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Initial Cleaning Validation
Acceptance Criteria and Control Level
Sanofi Pasteur, Swiftwater, MTech Process Technology, Deputy Director
Lan Zhang
Aug, 2015
1
Initial Cleaning Validation Acceptance Criteria and Control Level
Acknowledge
Odile Smith
Director
Manufacturing Technology Process Technology
Sanofi Pasteur, Swiftwater, US
Shawn Haynes
Director
Quality Validation
Sanofi Pasteur, Swiftwater, US
Initial Cleaning Validation Acceptance Criteria and Control Level: Agenda
● Definitions
● Initial Acceptance Criteria Calculation
● MAC Calculation Equation Selection Rationales
● MAC Calculation Equations and Applicable Conditions
● Initial Acceptance Criteria Calculation
● Control Level Calculation
● Parameters in Initial Acceptance Criteria Calculation
● Equipment Surface Area and Batch Volume
● Rinse Volume
● Examples of Initial Acceptance Criteria Calculation
●Product Dedicated Equipment
●Multi-Product Contact Equipment
Initial Cleaning Validation Acceptance Criteria and Control Level: Definitions
● Initial Cleaning Validation Acceptance Criteria● Calculated per the health based, toxicity based, daily dose based and/or general limit
based maximum allowable carryover (MAC) of the potential contaminants.
● The initial acceptance criteria are the limits that are safe to the patient.
● Process capability is built into the cleaning process during cycle design and
development. The Cleaning Validation initial acceptance criterion is not the goal for a
cleaning cycle design and development.
● Control Level● Calculated per the statistical analysis of the cleaning validation and cleaning monitoring
data.
● The control level reflects the cleaning process capability.
● The control level will be used as the acceptance criterion of cleaning revalidation or for
similar new process equipment.
Initial Cleaning Validation Acceptance Criteria and Control Level: Initial Acceptance Criteria Calculation
● MAC Calculation Equation Selection Rationales
●The potential contaminants may be removed during the purification process. The acceptance criteria for formulation and filling equipment may be more stringent than those for fermentation/inoculation, primary purification and purification equipment.
●Proteins are usually degraded during the cleaning process and became easy-to-clean and non-active.
●Usually the cleaning validation acceptance criteria for dedicated equipment and for indirect product contact equipment are calculated using the General Limit Based MAC Calculation only because:Cleaning Validation for product dedicated equipment is to demonstrate residues are
not accumulated on equipment, the degraded residues are removed, and the risk of bioburden and endotoxin are under control. It is not to validate the carryover of one product to another product.
Compared with direct product contact equipment, the product contamination risk from indirect product contact equipment is low.
Initial Cleaning Validation Acceptance Criteria and Control Level: Initial Acceptance Criteria Calculation
● MAC Calculation Equations and Applicable Conditions
MAC Calculation
Equation
Application Conditions
Cleaning/
Disinfecti
on/Decont
amination
Agent
Direct Product Contact Equipment Indirect
Product
Contact
Equipment
Multi-Product Equipment Dedicated
Equipme
ntNon-toxic
Intermediate
(bulk
manufacturing),
Media,
Non-toxic Buffer
Toxic
Intermediate
(bulk
manufacturing),
Toxic Buffer
Non-toxic
Formulati
on or
Final
Product
Toxic
Formulation or
Final Product
ADE/PDE
(Health)
Based MAC
Calculation
Refer to
APIC
Guidance;
Refer to
EMA
Guideline
N/A N/A N/A N/A Applicable N/A N/A
LD50 Based
MAC
Calculation
Refer to
APIC
Guidance
Applicable N/A Applicable N/A Applicable,
if the ADE
based MAC is
not available.
N/A N/A
Daily Dose
Based MAC
Calculation
Refer to
APIC
Guidance
N/A N/A N/A Applicable Applicable N/A N/A
General
Limit Based
MAC
Calculation
Refer to
APIC
Guidance
Applicable Applicable Applicable Applicable Applicable Applicable Applicable
Summary All the applicable equations, whichever is lower.
Initial Cleaning Validation Acceptance Criteria and Control Level: Initial Acceptance Criteria Calculation
● Initial Acceptance Criteria Calculation Equations
●TOC – MAC Based Calculation
●Bioburden – Process Equipment Bioburden Control Limit
Based Calculation
If the in-process product bioburden control limit is not
available, the initial acceptance criterion is 10CUF/mL (1/10
of the USP Purified Water Specification).
If the equipment is sterilized after cleaning, the initial
acceptance criterion is USP Purified Water specification
100CFU/mL.
Initial Cleaning Validation Acceptance Criteria and Control Level: Initial Acceptance Criteria Calculation
● Initial Acceptance Criteria Calculation Equations (continued)
●Endotoxin – Process Equipment Endotoxin Control Limit Based Calculation
If the in process product endotoxin control limit is not available, use USP WFI specification ≤0.25 EU/mL.
The initial acceptance criterion for formulation and filling equipment is USP WFI specification ≤0.25 EU/mL.
● Conductivity – MAC Based Calculation
Calculation from MAC,
Make Concentration – Conductivity - PH curve.
Convert the acceptance criteria from concentration to conductivity.
If the pH at the acceptance criterion calculated based on MAC is not within WFI specification 5.0 to 7.0, test both conductivity and pH.
The initial acceptance criterion for formulation and filling equipment is USP WFI specification. If the calculated acceptance criterion is lower than WFI specification, reduce the rinse volume.
Initial Cleaning Validation Acceptance Criteria and Control Level: Initial Acceptance Criteria Calculation
● Initial Acceptance Criteria Calculation Equations (continued)
● PH – MAC Based Calculation
Calculation from MAC,
Make Concentration-PH curve.
Convert the acceptance criteria from concentration to pH.
The initial acceptance criterion for formulation and filling
equipment is USP WFI specification.
Initial Cleaning Validation Acceptance Criteria and Control Level: Control Level Calculation
●Control Level Calculation
● Cleaning Validation data, cleaning monitoring data and
cleaning revalidation data are statistically analyzed using 99th
Percentile, Negative Binomial Distribution (for bioburden), or
other appropriate approaches for the control levels. Out of
limit data are excluded.
●Control levels shall not be lower than USP WFI specifications
and the QL of the test methods, and shall not be higher than
the initial cleaning validation acceptance criteria.
●Control levels shall be periodically calculated when more
data.
Initial Cleaning Validation Acceptance Criteria and Control Level: Parameters in Initial Acceptance Criteria Calculation
● Equipment Surface Area and Batch Volume
●When the contaminants can be removed from the downstream purification steps
The initial acceptance criteria for the equipment will be calculated separately. It is not by equipment train.
The Total Surface Area is the product contact surface area of the individual system, e.g. a fermenter and the transfer lines.
The batch volume is the batch volume at this step.
●When the contaminants cannot be removed from the downstream purification steps
The initial acceptance criteria will be calculated for the equipment train.
The Total Surface Area is the sum of the product contact surface areas of the systems in the equipment train.
The batch volume is the corresponding final product volume.
Initial Cleaning Validation Acceptance Criteria and Control Level: Parameters in Initial Acceptance Criteria Calculation
● Rinse Volume
●The rinse volume for rinse samples is generally 1 ml/cm2
or a more appropriate value. The rinse volume shall be
verified against the requirements below:
The rinse volume shall not cause the acceptance criteria
lower than the QL of the test method.
The rinse volume shall be executable.
The rinse volume is generally lower than the minimum
batch volume.
Grab sample (final rinse sample) is taken before
completion of the cleaning cycle; therefore, it is a worst
case. The rinse volume used to calculate the acceptance
criteria of grab samples shall ensure all product contact
surfaces of the system are covered. Usually the rinse
volume used for grab sample acceptance criteria
calculation is between the equipment minimum operating
volume and the minimum batch volume.
Initial Cleaning Validation Acceptance Criteria and Control Level: Examples of Initial Acceptance Criteria Calculation
● Product Dedicated Equipment
When the acceptance criteria calculated using the lowest MAC is too low compared with the background caused by the ingredients with higher MACs; the second lowest MAC will be used to calculate the cleaning validation acceptance criteria, and a specific test method shall be developed for the ingredient with the lowest MAC.
Initial Cleaning Validation Acceptance Criteria and Control Level: Examples of Initial Acceptance Criteria Calculation
● Multi-Product Contact Equipment
The product with the lowest calculated Cleaning Validation
acceptance criteria may not be the worst case soil of the
product group. If the cleaning cycle developed using the worst
case soil cannot reach the Cleaning Validation acceptance
criteria, the product causing the lowest acceptance criteria may
be manufactured using product dedicated equipment.
Cleaning Validation Acceptance CriteriaNote: After manufacturing of products A, B and C, the
equipment is cleaned using the same cleaning process.
The Next Product
A B C
The Current
Product
A AA AB AC
B BA BB BC
C CA CB CC
Cleaning Validation Acceptance Criteria
for the equipment and product group
The Minimum of the Acceptance
Criteria in this Table.
Initial Cleaning Validation Acceptance Criteria and Control Level: Examples of Initial Acceptance Criteria Calculation
● Equipment Group
Calculate the acceptance criteria for each equipment in the
equipment group. The lowest value is the Cleaning Validation
acceptance criteria for the equipment group.
