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Giovanni Vitali - CTP PDF
Giovanni Vitali - CTP PDF
PDA: A Global
State of art and regulatory
Association
trends in acceptance criteria
selection
G.Vitali
CTP System S.p.A
Agenda
*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
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 25-
100 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
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.
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
For example:
The choice of a specific starting point or critical effect for risk evaluation
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 multi-
product 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 DL50 allows the estimation of NOEL to be used for MAC calculation
BW = Body weight
SF = safety factor selected by toxicologist (generally max.1000)
DIB = Maximum daily intake of the next product (B)
MBSB= Minimum batch size of the next product (B)
SF1 = 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
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
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.
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
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
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
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.
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
NOELA = (LD50 X P) / SF
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 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
Default criteria
Analytical methods
In some cases the method could be preserved, shifting the analytical target on
lower range, and off course providing a new validation
Specimen A B C D
LC-UV Poor, 210 nm, Good, 254 Good, 254 Good, 254
sensitivity 60 g/mL nm, 10 g/mL nm, 10 g/mL nm, 10 g/mL
LC-MS-MS 100 ng/mL 10 ng/mL 10 ng/mL 20 ng/mL
sensitivity
Compound-related Acceptance Criteria
New challenges in developing Analytical Methods
for Cleaning Validation
Residui %
10
60000 0
-10 0 0,5 1 1,5 2
50000 -20
-30
-40
40000 R = 0,9999 g/cmq
Area
RF Fattore di Risposta su
30000
120
100
20000 80
Area
60
10000 40
20
0 0
0 0,5 1 1,5 2 0 0,5 1 1,5 2
g/cmq g/cmq
Compound-related Acceptance Criteria
New challenges in developing Analytical Methods
for Cleaning Validation
Residui %
30 10
0
-10 0 0,5 1 1,5 2
25
-20
Ratio Composto A / IS
-30
20 -40
g/cmq
RF Fattore di Risposta su
120
100
10
Ratio
80
60
5
40
20
0 0
0 0,5 1 1,5 2 0 0,5 1 1,5 2
g/cmq g/cmq
Questions?
31