Prepared by: Sambhujyoti Das, Quality Assurance

CLEANING VALIDATION
A NEW RISK INTEGRATED APPROACH

Total Slides: 40
 CONTENT:
• Definition of Cleaning Validation • Clinical Assessment

• What’s new? • Risk Assessment

• Why risk based approach is required? • Product selection criteria

• Risk based cleaning acceptance limit. • Fate of earlier approaches.

• Example for deriving acceptance limit • EU Timeline

• Hazard Assessment • Resources.

Slide No.: 02 of 40
 DEFINITION:

The process of removing contaminants from process equipment and monitoring the
condition of equipment such that the equipment can be safely used for subsequent
product manufacturing.

Dustin A. Leblanc.

Slide No.: 02 of 40
 WHAT’S NEW:

• ICH guideline on residual solvent.

• ISPE proposal on ADE in it’s Risk MaPP guideline.
• PDA reference on Technical report number 29.
• Adoption by EU.
• EU timeline on PDE strategy implementation.

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 WHY RISK BASED APPROACH IS REQUIRED?

• Single expression on quantitative health risk.

• Covering all parameters of health related risk.
• Universally accepted method.
• Useful for considering facility design and containments, level of personnel
protection required.

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
• “Permitted Daily Exposure” determination method:
NOAEL × Weight adjustment
PDE = F1 × F2 × F3 × F4 × F5 Where,

NOAEL = No Observable Adverse Effect Level,

F1 = Extrapolation between species (2-12),
F2 = Inter-individual variability (10),
F3 = Repeat dose toxicity studies of short duration (1-10),
F4 = Severe toxicity in reproductive toxicity studies (1-10),
F5 = Availability of NOAEL or LOAEL (10).

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
• “Acceptable Daily Exposure” determination method:

NOAEL × BW
ADE = UF × MF × PK Where,
C

BW = Body weight of patient taking next product (50 Kg),

UFC = A composite Uncertainty factors (F1 × F2 × F3 × F4 × F5),
MF = Modifying factor (1 or 10),
PK = Pharmacokinetic factor.

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
• In other way……..
PDE × BW
ADE =
MF × PK

Modifying Factor (MF):

 Extrapolation to sick population is required when clinical data is available on healthy
population only.
 Factor value 10 is assigned (for conversion), otherwise assign 1.
 The factor value can be assigned for product with high toxicity (i.e. teratogenicity,
genotoxicity, carcinogenicity, etc.).

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
Pharmacokinetic Factor (PK):
 Pharmacokinetic correction factor from route to route extrapolation.
 Applicable only when route specific bioavailability differs significantly, i.e. difference >
40%.
 If there is no bioavailability data available for concerned route, 100% respirable
absorption shall be considered as default and following Correction Factor to be derived.

For Example:
Correction Factor (oral to inhalation) = % oral absorption / 100% respirable absorption

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
Factor #1 (F1): Species Extrapolation Factor.
 The factor to account for extrapolation between species.
 Factor value varies from 2 to 12.

Value From To
5 Rats
12 Mice
2 Dogs
Humans
2.5 Rabbits
3 Monkeys
10 Other animals

 If NOAEL data is present on Rat, 5 shall be placed on F1 position in the equation.

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
Factor #2 (F2): Individual Variability Factor.
 A factor of 10 to account for variability between individuals.
 10 is used consistently.
 By default, 10 to be entered at the place of F2 in the equation.

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
Factor #3 (F3): Repeat Dose Toxicity Study Factor.
 The duration of toxicity study is considered.
 Lesser duration – Higher the factor value, Longer duration – Lower the factor value.
 Factor value varies from 1 to 10.
Study duration in Rodents Study duration in non-rodents
Value
(i.e. Rats, Mice & Mouse) (i.e. Rabbits, Cats, Dogs, Monkeys)
1 1 year (also in Rabbits) 7 years
2 6 months 3.5 years
5 3 months 2 years
10 For shorter duration i.e. less than 4 weeks
1 Reproductive study in which whole period of organogenesis is covered.

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
Factor #4 (F4): Severe Toxicity Study Factor.
 This factor that may be applied in cases of severe toxicity.
 Toxicities like non-genotoxic carcinogenicity, neurotoxicity or teratogenicity come under
severe toxicity.
 Factor value varies from 1 to 10 depending on the level of reproductive toxicity is
associated with or without maternal toxicity.
Value Reproductive toxicity condition
1 Fetal toxicity associated with Maternal toxicity.
5 Fetal toxicity without Maternal toxicity.
5 Teratogenicity with Maternal toxicity.
Slide No.: 13 of 40 10 Teratogenicity without Maternal toxicity.
 RISK BASED CLEANING ACCEPTANCE LIMIT:
Factor #5 (F5): Database Incompleteness Factor.
 This factor may be applied if the no-effect level (NOAEL value is absent) was not
established.
 When only an LOEL is available, factor value shall be 10.
 Severity of the toxicity should be considered while assigning
factor value.

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
Determination of MAC (Maximum Allowable Carryover) of Product A (Previous
product) to Product B (Next product).

ADE A × BS (B)
MAC =
LRDD (B)
Where,
BS = Batch size (Drug Product B)
LRDD = Largest Recommended Daily Dose (Drug Product B)

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 RISK BASED CLEANING ACCEPTANCE LIMIT:
Determination of Final Acceptance Criteria for swab sample (LS).

MAC × SA
LS =
SESA
Where,
SA = Swab sampling area
SESA = Shared Equipment Surface Area (Cumulative contact area of entire equipment
train)

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 EXAMPLE FOR DERIVING ACCEPTANCE LIMIT:
Let’s start with MSDS…….. General
Informatio
n

 MSDS from valid source is desirable.

 Adequacy of information.
 Consistency in illustrated data.
 Comparable with Toxicity databases (e.g. IRIS, CPDB,
DART, etc.).
MSDS data available on internet could be
partially or entirely wrong.

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 EXAMPLE FOR DERIVING ACCEPTANCE LIMIT:
Let’s start with MSDS…….. Material Safety Data Sheet Version No. 2.1
Date of Rev. 15/01/2016

SECTION 1: IDENTIFICATION OF THE SUBSTANCE AND COMPANY/UNDERTAKING

The first section of MSDS consists of Name of Company ABC Inc. Emergency Contact No.

Name of company, Name of substance and it’s Address

#504 West Celadon, 20nd Lane
Karnataka, India 560 064
1-800-429-1000

unique Chemical Abstracts Service number. Contact details +91 (0)2345 8871

Material Name Cupcake

Here (hypothetical example), CAS No. 590332-67-9

SECTION 2: HAZARD IDENTIFICATION

 Name of company is ABC Inc. Hazard Class Category Hazard statement

Skin irritation 2 H315

 Name of substance is Cupcake
 CAS Number is 590332-67-9

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 EXAMPLE FOR DERIVING ACCEPTANCE LIMIT:
The second section of MSDS consists of SECTION 2: HAZARD IDENTIFICATION

Hazard class information.

Hazard Class Category Hazard statement

Skin irritation 2 H315

Reproductive toxicity 1A H360

Here (hypothetical example), the Acute aquatic toxicity 3 H402

substance is having potential reproductive Chronic aquatic toxicity 3 H412

Signal word : Danger

toxicity. Hazard statements

H315 : Causes skin irritation.

H360 : May damage the unborn child.
H402 : Harmful to aquatic life.
H412 : Harmful to aquatic life with long lasting effects.

Page 01 0f 07

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 EXAMPLE FOR DERIVING ACCEPTANCE LIMIT:
 Sections like First Aid Measures, Fire Cupcake Version No. 2.1
Date of Rev. 15/01/2016

Fighting Measures, Handling and Storage, SECTION 11: TOXICOLOGICAL INFORMATION

etc. are irrelevant here.

The information included in this section describes the potential
General Information
hazards of the substance..
Acute Toxicity: (Species, Route, End Point, Dose)

 Here Section 11: Toxicological Information Rat Oral LD50 2750 mg/kg, Mouse Oral LD50 2830 mg/kg, Rat Intravenous LD50 990 mg/kg,
Dog Intravenous LD50 250 mg/kg.

is of prime interest. Acute Toxicity Comments:

A greater than symbol (>) indicates that the toxicity endpoint being tested was not
achievable at the highest dose used in the test.

Irritation / Sensitization: (Study Type, Species, Severity)

Skin Contact : Causes skin irritation.

Eye Contact : May cause eye irritation. May cause excessive watering of the eye
(lachrymation).

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 EXAMPLE FOR DERIVING ACCEPTANCE LIMIT:
Here, all toxicity data is available on Rat.
Hence,
 Species Extrapolation Factor (F1):
Factor value = 5 for Rat to Human.
 Repeat Dose Toxicity Factor (F3):
Factor value = 1 on 1 year data.
 Severe Toxicity Study Factor (F4):
Factor value = 5 for Fetal toxicity without Maternal toxicity, Non-teratogenic.
Slide No.: 21 of 40
Repeated Dose Toxicity: (Duration, Species, Route, Dose, End Point, Target Organ)
30 Day(s) Rat Oral 1 g/kg/day NOAEL Blood,
13 Week(s) Mouse Oral 12,500 ppm NOAEL Bladder,
9 Month(s) Dog Oral 50 mg/kg/day NOAEL Endocrine system,
1 Year(s) Rat Oral 2 g/kg/day NOAEL Kidney,
2 Year(s) Rat Oral 2.5 g/kg/day NOAEL Kidney.
Reproduction & Developmental Toxicity: (Study Type, Species, Route, Dose, End
Point, Effect(s)
Reproductive & Fertility Rat Oral 430 mg/kg/day NOAEL Fertility,
Embryo / Fetal Development Rat Oral 430 mg/kg/day NOAEL Not Teratogenic,
Embryo / Fetal Development Rat Oral 430 mg/kg/day LOAEL Fetotoxicity,
Embryo / Fetal Development Rabbit Oral 64 mg/kg/day LOAEL Fetotoxicity.
Genetic Toxicity: (Study Type, Cell Type/Organism, Result)
Bacterial Mutagenicity (Ames) Salmonella Negative with activation,
Chromosome Aberration Human Lymphocytes Negative,
Dominant Lethal Assay Mouse Negative.
Page 06 0f 07
 EXAMPLE FOR DERIVING ACCEPTANCE LIMIT:
 Database Incompleteness Factor
(F5):
Factor value = 1 presence of
NOAEL.
The lowest value NOAEL is considered
as 430 mg/kg/day from Reproductive and
Development toxicity studies.
Slide No.: 22 of 40
Cupcake Version No. 2.1
Date of Rev. 15/01/2016
Carcinogenicity: (Duration, Species, Route, Dose, End Point, Effect(s)
2 Year(s) Rat Oral 800 mg/kg/day NOAEL Not carcinogenic,
21 Month(s) Mouse Oral 750 mg/kg/day NOAEL Not carcinogenic.
Carcinogen Status: This substance is not listed as a carcinogen by IARC, NTP or OSHA.
SECTION 12: ECOLOGICAL INFORMATION
Harmful to aquatic life with long lasting effects. No information on this formulation. The
following information refers to Cupcake.
Toxicity : EC50 green algae 72 H biomass 22,8 mg/l
ErC50 green algae 72 H 58,3 mg/l (OECD 201)
NOEC green algae 72 H growth rate 7,5 mg/l (OECD 201)
EC50 Daphnia magna 48 H 120 mg/l (OECD 202)
NOEC Daphnia magna 48 H 30 mg/l (OECD 202)
LC50 Rainbow trout 96 H 130 mg/l (OECD 203)
NOEC Rainbow trout 96 H 32 mg/l (OECD 203)
 HAZARDS ASSESSMENT:
YES NO UNKNOWN
Genotoxicant   
Reproductive developmental toxicant   
Carcinogen   
Highly sensitizing potential   

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 CLINICAL ASSESSMENT:

• The clinical data is insufficient on sick population, hence the Modifying Factor
(MF) is to be 10 .
• The bioavailability data is available on desirable oral route, hence the
Pharmacokinetic Factor (PK) is to be 1 .

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 DETERMINATION OF ADE VALUE:

430 × 50
ADE = 5 ×10 × 1 × 5 × 1 × 10 × 1 = 8.6 mg.

Where,
NOAEL = 430 mg/kg/day.
BW = 50 Kg.
UFC = F1 = 5, F2 = 10, F3 = 1, F4 = 5 & F5 = 1
MF = 10.
PK = 1.

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 CONVERSION FROM ADE TO MAC:
8.6 × (50 × 1000 × 1000)
MAC = = 286667 mg.
(500 × 3)
Where,
ADE = 8.6 mg. for product A, i.e. Cupcake.
Batch Size = 50 kg for product B, i.e. next product (unit conversion done from Kg. to mg.)
Largest Recommended Daily Dose = 3 doses of 500 mg each for product B, i.e. next
product.

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 DETERMINATION OF FINAL ACCEPTANCE LIMIT:

286667 ×4
LS = = 14.98 mg./swab
76506
Where,
MAC = 286667 mg.
Swab area = 4 inch2.
Shared Equipment Surface Area = 76506 inch2.

Slide No.: 27 of 40
 DETERMINATION OF FINAL ACCEPTANCE LIMIT:
EU recommendations:
o A PDE Determination Strategy document
on first hand.
o A Curriculum Vitae of toxicologist
(with adequate academics and
experience) who performed
PDE/ADE determination.

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 POINTS TO BE NOTED:
 The ADE value derived acceptance limit is very high, i.e. 14.98 mg./swab which
indicates that the product is less hazardous.
 The Visual Residue Limit (VRL) of Cupcake is 8.5 µg/inch2 (hypothetical value).
 The acceptance limit for Cupcake is greater than VRL (14.98 / 4 = 3.75 mg/inch2).
Hence, the Detection level is high (Refer “Risk Assessment” section).
 The overall risk related to product Cupcake is low.

Slide No.: 29 of 40
 RISK ASSESSMENT:

Risk = Severity × Occurrence × Detection

Severity = Hazard associated with the drug substance (based on ADE value)
Occurrence = Solubility of drug product
Detection = Ability of product getting detected (based on acceptance limit vs VRL
and ARL)

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 RISK ASSESSMENT: continued……..

SEVERITY :
Categorization can be done by taking reference from TTC (Therapeutic Toxicological
Concern) criteria.
Derived ADE Value Severity Score Hazard level
ADE ≤ 10 µg 10 High
ADE > 10 µg & < 100 µg 5 Medium
ADE ≥ 100 µg 1 Low

Slide No.: 31 of 40
 RISK ASSESSMENT: continued……..

OCCURRENCE :
Categorization can be done by taking reference from official standards* on solubility.
Solubility of drug product Occurrence Score Probability level
Insoluble / Prac. insoluble (10000 <) 10 High
Very slightly soluble (1000 - 10000) 8
Medium
Slightly soluble (100 - 1000) 5
Soluble / Sparingly soluble (10 - 100) 3
Low
Very soluble / Freely soluble (<10) 1
Slide No.: 32 of 40 * USP 29
 RISK ASSESSMENT: continued……..

DETECTION :
Categorization can be done on the basis of derived acceptance limit vs Visual
Residue Limit (VRL) and Analytical Residue Limit (ARL).
Conditions Detection Score Detection level
Acc. Limit < ARL 5 High
Acc. Limit ≥ ARL but ≤ VRL 3 Medium
Acc. Limit ≥ VRL 1 Low

Slide No.: 33 of 40
 RISK ASSESSMENT: continued……..

RISK PRIORITY NUMBERING :

RPN = Severity score × Occurrence score × Detection score.

Risk Priority Number Risk level

Greater than 100 High
From 25 to 100 Medium
Less than 25 Low

Slide No.: 34 of 40
 RISK ASSESSMENT (FMEA METHOD):
Risk assessment can now be performed with the help of established risk matrix.
Sr. Active Pre-assessment Post-assessment
Name of Product Mitigation Strategy
No. Moiety Severity Occurrence Detection RPN Severity Occurrence Detection RPN

Cupcake Tablets 10
1
mg
Mango 1 3 1 3 Not required 1 3 1 3
Donut Capsules 12.5
2
mg
Banana 1 10 3 30 Not required 1 10 3 30
Detergent shall be
3 Eclair Capsules 1 mg Strawberry 10 10 3 300 used for cleaning 10 3 3 90
More sensitive
4 Froyo Tablets 5 mg Pineapple 5 5 5 125 analytical method to 5 5 3 75
be used
Solubility
Gingerbread Tablets
5
2 mg
Orange 10 10 3 300 enhancement not 10 10 3 300
possible

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 PRODUCT SELECTION CRITERIA:

 Product Risk Assessment as prerequisite.

 High Risk products to be funnelled out from entire product range.
 Cleaning validation to performed on selected products (Worst case product).
 Priority can be set based on the risk score and frequency of product
manufacturing.

Slide No.: 36 of 40
 FATE OF THE EARLIER APPROACHES:

• Therapeutic Dose Based approach / Toxicological approach (based on LD50) /

Default 10 PPM approach……………. STILL ALIVE.
• EU guidance is for “Shared Facilities” only.
• EU recommended timeline for implementation.

Slide No.: 37 of 40
 EU TIMELINE:

TIME’S
UP

COMING
UP

COMING
UP

Slide No.: 38 of 40
 Resources:
 ISPE Baseline Guide for New
and Renovated Facilities.
 APIC Guidance on aspects of
cleaning validation in active
pharmaceutical ingredient plants.
 ICH Q3C(R5) Impurities:
Guideline for residual solvents.
 PDA TR 29 (Revised 2012): Points
to consider for Cleaning
Validation.
 EMEA Guideline on setting health based
exposure limits for use in risk identification in
the manufacture of different medicinal products
in shared facilities.
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Slide No.: 40 of 40 Sambhujyoti Das, Quality Assurance