PEER-REVIEWED

Cleaning Limits—Why the

10-ppm Criterion Should Be Abandoned
Michel Crevoisier, Ester Lovsin Barle, Andreas Flueckiger, David G. Dolan, Allan Ader, and Andrew Walsh

The 10-ppm criterion for the acceptable

concentration of potential API in cleaning validation
to minimize cross contamination into to next product
T he revised Chapter 5 of Part 1 of the European Union’s
GMP guidelines and the European Medicines Agency’s
(EMA) Guideline on Setting Health Based Exposure Limits
has been employed for many years. It is, however, for Use in Risk Identification in the Manufacture of Different
arbitrary and does not take into account advances Medicinal Products in Shared Facilities came into effect
in toxicological risk-assessment methodologies in 2015 (1, 2). Both publications expect the industry to
that allow for robust and scientifically supportable use a “quality risk management process, which includes
approaches to establish safe or acceptable levels a potency and toxicological evaluation” when deciding
of a drug from one product to the next. Recent whether to use dedicated or shared facilities to produce
guidelines issued by the International Society of pharmaceuticals. Consequently, the same comprehensive
Pharmaceutical Engineers in 2010 and the European approach based on health risks should be followed to
Medicines Agency in 2014 employ health-based determine the acceptable limits set for cleaning shared
risk assessments as the basis for establishing equipment. The authors believe it is the right time to
acceptable limits of residual APIs into the next abandon the 10-ppm rule in favor of more scientific and
product manufactured and most importantly are data-driven health based limits.
protective for patient safety. This article describes
why the 10-ppm criterion, which was established Reasons for abandoning the 10-ppm rule
based on analytical limitations and estimates of Health authorities do not require shared equip -
acceptability, is no longer necessary and why a risk- ment to be cleaned to 10 ppm of the next product.
based approach should be universally adopted. Careful reading of GMP regulator y texts (3–11), FDA’s
Guide on Inspections—Cleaning Validation (12), and the
Pharmaceutical Inspection Convention and Pharmaceutical
Inspection Co-operation Scheme’s (PIC/S) Recommendations
on Cleaning Validation (13) yields no indication that any of
these health authorities or PIC/S ever explicitly prescribed
numerical cleaning limits. When it comes to cleaning limits,
these guidelines all follow a similar discourse—they expect
companies to abide by a general duty of care, sometimes
adding that the limits should be “based on the knowledge of
the materials involved.” Some of the texts mention the three
traditional rules originally proposed by Fourman and Mullen
(14) (i.e., visually clean equipment, residue levels ≤ 1/1000th
Michel Crevoisier is senior cleaning validation expert at Novartis
Pharma; *Ester Lovsin Barle is head of health hazard assessment
daily dose, and ≤10 ppm of next product) as examples but
center of excellence at Novartis Pharma; Andreas Flueckiger never as binding rules. In this case, consistent with other
is chief occupational health officer at Roche, David G. Dolan is performance-based regulations, the responsibility to estab-
director, Occupational, Environmental & Quality Toxicology at Amgen; lish and justify cleaning limits for shared facilities remains
Allan Ader is vice president at SafeBridge Consultants; and Andrew with pharmaceutical manufacturers.
Walsh is principal, PharmaClean Group, LLC and industry professor at The 10-ppm limit goes against the basic principle of
Stevens Institute of Technology.
toxicology that it is the dose that makes the poison.
*To whom all correspondence should be addressed.
Parts per million (ppm) is a concentration unit (i.e., a
The views expressed in this article are those of the authors relative number and not an absolute one). In chemistry
and not necessarily of their respective companies. parlance, it is an intensive property (such as density or
melting point) that is independent of the amount of the
Submitted: June 7, 2015. Accepted: June 22, 2015. material, and as such, it is not suitable to describe a dose,
which is an extensive property (such as mass or volume)
52 Pharmaceutical Technology JANUARY 2016 P h a r mTe c h . c o m
 Cleaning Limits

Figure 1: The weight of scientific justification of the three approaches of calculating the maximum safe surface
residue (MSSR) based on the 10 ppm, 1/1000 of the daily dose and permitted daily exposure (PDE) criteria.

MSSR based on MSSR based on MSSR based on

10 ppm 1/1000 daily dose PDE
Pharmacokinetics

Pharmacodynamics

Preclinical data

Clinical data

Minimal therapeutic dose Minimal therapeutic dose

Maximal therapeutic dose Maximal therapeutic dose

Batch size Batch size Batch size

that is dependent on the amount of material. Defined as a administered to the patient. Assuming that therapeutic
concentration, the limit dose will depend on the maximum doses range from 0.1 mg to 5000 mg per day, the amount
amount of something else, in this case, on the amount of a contaminating substance corresponding to 10 ppm
of the following product (or API, the approaches vary) will span the same range of 4 logs. Using a limit of 10 ppm

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Pharmaceutical Technology JANUARY 2016 53

Cleaning Limits

Table I: Basic data for 11 APIs made in a shared facility.

Equipment surface
Maximum daily dose PDE
Product (API) Batch size [kg] used to make the
[mg] [μg]
product [m2]

A 40 582 99 7

B 200 691 125 67

C 2000 179 99 200

D 300 330 180 83

E 100 470 188 83

F 300 1074 188 33

G 1440 216 59 10

H 100 310 78 333

I 750 207 220 15

J 3000 335 99 1000

K 450 120 99 5

without risk characterization of exposure is equivalent Can 10 ppm be used to identify risks according
to pretending that it makes no difference if a drug is to the EMA guideline on shared facilities?
contaminated by 1 ng (the equivalent of 10 ppm of 0.1 mg) The EMA guideline (2) describes primarily a method for com-
or by 50 mcg (the equivalent of 10 ppm of 5000 mg) of the puting health-based limits based on all available toxico-
same substance. logical and pharmacological information, which are termed
Whether the contaminant is Botox or a mild antacid, permitted daily exposure (PDE). The guideline’s focus is not
the limit amount computed by 10 ppm will be the same. on how to set cleaning limits. The PDEs are only one ele-
Therefore, involvement of a risk assessment scientist (e.g., ment needed to set cleaning limits, which are calculated as
toxicologist or physician) is crucial for the characterization MSSR. The other element is the knowledge of the efficiency
and differentiation of health risks and the overall risk of a cleaning process, which is independent from the next
management process. Figure 1 compares the weight of product. Therefore, while there is a link between PDEs and
scientific justification for three different approaches to cleaning limits, they are absolutely not the same. This is
compute the maximum safe surface residue (MSSR). In expressed in the EMA guideline, which says, “these levels
contrast to approaches targeting 10 ppm and 1/1000th of can be used as a risk identification tool and can also be used
the daily dose, the permitted daily exposure (PDE) approach to justify carryover limits used in cleaning validation.”
ensures that available preclinical and clinical data are An evaluation of the effect of using 10 ppm in addition to
considered in computation of the MSSR. PDE to identify risks was performed with the example of an
actual product portfolio of a multiproduct API manufacturing
Does the 10-ppm limit ensure good cleaning? facility making 11 different APIs. The basic data of the APIs
No; 10 ppm is a concentration unit that gives no indication are given in Table I.
on cleanliness. Operationally, a sensible physical unit for All changeovers from a preceding product (α) to a following
cleanliness must express the amount of residue per unit sur- product (β) were considered. The matrix of maximum
face area (e.g., mg/m2). By switching from carryover (amount safe carr yovers (MSC) was first calculated according
of residue [g]) to cleanliness [mg/m2], the surface is normal- to Equation 1. In a second step, the matrix of MSSR was
ized, and the cleanliness of all pieces of equipment of a calculated by dividing the MSC by the equipment surface
facility can be compared; cleaning results between facilities area used to make each following API (see Equation 2).
and even between companies can also be compared. When Each cell of the MSSR matrix shown in Table II reflects
speaking of cleanliness, the size of the equipment does an individual product change from an API α to an API β
not matter; “cleanliness” is an intensive property of the and contains the MSSR for the particular change (i.e., the
equipment. Therefore, until the 10 ppm has been converted cleanliness required to make the corresponding API β when
into a cleanliness value in [mg/m 2], it is not possible to say it is made after API α).
what level of cleanliness the 10 ppm eventually represent. The PDE-based matrix in Table II shows a vivid landscape
Depending on the particular situation, 10 ppm may mean with strong contrasts, with values from 5 to 146,970 mg/m2.
1 mg/m 2, which can be hard to reach, or 50 mg/m 2, which It is easy to identify the changeovers that pose the greatest
should be easy to reach. risks. Comparing the calculated MSSRs with the results of
54 Pharmaceutical Technology JANUARY 2016 P h a r mTe c h . c o m
 Cleaning Limits

Table II: Matrix of maximum safe surface residue (MSSR) based on permitted daily exposure (PDE).
MSSR values < 25 mg/m2 are underlined.

Following Product:
Preceding
A B C D E F G H I J K
Product
A 193 6 43 175 133 18 278 9 8 19
B 9847 61 409 1675 1276 170 2663 84 76 180
C 29394 5528 1222 5000 3809 508 7949 251 226 539
D 12198 2294 75 2075 1581 211 3299 104 94 224
E 12198 2294 75 507 1581 211 3299 104 94 224
F 4850 912 30 202 825 84 1312 41 37 89
G 1470 276 9 61 250 190 397 13 11 27
H 48941 9204 301 2035 8325 6341 847 418 376 897
I 2205 415 14 92 375 286 38 596 17 40
J 146970 27640 904 6111 25000 19043 2542 39744 1255 2694
K 735 138 5 31 125 95 13 199 6 6

Table III: Maximum safe surface residue (MSSR) (mg/m2) required when the 10-ppm criterion is applied compared to
the lowest MSSR required by applying the permitted daily exposure (PDE). MSSR < 25 mg/m2 are underlined.

Based on: A B C D E F G H I J K
10 ppm: 59 55 18 18 25 57 37 40 9 34 12
PDE: 117.6 110.6 4.5 30.6 50.0 95.2 12.7 79.5 6.3 5.6 13.5

approximately 250 swab results that were gathered over

two years, 99% of all swabs gave results <25 mg/m 2; high-
risk changeovers are identified as the ones that require a EMBO CAPS® - DESIGN
MSSR of < 25 mg/m2.

PDEα [μg] × Batch size β [kg] FOUR EMBO® SIX PRE-LOCK

MSC α [g] =
Maximum Daily Dose β [mg] [Eq. 1]
X X
X

AIR VENT
MSC α [g] × 1000
MSSR α [mg/m2] = [Eq. 2]
Surface for β [m2] SLOPED EDGE
X

EMBOs PREVENT
“SEMI-LOCK” BEFORE and MAIN LOCK
For example, the changeover from product D to product E SEPARATION AFTER FILLING
was calculated as follows:

83 μg × 470 kg
. Non-animal based capsules
Made from hypromellose (HPMC)
MSCD =
100 [mg]
83 × 10 -6 g x 470 × 103 g
. Extremely suitable for hygroscopic/
ŵŽŝƐƚƵƌĞƐĞŶƐŝƟǀĞŵĂƚĞƌŝĂůƐĂŶĚ
= ĨŽƌŵƵůĂƟŽŶƐ
100 × 10 -3 g ůƐŽƐƵŝƚĂďůĞĨŽƌĮůůŝŶŐůŝƋƵŝĚƐ

= 390.1 g
. 'ƌĞĂƚĂůƚĞƌŶĂƟǀĞƚŽĐŽŶǀĞŶƟŽŶĂů
ĐĂƉƐƵůĞƐĨŽƌǀĂƌŝŽƵƐĐƵůƚƵƌĂů#ƌĞůŝŐŝŽƵƐ#
and dietary requirements
Kh<ŽƐŚĞƌ!/&E,ĂůĂůĞƌƟĮĞĚ

390.1 g × 1000 www.suheung.com

MSSRD = 428 E. SATURN ST. BREA CA 92821
188 m2 [email protected] Tel:714.854.9887 | Fax:714.854.9896

= 2075 mg/m2
Pharmaceutical Technology JANUARY 2016 55
Cleaning Limits

Five products C, G, I, J, and K are potentially at risk, but the identification and analysis of cross contamination risks.
only when they follow certain products, like A, G, I, and Moreover, it may impose more stringent limits for cleanli-
K. Similarly A, G, I, and K represent a risk for the other ness than are required by health authorities without adding
products, but not for all of them. to the patient safety. Eliminating an unnecessary require-
The comparison of the matrix of MSSR based on PDE with ment serves to focus attention and resources on high-risk
the known efficiency of the cleaning processes allows for a situations. The 10-ppm criterion offers no scientific or prac-
sound identification of risks in line with the spirit of the EMA tical benefit and can be discontinued in cleaning validation
guideline. The comparison may give the concept of “worst- practice.
case approach to cleaning validation” a new orientation by
shifting the focus from the hazards of worst-case products Acknowledgements
(with regard to solubility, cleanability, toxicity, etc.) to the The authors would like to thank Ed Sargent and Courtney M.
worst-case risks, (i.e., to the “risky” changeovers between Callis for their views during compilation of this manuscript.
two products). Such risks will have to be mitigated, for
example, by development of better cleaning procedures, References
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scheduling and dedication of certain process lines or parts the European Union; Volume 4 EU Guidelines for Good Manufacturing
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cleaning alone. Identification in the Manufacture of Different Medicinal Products in
How does the risk identification work with the 10-ppm Shared Facilities (London, November 2014).
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of high risks. Practice for Finished Pharmaceuticals, www.accessdata.fda.gov/scripts/
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in Table III is followed, whenever C, D, I, or K is made, the sobre as Boas Práticas de Fabricação de Insumos Farmacêuticos Ativos
manufacturer has to meet the MSSR dictated by 10 ppm. (Brazil, December 2014).
The assumed cleaning limit of 25 mg/m 2 will not meet the 7. Agência Nacional de Vigilância Sanitária—Anvisa, Validação de limpeza
requirement to make C, D, I, or K in any case, independently para farmoquímicas, http://portal.anvisa.gov.br/wps/wcm/connect/244
of what the preceding product was. 3e9804f1af51ea138bdc88f4b6a31/Guia+de+valida%C3%A7%C3%A3o+d
The high MSSR values in Table II merely reflect the low e+limpeza+para+Farmoqu%C3%ADmicas.pdf?MOD=AJPERES, accessed
risk associated with the corresponding changeovers. They Dec. 1, 2015.
should not be read as cleaning limits. The suspicion that 8. Health Canada, Cleaning Validation Guidelines, Guide-0028 (Ontario,
production will set the cleaning limit at the level of the January 2008).
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for particular changeovers are high, this does not justify Human Use, Enforcement Regulation of Pharmaceutical Affairs Act
reducing the cleaning effort, because cleaning will still [Annex 2], http://wenku.baidu.com/view/42de6028ed630b1c59eeb53e.
have to fulfill the requirement of visually clean equipment. html, accessed Dec. 1, 2015.
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There is no scientific justification for a limit concentration Operational Qualification, Non-Sterile Process Validation, Cleaning
that ignores the hazards presented by potential contami- Validation; PI 006-03 (September 2007).
nants. Implementation of the 10-ppm criterion in cleaning 14. G.L. Fourman and M.V. Mullen, Pharmaceutical Technology, April issue,
validation does not ensure safe cleaning. and it may distort 54-60 (1993). PT
56 Pharmaceutical Technology JANUARY 2016 P h a r mTe c h . c o m