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

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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 inter-
mediate in a bulk pprocess)) the firm need only
y meet a criteria
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

of different p
products

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 Recovery from Recovery from
surface sample
1 FDA: 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

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Setting limits for impurities

Consider the manufacture of lots within a campaign

Upstream Materials Step 1:

St 1
Manufacture
Lot 1

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 (non-
specific)
– ≤ 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

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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)

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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

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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

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 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 isi so
that analytical monitoring may be omitted or reduced
to a minimum in the routine phase.”4
1. FDA's Guidance for Industry: Manufacturing, Processing, or Holding APIs (March 1998)
2. FDA’s Second Quarter 2001 Human Drug CGMP Notes
3. PIC/s document PI 006-1
For Internal Use Only. Amgen Confidential. 22

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