency (EMEA),
Australia's Therapeutic Goods Administration (TGA), etc. For example, the
2004 Code of Federal Regulations (CFR) Title 21, Volume 4, Section 211.67,
states:
 21 CFR 211.67 Equipment cleaning and maintenance
Equipment and utensils shall be cleaned, maintained and sanitized at
appropriate intervals to prevent contamination that would alter the safety,
identity, strength, quality or purity of the drug product.
 ICH Q7, cGMP, Section 12.7, Cleaning Validation
Cleaning procedures should normally be validated. In general, cleaning
validation should be directed to situations or process steps where
contamination or carryover of materials poses the greatest risk to API quality.

Thank You
Presented by:
Jahnavi KV
Sr. Validation & Process Engineer

Cleaning validation strategy & regulations

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