Setting
S
tti
Acceptance
A
t
C
Criteria
it i ffor
Cleaning Validation
Rizwan Sharnez, Ph.D.
Principal Engineer
Amgen
Overview
ƒ Introduction
– Impurities: are part of the batch
– Contaminants: are extraneous to the batch
ƒ Regulatory expectations
ƒ Setting limits for impurities and contaminants
ƒ Default versus Calculated Limits
ƒ Limits based on Acceptable Daily Intake (ADI)
ƒ Limits
Li it based
b
d on Dose
D
ƒ Maximum Allowable Carryover (MAC)
– Based on ADI
– Based on Dose
1
Regulatory expectations:
Cleaning between batches of the same product
“When the cleaning process is used only between batches
of the same product (or different lots of the same interprocess)) the firm need only
y meet a criteria
mediate in a bulk p
of “visibly clean” for the equipment.”1
“Such between batch cleaning processes do not require
validation.”1
Product A
Product B
COT
COT
Between batch cleanings
Leverage Changeover Testing (COT) to minimize testing between
lots of the same product
1FDA:
Guide to Inspections Validation of Cleaning Processes
For Internal Use Only. Amgen Confidential.
3
Regulatory expectations:
Cleaning between batches of different products
The carryover of the previous product into the next
product must be less than a predetermined amount that
is known to be safe.
safe
Product A
Product B
COT
COT
Cleaning between batches
products
of different p
Applies to all chemical contaminants
A Maximum Allowable Carryover (MAC) calculation is
used to determine acceptable carryover of contaminants
For Internal Use Only. Amgen Confidential.
4
2
Regulatory Expectations:
Analytical Methods
“The firm should challenge the analytical method in
combination with the sampling method(s) used to show
that contaminants can be recovered from the equipment
surface
f
and
d att what
h t level,
l
l i.e.
i 50% recovery, 90%,
90% etc.
t Thi
This
is necessary before any conclusions can be made based
upon the sample results”1
Residue
R
Total
x
=
≥ 50%
WFI
Total Recovery
1 FDA:
Recovery from
sample
Recovery from
surface
Guide to Inspections Validation of Cleaning Processes
For Internal Use Only. Amgen Confidential.
5
Impurities and Contaminants
ƒ An impurity is intrinsic to the batch/product
ƒ
Chemical: raw materials, by-products and degradates
ƒ
Biological: host cells
cells, debris and DNA
ƒ A contaminant is extrinsic to the batch/product
ƒ
Chemical: cleaning and disinfecting agents, equipment based,
and polymers/slip agents
ƒ
Biological: bioburden, endotoxins and viruses
ƒ Contaminants can be classified based on their source
ƒ
Equipment
q p
ƒ
Raw Materials
ƒ
Environment
ƒ
Conditioning Agents
ƒ
Other
3
Setting limits for impurities
Consider the manufacture of lots within a campaign
Step 1:
St
1
Manufacture
Lot 1
Upstream Materials
Lot 1 Xfer Out
For Internal Use Only. Amgen Confidential.
7
Step 2: Intra-campaign cleaning
Lot 1 Residue:
Impurity A
Is it critical to monitor clearance of impurity A
between batches of the same lot?
For Internal Use Only. Amgen Confidential.
8
4
Step 3: Manufacture next lot (Lot 2)
Upstream Materials
The next batch brings in bulk quantities of impurity A
For Internal Use Only. Amgen Confidential.
9
Setting limits for impurities (continued)
ƒ Impurities are intrinsic to the batch/product
ƒ Typically, limits for impurities are not based on a
MAC calc.
l
ƒ Instead, acceptable levels are based on:
ƒ Attaining predetermined product purity
ƒ Limiting concentration of substances that are growth promoting
ƒ Default limits are widely used to meet the above criteria
ƒ Visually clean
ƒ ≤ 10 ppm in rinsate
ƒ Direct surface analysis is generally not an expectation
ƒ Purification train is designed to remove impurities to acceptable
levels
ƒ Subsequent batch introduces much higher levels of impurities!
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Setting limits for contaminants
ƒ Contaminants are extrinsic to the batch/
product
ƒ Typically, acceptable limits for contaminants
are based on a MAC calculation
ƒ The two most widely used approaches are
based on:
ƒ Acceptable daily intake (ADI); i.e. Safety
ƒ Carryover of previous product
ƒ The latter is applicable only to multiproduct
equipment
Default Versus Calculated Limits
ƒ Commonly used default limits for impurities (nonspecific)
– ≤ 10 ppm ((rinsate)
i
t )
– Process capability
– USP limits for process water (WFI, Purified, RO, etc.)
• Conductivity (Stage I – III)
• Bioburden
• Endotoxins
ƒ Calculated limits are typically based on the MAC
of a specific contaminant
– Limits based on Acceptable Daily Intake (ADI)
– Limits based on Dose
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Maximum Allowable Carryover (MAC)
ƒ This will be an interactive exercise with the aid of a
white board
ƒ Equations are summarized in the subsequent
slides
MAC Calculation: Worked Example
Step 1: Determine the acceptable daily intake (ADI) of
component A in humans as follows:
ƒ ADI = LD50 * BW * SF
ƒ LD50 is the Lethal Dose obtained in a suitable animal model,
based on 50% mortality
– Could also use LD0 (based on no mortality) or NOEL (No Observed
Effect Limit)
ƒ BW is a conservative estimate of the Body Weight of an adult
human (50kg)
ƒ SF is a Safety Factor, typically 1/1000
7
MAC Calculation: Worked Example (cont’d)
ƒ Safety Factor (SF) of 1/1000 is based on a factor of
1/10 for each of the following three considerations:
– Conversion from animal model to humans
– Exposure over a lifetime
– Allowance for variability in data and individuals
ƒ
A lower SF may be used for
– Topicals (1/10) and Oral (1/100) formulations
– Intravenous
I t
f
formulations
l ti
that
th t are administered
d i i t
d for
f short
h t
durations (i.e. there is no prolonged exposure) (1/100)
MAC Calculation: Worked Example (cont’d)
Step 2: Determine the volumetric daily dose (VDOSE) of
drug product B in (mL/day)
ƒ VDOSE = DD / CDP
ƒ DD is the Daily Dose of drug product B (mg/day)
ƒ CDP is the Concentration of the drug product B (mg/mL)
8
MAC Calculation: Worked Example (cont’d)
Step 3: Determine the maximum concentration (CDP,MAX)
of component A in drug product B (g/L)
ƒ CDP, MAX = ADI / VDOSE
Step 4: Determine the MAC of component A in drug
product B
ƒ MACA→B = CDP,MAX * VDS
ƒ VDS is the smallest batch volume of the final drug product B
(before it is processed into smaller lots for filling)
MAC Calculation: Worked Example (cont’d)
Step 4: Calculate the total product contact surface area
ƒ SA1+ SA2 + SA3 + SA4 + …….. = Σ SAi = SAT
Step 5: Determine the maximum allowable surface
concentration of drug product B
ƒ CS,MAX = MACA→B / SAT
Step 6: Determine the acceptance criterion for swab
samples
ƒ ACS = CS,MAX * SASWAB / VEXTR
ƒ SASWAB is the surface area swabbed (typically 25 cm2)
ƒ VEXTR is the volume of the extractant per swab
9
MAC Calculation: Worked Example (cont’d)
Step 7: The above acceptance criterion for swab
samples can be expressed in terms of organic carbon
(OC) concentration:
t ti
ƒ ACSTOC = ACS * %OC
ƒ %OC is the mass fraction of carbon in component A
Step 8: Determine the acceptance criterion of rinse
samples for each equipment (ACRi)
ƒ ACRi = (MACA→B / SAT * SAi) / VFRi
ƒ SAi the surface area of ith piece of equipment
ƒ VFRi is the volume of final rinse for ith piece of equipment
MAC Calculation: Worked Example (cont’d)
Step 9: In terms of organic carbon, the acceptance
criterion of rinse samples (ACRTOCi)can be calculated
as follows:
f ll
ƒ ACRTOCi = ACRi * %OC
10
Questions?
Regulatory expectations:
Routine monitoring
ƒ Once CIP systems are validated, appropriate
documentation should be maintained to show that
critical parameters (KOPs) are achieved with each
cleaning cycle.”2
ƒ “Once cleaned by a validated procedure, a firm
generally should not be expected to analytically
examine equipment surfaces to demonstrate
cleanliness”3
ƒ ”One
”O purpose off having
h i cleaning
l
i validation
lid ti is
i so
that analytical monitoring may be omitted or reduced
to a minimum in the routine phase.”4
1.
2.
3.
FDA's Guidance for Industry: Manufacturing, Processing, or Holding APIs (March 1998)
FDA’s Second Quarter 2001 Human Drug CGMP Notes
PIC/s document PI 006-1
For Internal Use Only. Amgen Confidential.
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