Establishing

Scientifically Justified
Acceptance Criteria for the

Cleaning
Validation
of APIs
Destin A. LeBlanc

Establishing
Scientifically Justified
Acceptance Criteria for the

Cleaning Validation of APIs

Destin A. LeBlanc

STERIS

M
Setting limits based on sound scientific
principles is critical for cleaning validation
protocols. Residues in the manufacture of
active pharmaceutical ingredients (APIs)
must be considered directly because of
possible effects on any subsequently
manufactured API and, ultimately, regarding
how such APIs are used in finished drug
products. The author presents equations for
calculating various aspects of residue limits
for APIs.

ost published cleaning validation protocols have focused on the residue acceptance criteria for finished
drug products. The FDA guidance document for
cleaning validation simply states that the residue limits must be logical, practical, achievable, and verifiable (1). Most
presentations of residue limits focus on finished drug products
and use a variation of the methods proposed by Fourman and
Mullen (24). These presentations are based on the possible contamination of a product that is subsequently manufactured in
the same equipment. Unfortunately, no clear guidance exists for
residue limits in cleaning validation for the manufacture of an
active pharmaceutical ingredient (API), except for the directive
that the limit should be scientifically sound (5). Many pharmaceutical companies have established formulas for limits of API
residues based on the dosing of subsequently manufactured APIs.
The presentation of residue limits in this article reflects that
strategy, but it goes further into the development of such calculations. Such an exploration of that development is not necessary to the final calculation but can serve to elucidate the contribution of factors that appear, either directly or indirectly, in
any final calculation.
The immediate concern about setting residue limits for cleaning APIs is that the residue can be transferred to an API subsequently manufactured in the same equipment. The ultimate
issue is that the level of any residue present in the subsequently
manufactured API must be evaluated in light of the effects of
the residue on a finished drug product in which it is incorporated. Without taking into account how the subsequently manufactured API is used in a finished drug product (as well as factors such as dosage, routes of administration, and patient
population), establishing scientifically justified residue acceptance criteria for the cleaning validation of APIs will be difficult.

Effects of API cleaning process

residues on finished drugs
Destin A. LeBlanc is vice-president
of technical support at Steris Corporation,
7405 Page Avenue, St. Louis, MO 63133,
tel. 314.290.4790, fax 314.290.4650,
e-mail destin_leblanc@ steris.com.

Although one may approach residue data calculations in several

ways, the principle is the same the effects of any residue in API
manufacturing must be evaluated in light of the effect(s) of that
residue once it is present in a finished drug product and used by
the patient. Presenting an overall calculation of residue limits is
possible. However, this article separates the various parts of data

Calculations of residue limits

in API manufacturing

handling so that the

contributions of
each component
BL1
can be understood
the limit of the target residue in any finished drug
more clearly. Four
product in which the residue ultimately may be
calculations can be
found
made to express
BL2
limits at various
the limit of the residue in the API used in the
points in the overall
manufacture of those finished drug products
analysis. This approach may be imBL3
portant because
the limit of that residue per surface area of the
using worst-case
cleaned equipment used to manufacture the API
limits can distinBL4
guish between, for
the limit of the residue in the sample actually
example, limits in
analyzed by an appropriate analytical technique.
the final API and
limits per surface
area of equipment.
Key to terms
The first task is
to determine the
API
limit of the target
active pharmaceutical ingredient
residue in any finAPIA
ished drug product
the active pharmaceutical ingredient that initially
in which the
is manufactured in a specific piece of equipment
residue ultimately
may be found
APIB
(BL1). The second
a second API that is manufactured in the same
step is to calculate
equipment (following cleaning) and then
the limit of the
converted into one or more finished drug products
residue in the API
ProdB, ProdB1, ProdB2
used in the manufinished drug products made with APIB.
facture of those finished drug products
(BL2). The third is to calculate the limit of that residue per surface area of the cleaned equipment used to manufacture the API
(BL3). The fourth step is to determine the limit of the residue
in the sample actually analyzed by an appropriate analytical technique (BL4) (see sidebar Calculations of residue limits in API
manufacturing).
This paper will consider each calculation separately and then
combined. The author assumes that cleaning is done following
the manufacture of one API (APIA) (see sidebar Key to terms).
At least one target residue, most likely the API itself, will be
identified. In the same equipment (following cleaning), a second API (APIB) will be made. This second API will then be converted into one or more finished drug products (ProdB).

BL1 limit in final dosage form

After identifying the target residue for the cleaned equipment
and the final dosage form(s) of concern for the subsequently
manufactured API, one can calculate the limit of that residue
in the final dosage form. Assuming that the target residue is the
bulk active APIA and that the subsequently manufactured bulk
active (APIB) is formulated into a finished product (ProdB), the
equation introduced in Reference 3 for finished drugs should
be used, i.e.,

BL1

minimum daily dose of APIA

1,000,000 SF [1]
maximum daily dose of ProdB

In this case, BL1 is in parts per million (ppm), and the two
dosage numbers are the same units, such as mg or g. The minimum daily dose of APIA is the minimum daily dose of APIA when
administered in a finished drug product made with APIA. If
APIA is used in several dosage forms, the minimum among the
various dosage forms should be used for this calculation. The
maximum daily dose of ProdB is the maximum dosage of the
drug product containing APIB and is independent of what constitutes that APIB. If APIB is used in more than one finished drug
product, the maximum dosage of the finished product with the
highest maximum dosage should be used. The 1,000,000 figure
represents a conversion to ppm. SF is the safety factor, a value
based on risk analysis, typically 0.001. The calculated BL1 using
Equation 1 represents the maximum allowable concentration
of the target residue in the finished drug product made from
the subsequently manufactured API.
For example, after the manufacture of APIA, the equipment
is cleaned, and APIB is manufactured. APIB is formulated in finished drug ProdB1. If APIA is dosed at 20 mg of active from two
to four times per day and if ProdB1 is dosed at 2000 mg of finished drug product one to three times daily, then Equation 1
becomes

BL1

20 mg 2
1,000,000 0.001 6.67 ppm
2000 mg 3

[1a]

If APIB also is used for manufacturing a second finished drug

product (ProdB2) and this second product is dosed at 1500 mg
two to three times daily, then the BL1 limit for this alternative
situation would be

BL1

20 mg 2
1,000,000 0.001 8.89 ppm
1500 mg 3

[1b]

Although one may be tempted to select the lowest limit here,

both results (the BL1 limits for both ProdB1 and ProdB2) should
be carried forward to the next calculation. This BL1 calculation
only gives the maximum allowable level of target residue (in
this case APIA) in the finished product, ProdB.

BL2 limit in API

The next step is to calculate the maximum allowable residue
in the bulk active itself (that is, in APIB).This calculation is a
simple one because it simply determines the target residue
(APIA) as a portion of bulk active APIB not of the finished
drug (ProdB). This is accomplished by dividing the BL1 limit

by the fraction of active (APIB) in the finished drug (ProdB).

This is expressed as

BL2

BL1 100
%APIB in Prod

[2]

BL2

Because the BL1 limit and the %APIB in ProdB may be different for ProdB1 and ProdB2, the BL2 limit should be calculated
for each combination. Continuing with the same two examples
used for calculations of BL1: If ProdB1 contains 2% of APIB,
then the residue limit of APIA in APIB is calculated as

BL2

6.67 ppm 100

334 ppm
2

[2a]

If ProdB2 contains 4% of APIB, then the residue limit of APIA

in APIB is calculated as

BL2

8.89 ppm 100

222 ppm
4

[2b]

In these examples, BL1 was lower when APIB was formulated in ProdB1, and BL2 was lower for the case involving ProdB2.
If APIB can be used in either finished drug product, the lower
BL2 value (in this case 222 ppm) should be used for further
calculations.

Alternative BL2 calculation

Although the equations presented for BL1 and BL2 help separate the factors that contribute to the BL2 calculation, a simplified equation also can be used. Because

(daily dose ProdB) (%APIB in ProdB)

= daily dose of APIB

(minimum daily dose of APIA) 1,000,000 SF

maximum daily dose of APIB

40 mg 1,000,000 0.001
222 ppm
180 mg

[3a]

Either Equation 2 or Equation 3 can be used to calculate BL2.

Equivalent information is required for either calculation.
For finished products with very low percentages of APIs, the
calculated BL2 limits may be very high, even as high as 1000 ppm
or greater. In such cases, establishing a default limit of 1000 ppm
may be prudent so that residue limits are below the usual 0.1%
threshold that requires analysis and characterization of impurities in APIs dosed at 2 g/day (6). Caution should be taken in
adopting such a default limit because of the misuse of the 10-ppm
default limit that is often used for finished drug products (2). This
default value may be used only if the actual calculated value for
BL2 is 1000 ppm. If the value is 1000 ppm, then that actual
value should be used for subsequent calculations. This bears repeating so it is not misused the important issue is that the default value cannot be adopted automatically; the default value is
used only if the calculated value (the scientifically justified value)
is 1000 ppm.

BL3 limit per equipment surface area

The next step is to calculate the actual residue limit per surface
area of the cleaned equipment before the manufacture of APIB.
This step is basically no different from the surface-area calculations performed for finished drugs. This calculation takes into
account not only the limit of the residue in the subsequently
manufactured product but also the batch size and the equipment shared surface area. BL3 in g/cm2 is calculated as

BL3

BL2 (batch size of APIB) 1000

(shared surface area)

[4]

[2c]

This simplified approach combines Equation 1 into Equation

2 to express BL2 as

BL2

dose for APIB is therefore 180 mg. Using this value for the maximum daily dose of APIB in Equation 3 and the minimum daily
dose of 40 mg for APIA and a SF of 0.001, BL2 is calculated as

[3]

In this case, one must still select the maximum daily dose of
APIB (from among its possible dosing regimens). The result is
the same as Equation 2.
For example, using the information from the examples previously given, APIB will be dosed at a maximum rate of 120 mg
daily (6000 mg 2%) of APIB in ProdB1, and it will be dosed at
180 mg daily (4500 mg 4%) in ProdB2. The maximum daily

where the batch size is expressed in kg and the shared surface

area is expressed cm2. The figure 1000 in this equation converts
the batch size from kilograms to grams. The batch size is the
total amount of API only and does not include functional aids
such as solvents that may be used to facilitate manufacture. In
other words, although 1000 L of solvent may be used to manufacture a batch containing only 20 kg of APIs and is important
for determining product shared surface area, for calculating limits, only the amount of API itself is used for batch-size purposes.
Continuing with the previous example, if the batch size is
20 kg and if the shared surface area is 30,000 cm2, then BL3 is
calculated as

BL3

222 ppm 20 kg 1000

2

30,000 cm

148 g/cm

[4a]

In this case, the resulting BL3 limit of 148 g/cm2 is likely to

be a level of surface contamination that could be observed readily in a visual examination (a typical visual limit is approximately 14 g/cm2) (2,7). Using this scientific approach, most
cases involving residue limits for APIs could involve calculation
of BL3 limits considerably above any visual observation of no
detectable residues.

sample. These calculations may be combined into one equation. However, this should be done cautiously so that the principles underlying the calculation are fully understood. In both
of the following presentations, BL2 is expressed in the simplified form given in Equation 3. An equation for BL3, the surface
area limit in g/cm2, would be:
9

10 (batch size of APIB)

(maximum daily dose of APIB)

(minimum daily dose of APIA)(SF)
(shared surface area)

BL4 limit in the analyzed sample

This step calculates the residue limit in the analyzed sample.
Calculating the limit in the analyzed sample follows exactly the
calculation for finished drug products. For illustration purposes, the following analysis assumes that surfaces are sampled
by swabbing, desorbing the swab into a specified volume of an
appropriate solvent, and then using an appropriate analytical
technique to measure the target residue (APIA) in that solvent
sample. The limit in the analyzed sample in g/mL is

[6]

An equation for BL4, the limit in the analytical sample in

g/mL, would be
9

BL4

BL3 (swabbed surface area)

volume of solvent

[5]

Some scientists also will include the swab recovery factor

(percent recovery) in this equation. That recovery factor can be
included in Equation 5. However, it is preferable to include it
as part of the analytical data transformation so that residue limits do not change as analytical and sampling methods change.
Regardless of how recovery factors are handled, one must be
consistent to avoid a situation in which the recovery factor is
included in both the BL4 limit calculation and the analytical
data calculation. If the recovery factor was included in both calculations, product safety would not be compromised. However,
meeting the resultant calculated BL4 residue limit would be
more difficult.
Continuing with the same example, if the surface area swabbed
is 25 cm2 and the swab is desorbed into 5 mL of solvent, then
the limit in the desorbed solvent sample (in g/mL) is

148 g/cm 25 cm
740 g/mL
5 mL
2

BL4

[5a]

In this case, the BL4 analytical sample limit is considerably

higher than the limit in the bulk active itself (BL2) because of
the leveraging power of the sampling method (3). This effect is
similar to the situation for finished drug products. A similar
type of calculation can be used for collecting samples with a
rinse sampling procedure (8).

Presentation as one equation

These steps flow logically from determining the concentration
limit of a residue that is allowable in a finished product, to calculating the residue level allowed in the API itself, to calculating the allowable residue limit per surface area, and finally to
calculating the allowable residue limit in a specific analytical

10 (batch size of APIB) (minimum daily dose of APIA)

(maximum daily dose of APIB)(shared surface area)

(swabbed surface area)(SF)
[7]
(volume solvent)
Care must be used in expressing units, with both doses in the
same units (preferably mg), the batch size expressed in kg, surfaces areas expressed in cm2, and the desorbed solvent amount
in mL for the 109 factor to be correct. For this presentation of
data, SF is expressed as the decimal equivalent (that is, 0.001
rather than 1000).

Additional issues in API limits

Multiple finished dosage forms for APIA. If APIA is used only in one
dosage form, then these calculations may be relatively straightforward. They become more complex as that API is used in multiple dosage forms, which can then be dosed at various rates. As
discussed in the section on BL2, the BL2 limits for each combination should be calculated and the lowest result should be used
in the BL3 calculation.
Different routes of administration for APIA and APIB. Different
routes of administration would occur if, for example, APIA was
used only for oral dosage finished drugs and APIB was used only
for parenteral finished drug products. In such a case, one would
need information about the parenteral application of APIA to
calculate the appropriate limits. For example, the calculation
based on an application of SF to a no-effect intravenous dose
in animals may be suitable for calculating its limit in a parenteral
finished drug product.
Multiple subsequent API products. When calculating an acceptable BL3 limit per surface area of cleaned equipment following the manufacture of one active (APIA), the case may arise
where, depending on the manufacturing schedule, the cleaned
equipment will be used to manufacture APIs other than APIB,
(e.g., APIC, APID, or APIE). This involves calculating BL1, BL2,
and BL3 for each combination (i.e., APIA followed by APIB, APIA
followed by APIC, APIA followed by APID, and APIA followed by
APIE). In such cases, the lowest BL3 limit is selected for valida-

tion purposes to ensure that any of the other APIs may follow
APIA in the manufacturing order. If this is the situation, one
must also address limits for APIB in light of any of the other
APIs following in the manufacturing order. An alternative is to
consider restricting the manufacturing order, an option that
may or may not be acceptable depending on manufacturing
and economic factors.
Cleaning before a final purification. Any limit established for an
intermediate cleaning step of an API should be established according to how those residue levels contribute to the cleaning
residue levels in the final API. If one can demonstrate that those
residues (intermediates or cleaning agents) are effectively removed from the API during a final purification step (e.g., recrystallization) so that the residue level in the final API is consistent regardless of how much residue is present at any
intermediate step and if that consistent level is below the BL2
limit as calculated above, then one can scientifically argue that
those intermediate cleaning steps are not critical manufacturing steps. If they are not critical steps, then they should not require cleaning validation (9).
By conducting lab studies in which the preparation immediately before final purification is deliberately spiked with a target residue, one can demonstrate that residue levels in the final
API are independent of levels present at intermediate steps.
However, one also should demonstrate this with pilot- or fullscale manufacture. If this approach is taken, then it should be
addressed in the cleaning validation master plan and any specific decision about noncriticality should be documented clearly.
In such case, the final process purification step of the API is
clearly a critical process step and therefore requires process validation. Furthermore, despite the fact that cleaning may not be
validated in such intermediate steps, standard operating procedures for cleaning should be written and followed. Such an
overall strategy also does not relieve one of the obligation to
validate the final cleaning at the time of product changeover.

Summary
Residue limits for APIs for cleaning validation purposes can be
calculated using principles similar to those used for residue limits for finished drug products. The effect of any residue left in
cleaned equipment must be considered in regard to the transfer of that residue to the subsequently manufactured API and
ultimately to the effects of that residue in any finished drug
products made from that API. The fact that APIs are one step
removed from the finished dosage form usually makes scientifically justified residue limits relatively high (as compared with
limits for finished drug products). However, it is important to
make the actual calculations to demonstrate compliance in the
manufacture of APIs where cleaning validation is required.

References
1. FDA, Guide to Inspections of Validation of Cleaning Processes, Division of Investigations, Office of Regional Operations, Office of Regulatory Affairs, July 1993.
2. G.L. Fourman and M.V. Mullen, Determining Cleaning Validation
Acceptance Limits for Pharmaceutical Manufacturing Operations,
Pharm. Technol. 17 (4), 5460 (1993).
3. D.A. LeBlanc, Establishing Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished Drug Products, Pharm. Technol. 22 (10), 136148 (1998).
4. D.A. LeBlanc, Setting Acceptance Criteria, in Validated Cleaning Technologies for Pharmaceutical Manufacturing (Interpharm Press, Englewood, CO, 2000), pp. 135150.
5. PhRMA Quality Committee, Bulk Pharmaceuticals Work Group,
PhRMA Guidelines for the Validation of Cleaning Procedures for
Bulk Pharmaceutical Chemicals, Pharm. Technol. 21(9), 5673 (1997).
6. ICH Q3A(R), Draft Consensus Guideline, Impurities in New Drug
Substances, 7 October 1999.
7. K.M. Jenkins and A.J. Vanderweilen, Cleaning Validation: An Overall Perspective, Pharm. Technol. 18 (4), 6073 (1994).
8. D.A. LeBlanc, Rinse Sampling for Cleaning Validation Studies, Pharm.
Technol. 22 (5), 6674 (1998).
9. ICH Q7A, Draft Consensus Guideline, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, 19 July 2000. PT

Reprinted from PHARMACEUTICAL TECHNOLOGY, October 2000

Printed in U.S.A.

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