Total Slides: 40

Prepared by: Sambhujyoti Das, Quality Assurance

CLEANING VALIDATIONA NEW RISK INTEGRATED APPROACH

CONTENT:

Slide No.: 02 of 40

• 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.

DEFINITION:

The process of removing contaminants from process equipment and monitoring thecondition of equipment such that the equipment can be safely used for subsequentproduct manufacturing.

Slide No.: 02 of 40

Dustin A. Leblanc.

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.

Slide No.: 04 of 40

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.

Slide No.: 05 of 40

RISK BASED CLEANING ACCEPTANCE LIMIT:

• “Permitted Daily Exposure” determination method:

PDE = 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).

Slide No.: 06 of 40

RISK BASED CLEANING ACCEPTANCE LIMIT:

• “Acceptable Daily Exposure” determination method:

ADE =

Where,

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.

Slide No.: 07 of 40

RISK BASED CLEANING ACCEPTANCE LIMIT:

• In other way……..

ADE =

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.).

Slide No.: 08 of 40

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

Slide No.: 09 of 40

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.

If NOAEL data is present on Rat, 5 shall be placed on F1 position in the equation.Slide No.: 10 of 40

Value From To5 Rats

Humans

12 Mice2 Dogs

2.5 Rabbits3 Monkeys10 Other animals

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.

Slide No.: 11 of 40

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.

Slide No.: 12 of 40

ValueStudy duration in Rodents(i.e. Rats, Mice & Mouse)

Study duration in non-rodents(i.e. Rabbits, Cats, Dogs, Monkeys)

1 1 year (also in Rabbits) 7 years2 6 months 3.5 years 5 3 months 2 years10 For shorter duration i.e. less than 4 weeks1 Reproductive study in which whole period of organogenesis is covered.

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.

Slide No.: 13 of 40

Value Reproductive toxicity condition

1 Fetal toxicity associated with Maternal toxicity.

5 Fetal toxicity without Maternal toxicity.

5 Teratogenicity with Maternal toxicity.

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.

Slide No.: 14 of 40

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

MAC =

Where,

BS = Batch size (Drug Product B)

LRDD = Largest Recommended Daily Dose (Drug Product B)

Slide No.: 15 of 40

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

LS =

Where,

SA = Swab sampling area

SESA = Shared Equipment Surface Area (Cumulative contact area of entire equipment train)

Slide No.: 16 of 40

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

MSDS from valid source is desirable.

Adequacy of information.

Consistency in illustrated data.

Comparable with Toxicity databases (e.g. IRIS, CPDB, DART, etc.).

Slide No.: 17 of 40

General Information

MSDS data available on internet could be partially or entirely wrong.

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

The first section of MSDS consists of Name of company, Name of substance and it’s unique Chemical Abstracts Service number.

Here (hypothetical example),

Name of company is ABC Inc.

Name of substance is Cupcake

CAS Number is 590332-67-9

Slide No.: 18 of 40

Material Safety Data SheetSECTION 1: IDENTIFICATION OF THE SUBSTANCE AND COMPANY/UNDERTAKING

Version No. 2.1Date of Rev. 15/01/2016

Name of Company ABC Inc. Emergency Contact No.

Address #504 West Celadon, 20nd LaneKarnataka, India 560 064 1-800-429-1000

Contact details +91 (0)2345 8871

Material Name Cupcake

CAS No. 590332-67-9

SECTION 2: HAZARD IDENTIFICATION

Hazard Class Category Hazard statement

Skin irritation 2 H315

EXAMPLE FOR DERIVING ACCEPTANCE LIMIT:The second section of MSDS consists of Hazard class information.

Here (hypothetical example), the substance is having potential reproductive toxicity.

Slide No.: 19 of 40

SECTION 2: HAZARD IDENTIFICATION

Hazard Class Category Hazard statement

Skin irritation 2 H315

Reproductive toxicity 1A H360

Acute aquatic toxicity 3 H402

Chronic aquatic toxicity 3 H412

Signal word : Danger

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

EXAMPLE FOR DERIVING ACCEPTANCE LIMIT: Sections like First Aid Measures, Fire

Fighting Measures, Handling and Storage, etc. are irrelevant here.

Here Section 11: Toxicological Information is of prime interest.

Slide No.: 20 of 40

Cupcake

SECTION 11: TOXICOLOGICAL INFORMATION

Version No. 2.1Date of Rev. 15/01/2016

General Information The information included in this section describes the potential hazards of the substance..

Acute Toxicity: (Species, Route, End Point, Dose)

Rat Oral LD50 2750 mg/kg, Mouse Oral LD50 2830 mg/kg, Rat Intravenous LD50 990 mg/kg, Dog Intravenous LD50 250 mg/kg.

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).

EXAMPLE FOR DERIVING ACCEPTANCE LIMIT:Here, all toxicity data is available on Rat. Hence,

Species Extrapolation Factor (F1):

Factor value = for Rat to Human.

Repeat Dose Toxicity Factor (F3):

Factor value = on 1 year data.

Severe Toxicity Study Factor (F4):

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

5

1

5Factor value = for Fetal toxicity without Maternal toxicity, Non-teratogenic.

EXAMPLE FOR DERIVING ACCEPTANCE LIMIT: Database Incompleteness Factor

(F5):

Factor value = 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. 2.1Date 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)

1

HAZARDS ASSESSMENT:

Slide No.: 23 of 40

YES NO UNKNOWN

Genotoxicant Reproductive developmental toxicant Carcinogen Highly sensitizing potential

CLINICAL ASSESSMENT:

• The clinical data is insufficient on sick population, hence the Modifying Factor(MF) is to be .

• The bioavailability data is available on desirable oral route, hence thePharmacokinetic Factor (PK) is to be .

Slide No.: 24 of 40

10

1

ADE =

= 8.6 mg.

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

Slide No.: 25 of 40

DETERMINATION OF ADE VALUE:

Slide No.: 26 of 40

CONVERSION FROM ADE TO MAC:

MAC = .

= 286667 mg.

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.

DETERMINATION OF FINAL ACCEPTANCE LIMIT:

LS =

= 14.98 mg./swab

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.

Slide No.: 28 of 40

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 VRLand ARL)

Slide No.: 30 of 40

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 HighADE > 10 µg & < 100 µg 5 MediumADE ≥ 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 HighVery slightly soluble (1000 - 10000) 8

MediumSlightly soluble (100 - 1000) 5Soluble / Sparingly soluble (10 - 100) 3

LowVery 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 HighAcc. Limit ≥ ARL but ≤ VRL 3 MediumAcc. 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 HighFrom 25 to 100 MediumLess 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.

Slide No.: 35 of 40

Sr. No.

Name of ProductActive Moiety

Pre-assessmentMitigation Strategy

Post-assessment

Severity Occurrence Detection RPN Severity Occurrence Detection RPN

1 Cupcake Tablets 10 mg Mango 1 3 1 3 Not required 1 3 1 3

2 Donut Capsules 12.5 mg Banana 1 10 3 30 Not required 1 10 3 30

3 Eclair Capsules 1 mg Strawberry 10 10 3 300 Detergent shall be used for cleaning 10 3 3 90

4 Froyo Tablets 5 mg Pineapple 5 5 5 125More sensitive analytical method to be used

5 5 3 75

5 Gingerbread Tablets 2 mg Orange 10 10 3 300

Solubility enhancement not possible

10 10 3 300

Slide No.: 36 of 40

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 productmanufacturing.

• 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

FATE OF THE EARLIER APPROACHES:

Slide No.: 38 of 40

EU TIMELINE:

TIME’S UP

COMING UP

COMING UP

Resources:

Slide No.: 39 of 40

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.

Slide No.: 40 of 40

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Sambhujyoti Das, Quality Assurance