Cleaning Validation

PDA: A Global
State of art and regulatory
Association
trends in acceptance criteria
selection
G.Vitali
CTP System S.p.A

Agenda
Regulations/Guidelines: state of art

The evolution of Regulations: Acceptance Criteria

New analytical challenges

As it all began

1984: Samuel Harders The Validation of Cleaning Procedures

must be practical and achievable by a reasonable cleaning procedure
limitsverifiable by analytical methodology in the companyin line with residual
limits set for substances in food (referring to 21 CFR 193 of the age)

1988: FDA faced the first cross-contamination traceable to inadequate cleaning

and cleaning validation
Cholestryramine Resin USP contaminated with pesticide intermediates and
degradants

1989: Doug Mendenhalls Cleaning Validation

Proposes to establish acceptance limits in collaboration with tox and medical
authorities or the use of appropriate safety factors 10x or 100x

1993: Fourman-Mullens Determining Cleaning Validation acceptance limits for

pharmaceutical Manufacturing operations
The article proposes the 1/1000, 10 ppm and visible residue limit

1998: PDA Technical Report No.29 Points to consider for Cleaning Validation
Cleaning limits not be selected arbitrarily. Logical and scientific basis for the
numerical limit to be selected.

*All quotes on this page are from: Cleaning Validation for the 21St Century: Acceptance Limits for Active Pharmaceutical
Ingredients (APIs): Part I, Andy Walsh, Pharmaceutical Engineering 2011

Rules/Guidelines
State of art
Eudralex -The rules governing medicinal products in the European Union: Volume 4,
Good Manufacturing practices - Medicinal products for human and veterinary use
a) Part 1 Chapter 5 Production
b) Part 2 - Basic requirements for Active Substances used as Startings Materials
(ex Annex 18)
Annex 15 Qualification and validation 2001
FDA Guide to inspections of validation of cleaning processes 1993
ICH (International Conference of Harmonization) Q7 - GMP for Active
pharmaceutical ingredients, 2001, Sezione XII, Validation
PIC/S (Pharmaceutical Inspection Cooperation Scheme) PI 006-03 Recommendations on validation master plan, IQ, OQ, non-sterile process validation,
cleaning validation 2007
CEFIC/APIC (European Chemical Industry Council/Active Pharmaceutical
Ingredients Committee) - Guidance on aspects of cleaning validation in active
pharmaceutical ingredients plants 2000

Rules/Guidelines
State of art
PDA Technical Report n 49 Points to consider for Biotechnology Cleaning
Validation 2010
ISPE Risk-Based Manufacture of Pharmaceutical Products - A Guide to Managing
Risks Associated with Cross-Contamination, September 2010
EMA/CHMP/SWP/598303/2011 Concept Paper on the development of toxicological
guidance for use in risk identification in the manufacture of different medicinal
products in shared facilities, October 2011
PDA Technical Report n 29 Points to consider for Cleaning Validation Revised
2012
EMA/CHMP/ CVMP/ SWP/169430/2012 Guideline on setting health based exposure
limits for use in risk identification in the manufacture of different medicinal products in
shared facilities, DRAFT, December 2012

Rules/Guidelines
Acceptance Criteria: current common approach

The classical acceptance criteria described in literature are:

No visible residues must be present at the end of cleaning operations.
No more than 1/1000 of the normal therapeutic dose of the cleaned product
must be present in the maximum daily dose of the next product.
No more than 10 ppm of the cleaned product must be present in the next
product

Example: Safety Factor on the

Therapeutic Dose criteria
An easy way to calculate the Acceptable Residue Level (ARL) in the next drug
product, typically determined ad one-one thousandth (0.001), is based on
therapeutic dose, by calculating MAC (Maximum Allowable Carryover)
This approach is valid for non-highly hazardous active ingredient in nondedicated
equipment.
MAC = DTA X MBSB / SF X DGB
DTA = minimum daily dose of the active of the cleaned product (A)
DGB = the largest daily dose of the next product on the same equipment (B)
MBSB = the minimum batch size of the next product (B)
SF = safety factor (tipically 1000)
Swab limit: is obtained dividing the MAC value by the total exposed surface in
common with A and B. The result is multiplied by surface to be samples (tipically 25100 cm2)
Rinse Limit: is obtained dividing the MAC value by the total volume used to rinse
the exposed surface in common with A and B.

Rules/Guidelines
New ways to select the proper acceptance criteria

So far the 1/1000 or 10 ppm acceptance criteria (Acceptable Residue

Level, ARL) were widely applied to calculate Cleaning Validation
limits:
These limits do not consider pharmacologycal and toxycological
data and neither the duration of treatment.
In many cases these limits can be too restrictive or not restrictive
enough, without any assumption can be done to justify their choice
For these reasons a scientific sounding approach should be applied
on clinical data. The approach is valid specifically for multi-product
plants, but should be applied, in specific cases also to dedicated
equipment.

Rules/Guidelines
New ways to select the proper acceptance criteria
The improvement in the safety of patients should not be reached including
new safety factors to acceptance criteria. On the contrary, if the patient
safety is (and must be) the final scope, the most appropriate approach is to
focus on the safety of the residue.
For example: one aspect of safety profile for a drug is the theratogenic
effect.
o The theratogenic effect is dose related but not linked to the
therapeutic dose.

Modified from Pharmaceutical engineering, July-August 2011

Rules/Guidelines evolution
Approach based on Acceptable Daily Exposure

Many drugs can bring to a sensibilitation, causing a specific

immunitary reaction when administered to susceptible individues.
In these cases the reaction can be severe leading to anaphylaxis
and often to death.
The most known example is the penycillin that can bring to
sensibilization also at minimal doses.
How does the pharmacologic dose criteria take in account the
sensibilizing effect?

Rules/Guidelines evolution
Approach based on Therapeutic Index
All drugs are evaluated basing on their therapeutic index, that means the ratio
between the letal dose (LD50) and effective dose (ED50). This ratio indicates
the safety level of a specific drug. Higher is the ratio, safer is the drug.
The pictures compare two drug products with the same therapeutic dose (1.0
mg), but with very different therapeutic indexes.

Modified from Pharmaceutical engineering, July-August 2011

Evolution in Acceptance criteria calculation

ISPE Baseline Guide Risk-MaPP

The ISPERisk-Mapp guideline provide a scientific approach based on

risk, aligned to ICH Q9 guideline, useful to manage the risk of crosscontamination during drug substance and drug products manufacturing.
The Risk-Mapp proposes a scientifically based risk evaluation on patient
safety, in order to state the Acceptable Daily Exposure (ADE).
The ADE can be used as base to calculate the maximum amoung of any
substance, drug substance or secondary specimen from the cleaned
product, that can contaminate the next product.

Evolution in Acceptance criteria calculation

ISPE Baseline Guide Risk-MaPP
The ADE value is an estimation of allowed exposure to a specific substance
without any significative enhancement of risk for the population during the
average life expectancy.
The concept of ADE is similar to other limits provided by different regulatory
authorities in order to define safety limits for a drug substance.

For example:
WHO reports acceptable values (limits) for residuals of additivites and
pesticided in food

The US Environmental Protection Agency (EPA) reports the "Reference

Concentrations (RfCs) or "Reference Doses (RfDs) for chemical
substances by inhalation or oral assumption.
The ICH Q3C Guidelines on Residual Solvents describes the Permissible
Daily Exposure (PDE) for solvents

Evolution in Acceptance criteria calculation

ISPE Baseline Guide Risk-MaPP
The ADE evaluation includes:

A revision of toxicological and clinical data available for the substance

The choice of a specific starting point or critical effect for risk evaluation

A scientific evaluation of the dose basing on LOAEL or NOAEL (gathering

scientific data available for human or veterinary use).

Suitable risk assessment methodologies, comprising selection of security

factors needed to assure not-carginogenic effects

Provide scientific documentation to support the ADE value selection

Evolution in Acceptance criteria calculation

ISPE Baseline Guide Risk-MaPP
Acceptable Daily Exposure (ADE):
The maximum safe daily amount of a substance: limit of daily exposure
without observing adverse effects.
ADE (mg/day) = NOAEL (mg/kg/day) x BW (kg)
UFC x MF x PK
NOAEL = No Observed Adverse Effect Level
BW = body weight (eg. kg 50)
UFC = Composite Uncertainty Factor (toxicological factors)
MF = Modifying Factor (this factor is based on the judgment of the
toxicologist)
PK = Pharmacokinetic factor
In the risk assessement the ADE value can be used to estimate the risk
associated with the specific product and can be useful to detect, in multiproduct lines, the hazard related to the combination of cleaned product and
next product.
The ADE is used as base to calculate the limit in the cleaning procedure.

Acceptance criteria based on toxicity

What to do when Short-term studies are the only available:
eg. Cleaning Agent and Intermediates
The NOEL when short term studies are only available.
Typically for cleaning agents or intermediates
Typically for these substances there are not foreseen Daily Intake
Doses.
The DL50 allows the estimation of NOEL to be used for MAC calculation
NOELA = (LD50 X BW) / SF
MAC= NOELA X MBSB / SF1 X DIB
BW =
SF =
DIB =
MBSB=
SF1 =

Body weight
safety factor selected by toxicologist (generally max.1000)
Maximum daily intake of the next product (B)
Minimum batch size of the next product (B)
safety factor selected by toxicologist (generally max.1000)

Evolution in Acceptance criteria calculation

EMA - Concept Paper on the development of toxicological guidance for use in risk
identification in the manufacture of different medicinal products in shared facilities. 2011

For new production in a shared facility a more scientific approach, based on

current available pharmacological and toxicological information, is required to
establish threshold values to be used as part of the overall Quality Risk
Management
EMA highlights the difficult to define the toxicological risk and, subsequently,
the acceptable limit of probable contamination between products

EMA states the a new guideline will be issued developing a clear guidance on
appropriate toxicological assessment

Evolution in Acceptance criteria calculation

EMA Guideline on setting health based exposure limits for use in risk identification in
the manufacture of different medicinal products in shared facilities, Draft, 2012
For all critical effects identified, a NOEL should be established.

The NOEL is the highest tested dose at which no critical effect is observed.

If the critical effect is observed in several animal studies, the NOEL occurring
at the lowest dose should be used for calculation of the PDE value.

If no NOEL is obtained, the lowest-observed-effect level (LOEL) may be

used.

If different adverse effects are identified, calculating the related PDE values, the
more appropriate PDE value must be used as acceptance criteria in Cleaning
Validation.
The lowest PDE value should be used as default.

Evolution in Acceptance criteria calculation

EMA Guideline on setting health based exposure limits for use in risk identification in
the manufacture of different medicinal products in shared facilities, Draft, 2012
Permitted Daily Exposure (PDE):

PDE (mg/day) = NOEL (mg/kg/day) x BW (kg)

F1 x F2 x F3 x F4 x F5
F1: A factor (values between 2 and 12) to account for extrapolation between species
F2: A factor of 10 to account for variability between individuals
F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than
4 weeks
F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxic
carcinogenicity, neurotoxicity or teratogenicity
F5: A variable factor that may be applied if the no-effect level was not established. When
only an LOEL is available, a factor of up to 10 could be used depending on the
severity of the toxicity

Evolution in Acceptance criteria calculation

EMA Guideline on setting health based exposure limits for use in risk identification in
the manufacture of different medicinal products in shared facilities, Draft, 2012
Active substances with a genotoxic potential
For genotoxic active substances for which there is no discernible threshold, it is
considered that any level of exposure carries a risk.
However, a pre-defined level of acceptable risk for non-threshold related
genotoxicants has been established in the EMA Guideline on the Limits of Genotoxic
Impurities in the form of the Threshold of Toxicological Concern (TTC) of
1.5 g/person/day.
Active substances with a sensitising potential
Concerning topically applied medicinal products, literature data support that a nonsensitizing dose for active substances inducing skin sensitisation exists both with
respect to the induction of skin sensitisation and its elicitation. Hence, in case the
non-sensitising dose has been established in humans or target or laboratory
animals, a PDE value can be derived applying the PDE approach. For other routes
of administration, a safe level of exposure is more difficult to establish. Dedicated
facilities are required for manufacturing active substances and medicinal products
for which scientific data does not support a threshold value of sensitisation.

Evolution in Acceptance criteria calculation

EMA Guideline on setting health based exposure limits for use in risk identification
in the manufacture of different medicinal products in shared facilities, Draft, 2012
Lack of animal data on reproductive and developmental toxicity
The presence of residual active substance should be reduced to a level that will not
pose a risk for effects on reproductive and developmental parameters.
However, in the early phases of development, non-clinical data to assess the
potential of the new active substance to cause reproductive and developmental
toxicity may often be lacking.
In these cases, the use of a generic threshold value as is applied for genotoxic
substances may be considered. Such a threshold value could be conservatively
derived from a database of NOAELs obtained in animal studies of fertility and
embryo-fetal development conducted for active substances representing a wide
selection of pharmacodynamic effects.
In case the level of residual active substance cannot be reduced to the
established threshold value or when insufficient data are available to establish a
threshold value, the active substance should be manufactured in a dedicated facility

Evolution in Acceptance criteria calculation

PDA Technical Report n 29 (Revised 2012)
Points to consider for Cleaning Validation

Highly hazardous drug actives

Risk MaPP
Acceptable Daily Exposure (ADE)

Not highly hazardous drug actives

Risk MaPP
Acceptable Daily Exposure (ADE) or
therapeutic dose related criteria

Detergents and related substances

LD50 based criteria

Example of application 1

S-1004

P-1006
S-1005

R-1001A

R-1001B

R-1003

S-2001

S-2002

S-2003

S. A. 2000
MF-2001
P-2004
P-1011

Product: isomer of vitamin K2 (Menachinon-7, MK-7)

DL50 MK-7: 2000 mg/Kg
Batch size next product (MBSB): 20 Kg
Daily intake next product (DIB): 800 mg
Internal exposed surface area of equipment (S): 411,63 m2
Nota: The Vitamin begins to be produced in fermenter R.1003. Only product menachinon-7 (MK-7), contact equipment will
be considered in the calculations (blue tanks). The S-2002 and S-2003 are used as permeate harvest tanks. The permeate
will be discarded.

Safety factor (SF): 1000

Safety factor (SF1): 1000

Acceptance criteria calculation

NOELA = (LD50 X P) / SF
MAC= NOELA X MBSB / SF1 X DGB
NOEL = 2000 mg/Kg x 70 Kg = 140 mg
1000
MAC = 140 mg x 20.000.000 mg = 3500 mg
1000 x 800 mg
The calculated MAC was considered as distributed on whole product contact surface 411,63 m2
The corrisponding Menachinon-7 (MK-7) residue concentration is 8,5 mg/m2.
Rinse limit R3: 8,5 (mg/m2). x 164,73 m2= 0,07 mg/l
20000 l
Rinse limit MF-2001: 8,5 (mg/ m2).x 35,6 m2= 0,302 mg/l
1000 l
Rinse limit S-2001: 8,5 (mg/ m2).x 211,30 m2= 0,180 mg/l
10000 l

Example of application 2

Reactor RS 1781

Worst case: Propanolole HCl

Transfer line for

continuos flow
centrifugation

Centrifugation

Centrifuge
CE 129 or CE 130 or
CE 940

a.

Product with smaller batch-size (MBSB): Cromolin Na

(50 Kg)

b.

Product with higher daily intake (DIB): Metformine HCl

(3000 mg)

c.

Product with lower therapeutic dose (DTA): Cromolin

Na (20 mg)

Internal product contact surface area (S): 14 m2

Swab sampled area (s): 100 cm2
Safety factor (SF): 1000

Calculation and comparison

(worst-case selection)
Potency based criteria:
Swab limit = TDA x MBSBx s = 0,02g x 50000g x 100cm2 = 98,6 g/swab
SF x DGB x S
1000 x 3g x 140000cm2

Toxicity based criteria

NOEL = (LD50 X P) / SF = 560 mg/Kg x 70 Kg = 39,2 mg
1000
Swab limit = TDA x MBSBx s = 39,2 mg x 50.000.000 mg x 100cm2 = 467 g/swab
SF1 x DGB x S
1000 x 3000 mg x 140000cm2
Default criteria
Swab limit = 10 ppm x MBSB x s = 10 mg/Kg x 50 Kg x 100cm2 = 357 g/swab
S
140000cm2

Rules/Guidelines
Worst case Selection: Analytical Method and Monitoring/Re-Validation

Analytical methods
EU GMP part II: Validated analytical methods having sensitivity to detect
residues or contaminants should be used. The detection limit for each analytical
method should be sufficiently sensitive to detect the established acceptable
level of the residue or contaminant. The methods attainable recovery level
should be established.

Compound-related Acceptance Criteria

New challenges in developing Analytical Methods
for Cleaning Validation
In case of lower acceptance limits, the analytical methods perfomance
should be challenged.

In some cases the method could be preserved, shifting the analytical target on
lower range, and off course providing a new validation

In other cases optimization/technical upgrades must be done in order obtain

the necessary sensitivity and accuracy.

Specimen

LC-UV
sensitivity

Poor, 210 nm, Good, 254

60 g/mL
nm, 10 g/mL

Good, 254
nm, 10 g/mL

Good, 254
nm, 10 g/mL

LC-MS-MS
sensitivity

100 ng/mL

10 ng/mL

20 ng/mL

10 ng/mL

Compound-related Acceptance Criteria

New challenges in developing Analytical Methods
for Cleaning Validation
Residual (without IS) Linear
70000

Residui %

Area/Conc.

60000

50000
R = 0,9999

Area

40000

RF Fattore di Risposta su
Area

R = 0,9944
30000

20000

10000

0
0

0,5

1
g/cmq

40
30
20
10
0
-10 0
-20
-30
-40

1,5

0,5

1,5

g/cmq

Response Area/Conc. Linear

120
100
80
60
40
20
0
0

0,5

1
g/cmq

1,5

Compound-related Acceptance Criteria

New challenges in developing Analytical Methods
for Cleaning Validation
Residuals (with IS)
35

Residui %

Area/Ratio Specimen/IS

30

20

15

RF Fattore di Risposta su
Ratio

Ratio Composto A / IS

25

40
30
20
10
0
-10 0
-20
-30
-40

10

0
0

0,5

1
g/cmq

1,5

0,5

1,5

g/cmq

Response Factor Area/Ratio

120
100
80
60
40
20
0
0

0,5

1
g/cmq

1,5

Questions?

31