CLEANING VALIDATION

Cleaning Validation Concepts

Cleaning Validation (pt.1)

- Cleaning Validation Concepts

Federica Annovazzi
Project Manager
Process Validation Division

May 17-18, 2017

Polisano Facility, Sibiu (Romania)

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Cleaning Validation Concepts

Introduction

In the following presentation the regulatory background for Cleaning Validation and the
guidelines for prevention against cross-contamination are described

EMA guideline is deeply analyzed :

«Setting health based exposure limits for the use in risk identification in the manufacture of
different medicinal products in shared facilities»

Practical example from Industry will be reviewed :

- Risk Based Decision

- High Potent Products
- Dedicated or Multipurpose Equipments
- Prevention of Cross-Contamination
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Index (1/2)
1. Relevant Guidelines

1.1 EU Rules
1.1.1 EMA Guideline
1.1.2 Eudralex - Volume 4 - Annex 15
1.1.3 Eudralex – Volume 4 – Chapter 5 (Production)
1.1.4 Eudralex - Volume 4 – Chapter 3 (Premises & Equipment)

1.2 FDA Rules

1.3 PICs /PI 006-3

2. Maximum Allowable Limits od Carry Over (MACO)

2.1 1/1000 dose criteria 2.4 LD50/50000

2.2 10ppm 2.5 PDE
2.3 Visual Clean 2.6 TTC
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Index (2/2)
3. Cleaning Validation Documents

3.1 Cleaning Validation Protocol (Including Sampling Plans)

3.2 Cleaning Validation Report

4. API Register

5. Inspection Findings
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Cleaning Validation
Is the proof of efficiency of a cleaning process.
Should be demonstrated that the potential Carry Over of:

- APIs
- Detergents Used
- Microbial Burden
Is below predefined limits
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EU Rules
. EMA Guideline «on setting health based exposure limits for the use in risk identification in the manufacture of
different medicinal products in shared facilities» (EU GMP Vol. 4 guideline Part III – Chapter 3.3.6)

. EU GMP Guideline Part I Chapter 3 and 5 and Annex 15

APIs

PICs Cleaning . EU GMP Guideline Part II «Basic

Requirements for Active Substances Used as
PI 006-3 Validation Starting Materials»
. APIC : Guidance on Aspects of Cleaning
Validation in API Plants (May2014)
.ICH Q7

FDA Rules
. CFR 211.167 – Equipment Cleaning & Maintenance
. FDA Guide to Inspection Validation of Cleaning Processes
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1.1 EU Rules

1.1.1 «Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in
the Manufacture of Different Medicinal Products in Shared Facilities»
EMA/CHMP/SWP/169430/2012

Ref. To EUDRALEX Volume 4 Chapter 3.3.6

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1.1 EU Rules

Published in 2015 (June)

- June 1, 2015 : New Requirements valid for the NEW PRODUCTS evaluated in dedicated or
multipurpose facilities for the first time

- December 1, 2015 : New Requirements valid for PRODUCTS ALREADY MANUFACTURED in

multipurpose facilities
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. EMA Guideline on «setting health based exposure limits for the use in risk identification
in the manufacture of different medicinal products in shared facilities»
(EU GMP guideline Part III – Chapter 3.3.6)

01.06.2015 28.02.2015 28.02.2015

EU GMP guideline
EU GMP guideline EU GMP guideline
ANNEX 15
Part I Chapter 5 Part I Chapter 3
«Qualification &
«Production» «Premises and Equipment»
Validation»
 CLEANING VALIDATION
Cleaning Validation Concepts

. EMA Guideline on «setting health based exposure limits for the use in risk identification
in the manufacture of different medicinal products in shared facilities»
(EU GMP guideline Part III – Chapter 3.3.6)

01.06.2015 28.02.2015 28.02.2015

EU GMP guideline
EU GMP guideline EU GMP guideline
ANNEX 15
Part I Chapter 5 Part I Chapter 3
«Qualification &
«Production» «Premises and Equipment»
Validation»
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EMA Guideline : Features

√ Scientific «case by case» approach is warranted for all classes of pharmaceutical substances

√ Toxicological evaluation for establishing treshold values for risk identification

√ Limits take in account to pharmacological and toxicological data

√ Applies to veterinary and human medicinal products and APIs

√ Permitted Daily Exposure (PDE) as described in Appendix 3 of ICH Q3 Impurities : Guidelines

for Residual Solvents (*)

√ PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an

individual is exposed at or below this dose every day for a lifetime

√ TTC : Treshold of Toxicological Concerns for genotoxic compounds

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(*)PDE values for residual solvents are published in ICH Q3 (R5)

PDE data for API limits

are currently published
only occasionally
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2.5 PDE (Permitted Daily Exposure)

«Substance Specific Dose that is unlikely to cause an adverse effect if an individual is
exposed at or below this dose every day for a lifetime»

PDE = NOAEL x Weight Adjustment [mg/day]

F1 x F2 x F3 x F4 x F5

NOAEL = No – Observed – Adverse – Effect – Level [mg/Kg/day]

Weight Adjustment = 50Kg

F1  F5 = Adjustment Factors
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PDE – Adjustment Factors (1/2)

PDE is derived by dividing the NOAEL for the critical effect by various adjustment factors :

F1 – A Factor to account for extrapolation between species

F1 = 5 (extrapolation from Rats to Human)
F1 = 12 (extrapolation from Mice to Human)
F1 = 2 (extrapolation from Dogs to Human)
F1 = 2.5 (extrapolation from Rabbits to Human)
F1 = 3 (extrapolation from Monkeys to Human)
F1 = 10 (extrapolation from other animals to Human)

F2 – A Factor of 10 to account for variability between individuals

F3 – A variable Factor to account for toxicity of short-term exposure

F3 = 1 (for studies that last at least one half lifetime (ex. 1 year for rodents or rabbits)
F3 = 1 (for reproductive studies in which whole period of organogenesis is covered)
F3 = 2 (for a 6-month study in rodents, or 3/5-year study in non-rodents )
F3 = 5 (for a 3-month study in rodents, or a 2-year study in non-rodents)
F3 = 10 (for studies of a shorter duration)
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PDE – Adjustment Factors (2/2)

F4 – A Factor that maybe applied in case of severe toxicity (e.g. non-Geno toxic carcinogenic,
neurotoxicity or teratogenicity) in studies of reproductive toxicity, the following factors are used:

F4 = 1 (for fetal toxicity associated with maternal toxicity)

F4 = 5 (for fetal toxicity without maternal toxicity)
F4 = 5 (for a teratogenic effect with material toxicity)
F4 = 10 (for a teratogenic effect without maternal toxicity)

F5 – A Variable Factor that may be applied if the no-effect level was not established. When only
a NOAEL is avaiable, a factor up to 1 could be used depending on the severity of the toxicity.

F6 – (FACULTATIVE – depends on the Toxicologist) : rating of the Data-Set used

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PDE – development & evaluation

Where can the information for PDE and NOAEL can be retrieved from?

 NOAEL : not always available (in cases of traditional drugs or standard market
authorization)

 The guideline requires an expert review

 The expert should be an experienced occupational toxicologist

 Alternative methods to evaluate PDE can be followed (OEL derived)

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PDE Data vs Previous Approach (10ppm – 1/1000)

PDE evaluations in the cleaning validation limit calculation, showed that :

 In the majority of cases the conservative acceptance criteria like 10ppm or 1/1000
were lower than PDE based limits

 Only in some cases the PDE based limits were stricter

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. EMA Guideline on «setting health based exposure limits for the use in risk identification
in the manufacture of different medicinal products in shared facilities»
(EU GMP guideline Part III – Chapter 3.3.6)

01.06.2015 28.02.2015 28.02.2015

EU GMP guideline
ANNEX 15
«Qualification &
Validation»
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1.1 EU Rules
1.1.2 Eudralex Volume 4 – Annex 15 : «Qualification & Validation»

What’s New In paragraph 10.Cleaning Validation

√ Limits for Max. Allowed Carry Over : PDE

√ Worst Case Approach : Toxicity (PDE) and Solubility should be considered
(Bracketing/Grouping for Products)
√ Visual Clean is not acceptable as sole indicator
√ Bracketing of Equipment is permitted if justified
√ Cleaning Verification for Infrequently Manufactured Products
√ Omission of 3 CV runs, number of runs can be defined based on Risk Assessment
√ Dirty Hold Time (DHT), Clean Hold Time (CHT)
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Bracketing of Equipment

Visual Clean alone not acceptable

Concurrent Cleaning Validation

Automatic /Manual Cleaning

Variable Factors

PDE / Toxicological Evaluation

Annex 15 – 1/3
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PDE – Macromolecules/Peptides

TOC

Microbial and Endotox Burden

DHT / CHT

CV in Production Campaign

Worst Case  PDE

Annex 15 – 2/3
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Sampling Location (Rationale)

Sampling Method

NO OBLIGATION FOR 3CV RUNS

Dedicated Equipment

Manual Cleaning

Annex 15 – 3/3
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. EMA Guideline on «setting health based exposure limits for the use in risk identification
in the manufacture of different medicinal products in shared facilities»
(EU GMP guideline Part III – Chapter 3.3.6)

28.02.2015

EU GMP guideline
Part I Chapter 5
«Production»
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1.1 EU Rules

1.1.3 Chapter 5 - Production

What’s New In Chapter 5

√ Pesticides and Herbicides should be handled separately

√ Robust room and Equipment Design appropriate to prevent cross contamination,
Technical and Organisational Measures (incl. Validation)
√ Potency and Toxicological evaluation should be used to assess cross contamination
√ QRM Process for Critical Parameters
 Room and Equipment design
 Personnel and Material Flow
 Physico-Chemical Characteristics
 Process Characteristics
 Cleaning Processes and Analytical Capabilities

(see next example for dedicated area)

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Prevention Of Cross-Contamination

Pesticides and Herbicides

Assess Risk of Cross Contamination

Prevent Cross Contamination by

Adequate Equipment Design

Eudralex Vol.4 : Chapter 5 / Production – 1/5

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Prevention Of Cross-Contamination

Cross Contamination
Assessment should consider
potency and toxicological
characteristics of the
contaminant

QRM  Technical and

Organisational Measures (*)

Eudralex Vol.4 : Chapter 5 / Production – 2/5

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Measures To Control Cross-Contamination

Eudralex Vol.4 : Chapter 5 / Production – 3/5

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Measures To Control Cross-Contamination

Eudralex Vol.4 : Chapter 5/Production – 4/4

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Measures To Control Cross-Contamination

The List of technical and organizational measures should be used as a check list for the
decision if it is adequate to process differents products in a multipurpose equipment

The following criteria should be used :

 Prevention of Cross-Contamination by Technical and Organizational Measures

 Allergen Potential (Sensitizing Compounds)

 Toxicology of Compounds (PDE)

 Outcome of Cleaning Validation

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Open
Systems
Kg

1 min <---------– DURATION –---------> 8h

Local
Exhaustion
<------- QUANTITY ------->

Closed
System

High
Containment

High <---------- POTENCY ---------> Mild

Mg

Powder <---- PHYSICO-CHEMICAL PROPERTIES ----> Coated

1.1.3 Chapter 5 – Production : Risk Assessment per Process Step

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Cross-Contamination Risk : Dedicated Area (example) 1/2

Process Step : Physical-Chemical Properties of Amount of API /Batch Size Duration of Process Step
Transfer of Materials API and Formulation per Day per Operator

Description Criticality Description Criticality Description Criticality

Dispensing Isolators Powder ++ Kg ++ Approx. 0.5h +

 Granulators Pure API

Granulator Granulate ++ Kg + Approx. 1h +

 tablet press Dry Blend (diluted by
excipients)

Tablet Press Tablets + Kg + Approx. 1h +

 film and sugar coating (diluted by
excipients)

Cleaning of Drums API + mg - g + Approx 1h +

Excipients

++ = very critical, + = critical, 0 = uncritical

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Cross-Contamination Risk : Dedicated Area (example) 2/2

Conclusion : Very Critical for Powder and Granulate, Critical for Uncoated Tablets

Actions : Use of specific equipments (ex. Clear Layout and pressure controls, Isolators, Closed
Containment Drums – CCDs , equipped with specific valves and special cleaning procedures)
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. EMA Guideline on «setting health based exposure limits for the use in risk identification
in the manufacture of different medicinal products in shared facilities»
(EU GMP guideline Part III – Chapter 3.3.6)

28.02.2015

EU GMP guideline
Part I Chapter 3
«Premises and Equipment»
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1.1 EU Rules

1.1.4 EU GMP Guideline Chapter 3 – Premises and Equipment (1/3)

The revision concerns only the section 3.6 as part of the improved guidance on prevention of
cross-contamination involving also Chapter 5

Current version of Section 3.6 states that the measures to prevent cross-
contamination should be commensurate with the risk, and the
principles of Quality Risk Management should be used to assess and
control the risks
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1.1.4 EU GMP Guideline Chapter 3 – Premises and Equipment (2/3)

Dedicated Facilities are required if

a) The Risk cannot be adequately controlled by Operational and/or Technical Measures

b) Scientific Data from the Toxicological Evaluation does not support a controllable risk (e.g.
allergenic potential from highly sensitising materials such as b-Lactams)

c) Relevant Residue Limits, derived from Toxicological Evaluation cannot be satisfactorily

determined by a Validated Analytical Method

In practical :

DEDICATED FACILITIES MANDATORY FOR (a) (b) (c)

ALL OTHER CASES CAN BE PRODUCED IN SHARED FACILITIES

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1.1.4 EU GMP Guideline Chapter 3 – Premises and Equipment (3/3)

Increase level of attention to classes of compounds reported into PIC/s :

a) Allergenic Ingredients

b) Penicillins, Cephalosporins (b-Lactams)

c) Potent Steroids

d) Cytotoxics
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1.2 FDA Rules - 21 CFR Part 211.167 (1/4)

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1.2 FDA Rules - 21 CFR Part 211.167 (2/4)

Equipment Cleaning (211.167) was included in the 1978 cGMP regulations

General Written Requirements :

√ Written Procedures for Cleaning

√ Written Procedures for Cleaning Validation :

- Who is Responsible
- Acceptance Criteria
- Revalidation

√ Validation Protocols

√ Validation Studies According to Validation Protocols

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1.2 FDA Rules - 21 CFR Part 211.167 (3/4)

1993 Fourman / Mullen publication(*) for Acceptance Criteria

√ 10 ppm

√ 1/1000 dose

√ Visual Clean

MEASURE CONTAMINATION  EVALUATE RESULTS

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1.2 FDA Rules - 21 CFR Part 211.167 (4/4)

Guide To Inspection Validation of Cleaning Processes (7/93) (*)
The Guide to Inspections are mainly based on the Fourman & Mullen publication :

Evaluation of Cleaning Validation

- At what point does a piece of equipment become clean?
- Does it have to be scrubbed manually?
- How variable are manual cleaning processes?
- Equipment Design (CIP, Manual Cleaning)
- Cleaning Process Written (SOP)
- Analytical Test Methods
- Sampling

Establishment of Limits
- Rationale for Residues Limits
- 10ppm
- 1/1000 dose
- No Visible Residues
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1.3 PIC/s
PI 006-3 dated 25/09/2007 that includes recomendations on :

√ Validation Master Plan

√ Installation & Operational Qualification
√ Non Sterile Process Validation
√ Cleaning Validation

The contents of the Cleaning Validation Chapter is close to FDA requirements including the
Acceptance Criteria for Maximum Carry Over (MACO) of product residues :

√ 1/1000 dose (Therapeutic Daily Dose – TDD)

√ 10ppm
√ No Residues Visible
√ Allergenic ingredients, Penicillins, Cephalosporins, or Potent Steroids and Cytotoxics
Residue < Detection Limit by best available analytical methods.
In practice this means that dedicated plants are therefore required.
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2 Maximum Allowable Limits for Carry Over (MACO) (1/9)

2.1 1/1000 dose criterion (TDD)

2.2 10ppm Conservative LIMITS
2.3 Visual Clean (e.g. Pharmacological Evaluation for 1/1000)
2.4 LD50 – 1/50000

LIMITS based on EMA guidelines on «Guideline on Setting Health

2.5 PDE Based Exposure Limits for Use in Risk Identification in the
2.6 TTC Manufacture of Different Medicinal Products in Shared Facilities»
(Toxicological Evaluation)
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2 Maximum Allowable Limits for Carry Over (MACO) (2/9)

2.1 1/1000 dose criterion (TDD)

Generally it is assessed that 1/10 of the MINIMUM THERAPEUTIC DOSE does not show an effect.
In addition a Safety Factor of 100 is considered

 This leads to the conservative acceptance limit of 1/1000 dose

An API should not be present in a subsequently produced product at

levels higher than 1/1000 of the Minimum Daily Dose of the API in a
Maximum Daily Dose of the subsequent product.
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2 Maximum Allowable Limits for Carry Over (MACO) (3/9)

2.1 1/1000 dose criterion (TDD)

Acceptance Limit (MACO) = (X / MDDnext) x (BS / PTS) x 1000 [mg/cm2]

X [mg/day] = 1/1000 of the lowest therapeutic dose of the API of the Previous Product

MDDnext [mg/day] = Maximum Daily Dose of the following Product in dosing units per day

BS [mg] = Number of Dosing Units per Batch of the Following Product (Minimum Batch Size)

PTS [cm2] = Total Product Touching Surface

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2 Maximum Allowable Limits for Carry Over (MACO) (4/9)

2.2 10ppm
The 10ppm criterion is not considering any Toxicological or Pharmacological properties of the
API or the product (residues). It depends only on the Batch Size of the Following Product.

Can be applicable if the 10ppm calculation leads to stricter limits than the one derived from
1/1000 dose calculation

Acceptance Limit (MACO) = X x (BS / PTS) x 1000 [mg/cm2 ]

X [mg] = 10mg residual substance per Kg of the following product = 10ppm

BS [Kg] = Smallest Batch Size of the Following Product (variable factor)

PTS [cm 2] = Total Product Touching Surface

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2 Maximum Allowable Limits for Carry Over (MACO) (5/9)

2.3 Visual Clean

Experimentally acquired value from visual clen studies

Visual clean status is the minimum requirement after cleaning. It cannot stand alone and has to
be supported by cleaning validation studies based on real measurements for API studies.

In literature(*) can be found often the following limit .

1-4 [mg/cm2]

(*) Buscalferri; Lorenzen; Schimdt; Schwarm; Anhalt; Herzog; Ziegler (2000) Reinigungsvalidierung - Pharm. Ind. (62), Nr. 6, 411-414
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2 Maximum Allowable Limits for Carry Over (MACO) (6/9)

2.4 1/50000 of the LD50

Not on Scientific Base

Should not be used for API residues because:

- LD50 stands for Acute Toxicity

- Does not correlate to Toxicity after long term exposition
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2 Maximum Allowable Limits for Carry Over (MACO) (7/9)

2.5 PDE
It represents a substance-specific dose that is unlikely to cause an adverse effect if an individual
is exposed at or below this dose every day for a lifetime

Acceptance Limit (MACO) = (PDE / MDDnext) x (BS / PTS) x 1000 [mg/cm2]

PDE [mg/day] = Permitted Daily Exposure of the Product to be Tested

MDDnext [mg/day] = Maximum Daily Dose of the following Product in dosing units per day

BS [mg] = Number of Dosing Units per Batch of the Following Product (Minimum Batch Size)

PTS [cm2] = Total Product Touching Surface

1000 = Conversion Factor mg  mg

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2 Maximum Allowable Limits for Carry Over (MACO) (8/9)

2.6 TTC = Threshold of Toxicological Concern

- Threshold Value for GENOTOXIC APIs

- TTC is a level of exposure of any genotoxic API that does not lead to a toxicological risk and is
set to : 1.5 mg/person/day

- A dose that do not have a relevant toxicological effect and is therefore assessed as harmless
for human health

TTC for Human = 1.5 mg/person/day

TTC for Veterinary Products = 0.03 mg/kg x bw/day

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2 Maximum Allowable Limits for Carry Over (MACO) (9/9)

2.6 TTC = Threshold of Toxicological Concern

Acceptance Limit (MACO) = (TTC / MDDnext) x (BS / PTS) [mg/cm2]

TTC [mg/day] = Threshold of Toxicological Concern = 1.5 mg/person/day [mg/day]

MDDnext [mg/day] = Maximum Daily Dose of the following Product in dosing units per day

BS [mg] = Number of Dosing Units per Batch of the Following Product (Minimum Batch Size)

PTS [cm2] = Total Product Touching Surface

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3 Cleaning Validation Documents

3.1 Cleaning Validation Protocol

Ex. - FDA Expectations

 To have written general procedures on how cleaning processes will be validated

 Who is responsible for performing and approving the validation study, the acceptance
criteria, and when revalidation will be required

 Specific written validation protocols in advance for the studies to be performed on each
manufacturing system or piece of equipment which should address such issues as sampling
procedures and analytical methods to be used

 Conduct the validation studies in accordance with the protocols

 Document the results of studies in a validation report

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3 Cleaning Validation Documents

3.2 Cleaning Validation Report

Ex. - FDA Expectations

 A Final Validation Report

 Approved by Management

 Stating whether or not the cleaning process is valid

The data should support a conclusion that residues

have been reduced to an «acceptable level»
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3 Cleaning Validation Documents

3.2 Cleaning Validation Report

The Report Summarizes all Results

 For API Residues

 Cleaning Agents Residues

 Microbial Burden

 Outcome of DHT and CHT Studies

The final validation report should be approved by Management and should clearly
state whether or not the cleaning process is valid. The data should support a
conclusion that residues have been reduced to an «Acceptable Level»
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4 API Register
For the toxicological evaluation of APIs or products used in shared facilities an API register
should be established.

The APIs are categorized therein according their OEL / OEB Class (example) :

+ Potency - Potency
API OEB Classes (mg/m3) OEL
Class 5 Class 4 Class 3 Class 2 Class 1 (mg/m3)
≥0.05 / <1 ≥1 / <10 ≥10 / <100 ≥100 / <1000 ≥1000

API 1 x 0.1
API 2 x 10
API 3 x 0.1
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4 API Register

OEL (Occupational Exposure Limit)

 Upper Limit on the acceptable concentration of a hazardous substance in workplace air

 Typically set by competent national authorities and enforced by legislation to protect

occupational safety and health

 Can be found in Material Safety Data Sheet (MSDS) of APIs

 Air Concentration at workplace [mg/m3]

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4 API Register - OEB (Occupational Exposure Band) - Classes

<500ng

Isolator System 5 <1 Highly Toxic

<1 mg/m3

Liner Connecting System 4 0.1-1 Toxic

1-10 mg/m3
Protective Liner
Connecting System 3 1-10
10-100 mg/m3 Less Toxic
Trickle Protection

2 100-1000 mg/m3 10-100 Almost Non Toxic

Local Aspiration

1 1000-5000 mg/m3 >100 Non Toxic

OEB OEL Potency (mg/day)

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5 Inspection Findings (1/6)

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5 Inspection Findings (2/6)

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5 Inspection Findings (3/6)

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5 Inspection Findings (4/6)

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5 Inspection Findings (5/6)

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5 Inspection Findings (6/6)

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workflow

Quotation
Customer Identifying support level TOXICOLOGICAL REPORT
PDE (*)
Request/Contact (PDE  Whole Project) (PDE)
Order

Whole
Project
(*) CLEANING VALIDATION
REPORT
Data Review : Info on (CVQ) :
- New Project Product(s)
- Existing Project Process
(Gap Analysis) Equipment(s)…..

Quotation Order Risk Analysis

DOC Data

FIELD VALIDATION
PDE Review

Bracketing/Grouping
Protocol(s) Issue
Existing Doc. Review Lab Scale trials Laboratory DOC Data
Support Review
AOB(?)…..
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