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An ADE-Derived Scale For Assessing Product Cross-Contamination Risk In Shared Facilities

  • Center for Pharmaceutical Cleaning Innovation, LLC
  • Private; freelance consultant

Abstract and Figures

This article discusses how to derive a Toxicity Scale from the ADE (with scores form 1-10) and how the ADE of any compound can be directly converted into a score on this scale. This Toxicity Scale can be used to quickly assess the potential for the risk of cross contamination in manufacturing situations through an easy to use visual scale. This Toxicity Scale can be used as the "Severity" Score in FMEAs of Cleaning Processes.
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An ADE-Derived Scale For Assessing Product Cross-An ADE-Derived Scale For Assessing Product Cross-
Contamination Risk In Shared FacilitiesContamination Risk In Shared Facilities
By Andrew Walsh; Ester Lovsin Barle, Ph.D.; Michel Crevoisier, Ph.D.; David G. Dolan, Ph.D.; Andreas
Flueckiger, MD; Mohammad Ovais; Osamu Shirokizawa; and Kelly Waldron
Part of the Cleaning Validation for the 21st
Century series
By Andrew Walsh; Ester Lovsin Barle, Ph.D.;
Michel Crevoisier, Ph.D.; David G. Dolan, Ph.D.;
Andreas Flueckiger, MD; Mohammad Ovais;
Osamu Shirokizawa; and Kelly Waldron
Beginning in 2004, a global team of
pharmaceutical toxicologists, industrial
hygienists, quality assurance professionals, a
cleaning validation professional, and a
representative from the US FDA participated in the development of the International Society for
Pharmaceutical Engineering's (ISPE) Risk-Based Manufacturing of Pharmaceutical Products (Risk-
MaPP) Baseline Guide. The purpose of the Risk-MaPP Guide was to provide a "scientific, risk-based
approach to manage the risk of cross-contamination." The Risk-MaPP Guide was based on the
International Conference on Harmonisation's Quality Risk Management Guideline (ICH Q9) and
encouraged the "selection of the appropriate risk control strategies to be implemented on a case-by-case
basis to maintain patient safety and assure product quality."
Guidance On Managing Risk In Shared Facilities
From a cGMP (quality) perspective, Risk-MaPP provided guidance on how to manage the risk of product
cross-contamination in shared facilities, from the four main sources the Risk-MaPP guide identified:
1. Mix-up (wrong material being used)
2. Retention (residues left in equipment after cleaning)
3. Mechanical transfer (transfer of material on contaminated non-product contact surfaces )
4. Airborne transfer (material movement through air)
During the planning meetings for the Risk-MaPP Guide, the FDA specifically requested that this guide:
provide an approach to quantify the toxicity of drugs
provide a risk management/assessment model that gives a clear view on how to address the
controls to comply with 21 CFR 211.42(c) — for separation/dedication in facilities, etc.
discuss how the approach fits into cleaning validation.
ADE As A Metric For Assessing Risk
In 2010, the Risk-MaPP Guide was published and introduced the acceptable daily exposure (ADE) as an
appropriate metric for assessing pharmaceutical manufacturing risks for worker exposure, and for
patient safety (e.g., in cleaning validation), as it is a value based on all the available pre-clinical and
clinical data for a compound. In accordance with the principles of ICH Q9, the level of controls required
— and the level of effort, formality, and documentation needed (including validation) — are
commensurate with the level of risk. Consequently, it is critical to have a means of measuring the level of
risk. It should be understood from this article that simply dividing compounds into two classes (highly
hazardous and non-hazardous) is fallacious, and that the hazards that drugs present to patients should
Guest Column | May 22, 2017
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be viewed on a continuum, as envisioned by Risk-MaPP. This article presents a new hazard rating scale
approach derived from the ADE concept that can be used as a visual tool to quickly evaluate and
prioritize the relative hazards posed by drugs manufactured in a shared facility or equipment train.
ICH Q9 And Applying Risk In The Manufacturing Environment
The principles behind applying risk in pharmaceutical and biopharmaceutical manufacturing were
introduced in ICH Q9, which was formally adopted by US FDA in 2006. ICH Q9 mentioned its
applicability to cleaning (including acceptance limits) in Annex II.4 and to validation in Annex II.6.
According to ICH Q9, risk is defined as the combination of the probability of occurrence of harm and the
severity of that harm. This can be expressed as:
Risk = f (Severity of Harm, Probability of Occurrence of That Harm)
Risk, in terms of a hazard (i.e., the potential source of harm), can also be expressed as:
Risk = f (Severity of a Hazard, Level of Exposure to That Hazard)
If the hazard is intrinsic to an active pharmaceutical ingredient (API), then this general
equation can be further refined to:
Risk = f (Toxicity , Level of Exposure )
Calculating Cleaning Risk
Patient risk for adverse effects increases as exposure to a given API or other compound rises above the
ADE (which is synonymous with the permissible daily exposure [PDE]; and health-based exposure limits
[HBEL], as used in the EU ). This risk is a function of the unique dose-response-duration relationship
for each compound and the level of exposure to the compound from, for example, residual API carryover
after cleaning. Note that this methodology can be applied to any agent or compound, and is therefore not
exclusive to APIs. Consequently, the ADE provides a value that can be used as a surrogate for severity to
calculate the potential cleaning risk, as shown in the following equation:
Cleaning Risk = f (ADE , Level of Exposure )
This equation tells us that the risk to a patient from cleaning is a function of the toxicity of the drug and
the level of exposure (residues) found after cleaning.
Introducing The Toxicity Scale and Toxicity Scores
Since ADE values vary over several orders of magnitude, they are hard to compare directly. However, to
facilitate such a comparison, the values can be converted into a logarithmic scale in a manner similar to
that used to create the pH scale. By converting the ADE values into units of grams per day and taking
their negative logarithms, a continuous toxicity scale can be generated, as shown in Table 1. The resulting
toxicity scores are shown ranging from 0 to 10. However, it should be understood that toxicity score
values above 10 and below 0 can still be legitimately obtained.
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Similar to how the pH scale provides a convenient means of quickly assessing and comparing the acidity
or alkalinity of solutions, this toxicity scale can be used as a means of comparing the toxicities or hazard
levels of pharmaceutical compounds.
Practical Examples And Insights
For example, in Figure 1, the ADE values for four well-known compounds were converted to this toxicity
scale. The first compound is dioxin (i.e., 2,3,7,8-Tetrachlorodibenzo-p-dioxin), a well-known and very
hazardous compound with an ADE of 35 picograms/day (toxicity score = 10.5). The second compound is
arsenic trioxide, a relatively hazardous compound used to treat acute promyelocytic leukemia, with an
ADE of 13 µg/day (toxicity score = 4.9). The APIs also include two low-hazard compounds: aspirin, with
an ADE of 5 mg/day (toxicity score = 2.3), and sodium chloride, with an ADE of 26 mg/day (toxicity
score = 1.6).
Figure 1: Comparison of pH and toxicity scales
While it is not unexpected to see aspirin and sodium chloride occupying the low end of the toxicity scale
and dioxin at the high end, readers may find it surprising to see arsenic trioxide, a compound most
people would consider to be quite hazardous, occupying a place at the midpoint of the scale. This
illustrates the ADE concept at work: The toxicity of a compound is dose-dependent, so while higher doses
of a compound may generate extreme adverse effects, somewhat lower doses may be harmless. The
toxicity scale helps to reveal this in relation to other compounds/APIs. It should also be understood that
exceeding the ADE by a small amount does not necessarily put patients at risk. For example, a swab
result exceeding the ADE-derived limit by a small amount during a cleaning validation study is not an
immediate cause for alarm.
A Large-Scale Study Demonstrating The Toxicity Scale Concept
In our previous article , the ADEs of 304 APIs were compared to their 0.001 dose-based limits as a
demonstration of how inaccurate and overly conservative the 0.001 dose-based approach is in estimating
safe levels for exposure in patients, which could lead to impractical and unachievable limits. The
distribution of these ADE values fits well within the presented scale, with an average toxicity score of 3.7;
a median of 3.6; a mode (16 compounds) of 3.3; and a slightly positive skewness of 0.42, indicating a
fairly normal distribution for these values (Figure 2). While the analysis did not include all known
pharmaceutical compounds, a significant sample of these compounds was represented, with the results
indicating that there was not a bias toward highly toxic or relatively nontoxic compounds in the dataset.
The analysis also demonstrates that the toxicity scale encompasses the typical range of ADEs quite well.
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Figure 2: Histogram of ADE-derived toxicity scores for 304 APIs
Practical Uses Of The Toxicity Scale
The toxicity scale can be used to visualize and, quite quickly, understand the relative hazard of different
compounds that are manufactured in a common facility. The scale can also satisfy the US FDA's desire
for a tool that both identify the hazard of a drug from a maximum safe carryover (MSC) perspective and
provides a linkage to cleaning validation. Figure 3 provides examples of how the toxicity scale can be
used to visualize the hazards of drug products (as expressed by their toxicity scores and, thus, their
ADE values) manufactured in facilities where the hazards are low, moderate, and high; and one where
the hazards are mixed.
Figure 3: Comparison of four facilities with five products each, using the toxicity scale
In the above examples we can clearly see that, in Facility A, the products are of very low hazard. To
manage the risks of operator and patient exposure, this facility would not need to employ the same level
of controls as a facility with high-hazard products. Conversely, Facility C handles highly hazardous
products and would need to have significant controls in place. It should be understood that, all other
factors being relatively equal, lower-hazard products mean lower manufacturing risk and higher-hazard
products mean higher manufacturing risk. Using this model, a company can quickly assess whether one
facility requires a greater degree of controls than another facility, or, as suggested by the Risk-MaPP
Guide, whether a given product is appropriate for introduction and manufacture in an existing facility
with its equipment and cleaning practices, or whether adaptation of one or the other is necessary.
Applications To Cleaning Validation
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From a cleaning perspective, it should also be clear that Facility A has very low hazards associated with
its products, and therefore should not have to put the same cleaning validation program in place that
Facility C may require. Facility A may actually be able to use "visually clean" as its sole acceptance
criterion for cleaning validation if the maximum safe surface residues (MSSRs) calculated from these
ADEs are well above the level that is visible and all surfaces are capable of being inspected. There may
also be limited need, or no need, for any continued monitoring based on risk management criteria of an
individual facility. On the other hand, the MSSRs for Facility C would most likely be well below the level
that is visible for these APIs, so swab/rinse sampling would be required and specific analytical methods
may even be needed. Continued monitoring may be necessary. Facility D presents a unique mixture of
low, medium, and high hazards. In a case such as this, comprehensive manufacturing controls,
swab/rinse, sampling, and continued monitoring may be necessary after Drug 1 (toxicity score = 9.6).
Decontamination and other cross-contamination mitigation steps may even be necessary. But Drug 4
(toxicity score = 2.7) and Drug 5 (toxicity score = 2.5) may only require "visually clean" as their sole
acceptance criterion for cleaning validation, especially if they are followed by products with low
maximum daily doses.
Benefits To Regulators
The toxicity scale can benefit regulators, as well, since an inspector seeing an API toxicity scaling graphic
within a facility risk assessment may choose to focus less inspection effort on the cross-contamination
controls for Facility A, and move on to Facility C, which presents higher cross-contamination risk. Based
on the relatively hazardous products manufactured in Facility C, it would be appropriate for an inspector
to spend more energy exploring the cross-contamination controls for such a facility. Facility D has a mix
of low-, moderate-, and high-hazard products, and may have different levels of controls in place for
handling them. As such, inspectors might elect to investigate how this facility handles these products and
may want to focus their inspection on the risk reduction and cross-contamination controls due to Drug 1
and how these products interact with the other products (e.g., mix-up, retention, mechanical transfer,
and airborne transfer).
As stated earlier, the US FDA, EU, and other health authorities have, during the development of the Risk-
MaPP Guide and through other published guidelines, expressed a strong interest in an "approach for
identifying highly hazardous drugs." We believe that dividing pharmaceutical compounds into two
classes, highly hazardous and non-hazardous, cannot be scientifically justified, and that the hazards that
drugs present to patients should be viewed on a continuum. The new toxicity scale described in this
article provides such an approach, and potentially could be used:
1. to visually compare the hazard levels or toxicities of pharmaceutical compounds processed within
the same or across different facilities
2. as a measure of severity in assessing cross-contamination risks in facilities and identifying or
determining appropriate control strategies
3. to communicate relative severity levels of hazards to internal (e.g., QA, RA) and external (e.g.,
customers, regulators) stakeholders
4. by manufacturers as a tool to quickly assess if a new product can be introduced into an existing
5. to assist inspectors in identifying facilities and areas with the greatest risk to focus on prior to or
during their inspections, potentially accelerating inspections — a benefit to both regulator and
6. as a health-based severity scale for use in cleaning process FMEAs/FMECAs (failure mode and
effects analysis/failure modes, effects, and criticality analysis).
Future Publications
The toxicity scale presented in this article provides a way to measure the relative toxicity of compounds
with regard to cross-contamination. A subsequent article will discuss a new scale for probability based on
process capability values. Another article will discuss a new scale for detectability based on visual residue
limits (VRLs) and maximum safe surface limits. A final article will discuss how these three scales in
combination can be used in FMEAs/FMECAs for risk assessment of cleaning or other processes.
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The authors wish to thank Thomas Altmann; James Bergum, Ph.D.; Alfredo Canhoto, Ph.D.; Parth Desai;
Mallory DeGennaro; Igor Gorsky; Michael Hyrtzak, Ph.D.; Robert Kowal, Mariann Neverovitch; and Joel
Young for reviewing this article, and for their insightful comments and helpful suggestions.
1. ISPE Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products: A Guide to Managing
Risks Associated with Cross-Contamination. (ISPE, Tampa, FL, First Edition, 2010), Vol. 7, p. 186.
2. ICH Q9: Quality Risk Management (Step 4) (International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH], London, 2005).
3. EMA Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the
Manufacture of Different Medicinal Products in Shared Facilities,
About The Authors:
Michel Crevoisier retired from Novartis Pharma in 2015. In his last position, he was a senior QA expert
for qualification and validation.
David Dolan, Ph.D., is an occupational, environmental, and quality toxicologist at Amgen Inc.
Andreas Flueckiger has been in charge of occupational health including occupational toxicology in the
Roche Group for 30+ years. His department also establishes Roche's health-based limits values used in
GMP cleaning.
Ester Lovsin Barle is head of health hazard assessment in Novartis Global HSE & BCM, where she is
responsible for development of health-based exposure limits (HBELs), occupational toxicology, and
patient safety-related process in support of manufacturing in Novartis globally.
Mohammad Ovais is scientific affairs manager for Xepa-Soul Pattinson (M) Sdn Bhd, Malaysia and a
long-time student of cleaning validation.
Osamu Shirokizawa is a director and senior consultant of Life Scientia Limited, a pharmaceutical
engineering and consultancy firm.
Kelly Waldron is a senior consultant with Valsource and a regulatory science researcher with the
Pharmaceutical Regulatory Science Team at the Dublin Institute Technology.
Andrew Walsh is president of the Center for Pharmaceutical Cleaning Innovation, a non-profit research
and educational organization.
... Another recent article has shown how these residues can be compared to true health-based limits to determine the "margin of safety" the removal of these residues provides which also offers an indication of the level of risk. This "margin of safety", or level of risk, can be quantified using the statistical technique of Process Capability (20). As with the Toxicity Scale derived from the PDE, it would be convenient and informative to have a similar scale for Process Capability. ...
... Another Scale has been developed that is converts the Process Capability value into a value on a "Process Capability Scale" which ranges from 0 -10, with 0 being the lowest exposure level and 10 being the highest exposure level. This scale is also potentially useful as a scale for Occurrence or Likelihood FMEAs (20). While these scales have several potential applications, at the most basic level they can be used to clearly visualize the level of risk, and for the purposes of this article, why HPAPI does not necessarily translate to "high risk". ...
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The terms highly hazardous, highly active and highly potent are often used in mixed or inconsistent contexts regarding good manufacturing practice and worker safety. This article provides an overview of definitions and criteria used for classifying active pharmaceutical ingredients (APIs) and the use of these terms for identification of risks in cleaning validation. While competent toxicological evaluation is required to identify and characterize the health hazards for each drug substance and then calculate a health based exposure limit, further steps in risk assessment for cross-contamination include batch size, maximal daily dose of subsequent products, equipment surface areas, cleaning process parameters and process capability. Risks presented by drug substances cannot be managed by simple classification into highly potent and highly hazardous categories.
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In April of 2018, the European Medicines Agency (EMA) posted a Q&A on their guideline for setting health-based exposure limits. In it, two new questions and answers appeared (Q#7 and Q#8) that are directly applicable to the use of visual inspection in cleaning. In these two Q&As, the regulatory requirements for implementing visual inspection as one of the tools available for cleaning validation were now rather well defined and all that was needed now was a detailed guidance on how to implement cleaning programs that satisfy these criteria. In March of 2019, members of the ASTM E55 Committee on Manufacture of Pharmaceutical and Biopharmaceutical Products and members of the ASTM F04 Committee on Medical and Surgical Materials and Devices collaborated on writing a new Standard Guide on Visual Inspection that resulted in the publication of ASTM E3263-20 in December 2020. The ASTM E3263-20 had been written, in part, to provide the necessary guidance for establishing qualified visual inspection programs to comply with these newly clarified regulatory expectations. A detailed article introducing the standard was announced in social media discussion groups involved with pharmaceutical and medical device cleaning. Shortly after announcing these articles, the article authorship team was contacted by a former inspector with the Medicines and Healthcare Products Regulatory Agency (MHRA) to obtain a copy of this standard, which was provided by ASTM. After review, the former MHRA inspector asked if it was possible to make some revisions to make the standard more acceptable to the Pharmaceutical Inspection Co-Operation Scheme (PIC/S), which had recently adopted the European Medicines Agency’s (EMA) Q&A on Health Based Exposure Limits. The E55/F04 Joint Cleaning Team initiated a new Work Item on the ASTM website to revise the ASTM E3263 with the participation of the former MHRA inspector, and with the addition of a WHO inspector and three representatives of the FDA. This article is focused on the updates as compared to the 2020 Standard
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The International Congress on Harmonization Quality Risk Management Guidance (ICH Q9) lists both cleaning (in Annex II.4) and validation (in Annex II.6) as potential areas for the application of quality risk management. This clearly implies that the ICH Q9 principle for adjusting the level of "effort, formality, and documentation" based on the level of risk could be applied to cleaning and its validation. Previous articles discussed how science-based and data-derived scales could be created from HBELs (health-based exposure limits), from the process capability (Cpu) of cleaning processes, from the detection limits for total organic carbon (TOC) analyses of these compounds, or from visual inspection. Another article discussed how these scales could be used to measure the level of risk in cleaning validation. This article builds on these discussions and shows how these HBEL-based and process capability-based scales can be combined into a matrix that provides a clear visual guide for adjusting the level of effort, formality, and documentation for cleaning validation based on the level of risk.
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This article discusses how the detection limit for analytical methods can be combined with cleaning validation swab limits to create a detectability scale similar to that described in our earlier article on visual inspection. This new detectability scale can assist in determining whether an analytical method is acceptable for use in a cleaning validation or verification. Combined with the HBELderived toxicity scale and Cpu (process capability)-derived probability scale, it can also provide for a total measure of risk in cleaning.
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Two previous articles discussed how the acceptable daily exposure (ADE) of a compound and the process capability (Cpu) of its cleaning process can be used to assess the level of risk associated with cross contamination in shared facilities. This article will discuss how the maximum safe surface residue (MSSR) can be combined with the visual residue limit (VRL) to assess the acceptability of visual inspection for detecting the possibility of compound carryover in shared facilities. Combined with the ADE-derived toxicity scale and Cpu-derived probability scale, this new detectability scale can provide for a total measure of risk, and this new scale can also assist in determining whether visual inspection is acceptable for use in cleaning validation or verification.
Risk-Based Manufacture of Pharmaceutical Products: A Guide to Managing Risks Associated with Cross-Contamination
  • Ispe Baseline Guide
ISPE Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products: A Guide to Managing Risks Associated with Cross-Contamination. (ISPE, Tampa, FL, First Edition, 2010), Vol. 7, p. 186.
is an occupational, environmental, and quality toxicologist at
  • David Dolan
David Dolan, Ph.D., is an occupational, environmental, and quality toxicologist at Amgen Inc.