ASTM E3106-22

Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation

SIGNIFICANCE AND USE
4.1 Application of the approach described within this guide applies risk-based concepts and principles introduced in ICH Q9. As stated in ICH Q9, the level of effort, formality, and documentation for cleaning should also be commensurate with the level of risk.  
4.2 Application of the approach described within this guide applies many of the science-based, risk-based, and statistical concepts and principles introduced in the FDA’s Guidance for Industry Process Validation: General Principles and Practices   (3) and Quality Management Maturity for Finished Dosage Forms Pilot Program for Domestic Drug Product Manufacturers; Program Announcement.  
4.3 This guide supports, and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, ICH Q11, and ICH Q12.  
4.4 This guide supports and is consistent with the content and intent of ISO 14971.  
4.5 Key Concepts—This guide applies the following key concepts: (1) quality risk management, (2) science-based approach, (3) statistics-based approach, (4) process understanding, (5) continued improvement, and (6) life-cycle management as described in the ICH Q series.
SCOPE
1.1 This guide applies the life-cycle approach to cleaning process validation, which includes the development, qualification, and verification of cleaning processes. It is applicable to pharmaceuticals (including active pharmaceutical ingredients (APIs)); all dosage forms; over-the-counter medicinal and neutraceutical products, veterinary products, biologics, clinical supplies, advanced therapy medicinal products (ATPM), medical device manufacturing; and is also applicable to other health, cosmetics, and consumer products.  
1.2 This guide is focused only on the cleaning of equipment product contact surfaces and medical device surfaces and does not cover disinfection, sterilization, or non-product contact surfaces (which are covered under other existing guides: Ref (1),2 USP , Guide E2614, ISO 14698, and ISO 14937).  
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.4 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.  
1.5 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.

General Information

• Status: Published
• Publication Date: 31-Oct-2022
• ICS: 13.020.60 - Product life-cycles
• Technical Committee: E55 - Manufacture of Pharmaceutical and Biopharmaceutical Products
• Drafting Committee: E55.13 - Process Evaluation and Control

Relations

• Refers: ASTM E2614-15(2020)e1 - Standard Guide for Evaluation of Cleanroom Disinfectants
• Effective Date: 01-Apr-2020
• Refers: ASTM F3357-19 - Standard Guide for Designing Reusable Medical Devices for Cleanability
• Effective Date: 01-Aug-2019
• Refers: ASTM G121-18 - Standard Practice for Preparation of Contaminated Test Coupons for the Evaluation of Cleaning Agents
• Effective Date: 01-Dec-2018
• Refers: ASTM E1325-15 - Standard Terminology Relating to Design of Experiments
• Effective Date: 01-Oct-2015
• Refers: ASTM E2614-15 - Standard Guide for Evaluation of Cleanroom Disinfectants
• Effective Date: 01-May-2015
• Refers: ASTM E2500-07(2012) - Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment
• Effective Date: 15-Oct-2012
• Refers: ASTM E2281-08a(2012)e1 - Standard Practice for Process and Measurement Capability Indices
• Effective Date: 01-Oct-2012
• Refers: ASTM E2476-09 - Standard Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture
• Effective Date: 15-May-2009
• Refers: ASTM E2281-08a - Standard Practice for Process and Measurement Capability Indices
• Effective Date: 01-Oct-2008
• Refers: ASTM G122-96(2008) - Standard Test Method for Evaluating the Effectiveness of Cleaning Agents
• Effective Date: 01-Sep-2008
• Refers: ASTM E2614-08 - Standard Guide for Evaluation of Cleanroom Disinfectants
• Effective Date: 01-Apr-2008
• Refers: ASTM E1325-02(2008) - Standard Terminology Relating to Design of Experiments
• Effective Date: 01-Apr-2008
• Refers: ASTM E2281-08 - Standard Practice for Process and Measurement Capability Indices
• Effective Date: 01-Apr-2008
• Refers: ASTM E2500-07 - Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment
• Effective Date: 01-Jun-2007
• Refers: ASTM G121-98(2015)e1 - Standard Practice for Preparation of Contaminated Test Coupons for the Evaluation of Cleaning Agents
• Effective Date: 01-Sep-2004

Overview

ASTM E3106-22: Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation provides a comprehensive framework for developing, qualifying, and verifying cleaning processes in regulated environments. This guide emphasizes a science-driven, risk-based approach rooted in internationally recognized principles such as those articulated in ICH Q8 to Q12, ISO 14971, and pertinent FDA guidance.

The standard applies a life-cycle methodology to cleaning validation, covering the design, implementation, and ongoing verification of cleaning processes. Its guidance is relevant to a wide array of sectors, including pharmaceuticals (APIs and dosage forms), biologicals, over-the-counter medicines, veterinary products, clinical supplies, advanced therapies, nutraceuticals, and device/consumer product manufacturing.

Key Topics

• Risk-Based and Science-Based Methodology: The guide integrates concepts from global frameworks (ICH Q9, FDA Process Validation) to ensure that the cleaning process design, validation, and monitoring are proportional to the assessed level of risk.
• Life-Cycle Approach: It covers cleaning process development from initial risk identification and process understanding, through process qualification, to ongoing verification and improvement.
• Quality Risk Management: Central to the document is the application of structured risk management techniques to cleaning process control, including risk assessments using tools such as FMEA.
• Focus on Product Contact Surfaces: The scope includes cleaning of product contact surfaces in equipment and medical device manufacturing-not disinfection, sterilization, or non-product contact cleaning, which are addressed by other standards.
• Statistical Principles: The standard highlights the importance of applying appropriate statistical analysis to support science- and risk-based decision-making throughout the cleaning process validation life-cycle.
• Regulatory Compliance: Guidance from international standards bodies, FDA, EMA, and USP are harmonized to support consistent, audit-ready practices.
• Key Definitions: The guide defines commonly used regulatory and technical terms, such as acceptable daily exposure (ADE), permitted daily exposure (PDE), and health-based exposure limits (HBELs), supporting clear communication and compliance.

Applications

The practical applications of ASTM E3106-22 span several regulated industries:

• Pharmaceutical and Biopharmaceutical Manufacturing: Ensures equipment surfaces are clean to prevent product cross-contamination, meet health-based exposure limits, and comply with GMP.
• Medical Devices: Guides manufacturers in validating cleaning procedures for device surfaces, reducing patient risk and ensuring device performance.
• Cosmetic and Consumer Products: Assists manufacturers in maintaining product quality and safety by preventing contamination and supporting regulatory compliance.
• Veterinary and Nutraceutical Products: Applies risk-based approaches to cleaning validation for a broad range of health-related products.
• Advanced Therapy Medicinal Products (ATMPs): Supports the unique cleaning validation requirements associated with regenerative medicine and cell-based therapies.
• Facility and Equipment Design: Encourages an upfront focus on equipment cleanability and process optimization to reduce cleaning failures and ease validation burden.
• Continuous Improvement: The life-cycle approach also emphasizes ongoing process monitoring, periodic review of cleaning effectiveness data, and process updates as necessary.

Related Standards

Practitioners employing ASTM E3106-22 should consider it alongside these key international standards and regulations:

• ICH Guidelines: ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk Management), Q10 (Pharmaceutical Quality System), Q11 (Development of Drug Substances), and Q12 (Lifecycle Management).
• ISO Standards: ISO 9000 (Quality Management Systems), ISO 14971 (Risk Management for Medical Devices), ISO 10993-1 (Biological Evaluation), and ISO 14698/14937 (Cleanroom and Sterilization Processes).
• FDA Guidance: Guidance for Industry Process Validation: General Principles and Practices.
• USP Standards: USP <1072> Disinfectants and Antiseptics.
• Relevant ASTM Standards: E1325 (Design of Experiments), E2500 (Specification and Verification of Manufacturing Systems), F3127 (Validating Cleaning Processes for Medical Devices), and others listed within the standard.
• EU GMP: EudraLex Volume 4, Annex 15 (Qualification and Validation).

ASTM E3106-22 equips organizations with a robust, harmonized approach to cleaning process validation, promoting patient safety, product quality, and regulatory compliance through science- and risk-based practice.

Standards Content (Sample)

This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the
Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
Designation: E3106 − 22
Standard Guide for
Science-Based and Risk-Based Cleaning Process
Development and Validation
This standard is issued under the fixed designation E3106; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope 2. Referenced Documents
1.1 This guide applies the life-cycle approach to cleaning 2.1 ASTM Standards:
process validation, which includes the development, E1325 Terminology Relating to Design of Experiments
qualification, and verification of cleaning processes. It is E2281 Practice for Process Capability and Performance
applicable to pharmaceuticals (including active pharmaceutical Measurement
ingredients (APIs)); all dosage forms; over-the-counter medici- E2476 Guide for Risk Assessment and Risk Control as it
nal and neutraceutical products, veterinary products, biologics, Impacts the Design, Development, and Operation of PAT
clinical supplies, advanced therapy medicinal products Processes for Pharmaceutical Manufacture
(ATPM), medical device manufacturing; and is also applicable E2500 Guide for Specification, Design, and Verification of
to other health, cosmetics, and consumer products. Pharmaceutical and Biopharmaceutical Manufacturing
Systems and Equipment
1.2 This guide is focused only on the cleaning of equipment
E2614 Guide for Evaluation of Cleanroom Disinfectants
product contact surfaces and medical device surfaces and does
E3219 Guide for Derivation of Health-Based Exposure Lim-
not cover disinfection, sterilization, or non-product contact
its (HBELs)
surfaces (which are covered under other existing guides: Ref
E3263 Practice for Qualification of Visual Inspection of
(1), USP <1072>, Guide E2614, ISO 14698, and ISO 14937).
Pharmaceutical Manufacturing Equipment and Medical
1.3 The values stated in SI units are to be regarded as
Devices for Residues
standard. No other units of measurement are included in this
F3127 Guide for Validating Cleaning Processes Used During
standard.
the Manufacture of Medical Devices
1.4 This standard does not purport to address all of the
F3357 Guide for Designing Reusable Medical Devices for
safety concerns, if any, associated with its use. It is the Cleanability
responsibility of the user of this standard to establish appro-
G121 Practice for Preparation of Contaminated Test Cou-
priate safety, health, and environmental practices and deter- pons for the Evaluation of Cleaning Agents
mine the applicability of regulatory limitations prior to use.
G122 Test Method for Evaluating the Effectiveness of
1.5 This international standard was developed in accor- Cleaning Agents and Processes
dance with internationally recognized principles on standard-
2.2 ICH Guidelines:
ization established in the Decision on Principles for the
Q8 Pharmaceutical Development
Development of International Standards, Guides and Recom-
Q9 Quality Risk Management
mendations issued by the World Trade Organization Technical
Q10 Pharmaceutical Quality System
Barriers to Trade (TBT) Committee.
Q11 Development and Manufacture of Drug Substances
1 3
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture For referenced ASTM standards, visit the ASTM website, www.astm.org, or
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of contact ASTM Customer Service at [e-mail]. For Annual Book of ASTM
Subcommittee E55.13 on Process Evaluation and Control. Standards volume information, refer to the standard’s Document Summary page on
Current edition approved Nov. 1, 2022. Published December 2022. Originally the ASTM website.
ɛ1
approved in 2017. Last previous edition approved in 2018 as E3106 – 18 . DOI: Available from International Conference on Harmonisation of Technical
10.1520/E3106-22. Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH
The boldface numbers in parentheses refer to a list of references at the end of Secretariat, 9, chemin des Mines, P.O. Box 195, 1211 Geneva 20, Switzerland,
this standard. http://www.ich.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E3106 − 22
Q12 Implementation Considerations for FDA-Regulated 3.1.4.1 Discussion—COP systems can range from elaborate
Products washing cabinets with automatic control systems to simple
2.3 ISO Standards: dishwasher type units. Many medical devices may be cleaned
ISO 9000 Quality Management Systems—Fundamentals in these types of systems (for example, mechanical washers,
and Vocabulary ultrasonic baths, and so forth).
ISO 10993-1 Biological evaluation of medical devices—
3.1.5 cleanability, n—relative difficulty for cleaning a piece
Part 1: Evaluation and testing within a risk management
of equipment, product, or device. G122, F3357
process
3.1.6 cleaning control strategy, n—planned set of controls
ISO 14698 Guide for Evaluation of Cleanroom
derived from the risk assessment and current cleaning process
Disinfectants, Parts 1–3.
understanding that ensures reliable and consistent cleaning
ISO 14937 Sterilization of Health Care Products—General
process performance. ICH Q10
Requirements for Characterization of a Sterilizing Agent
3.1.6.1 Discussion—The controls can include parameters
and the Development, Validation and Routine Control of a
and attributes related to materials and tools used for cleaning,
Sterilization Process for Medical Devices
cleaning procedure(s), equipment operating conditions, and the
ISO 17664 Processing of health care products
associated sampling plans, methods for validation, and routine
2.4 Federal Regulations:
monitoring.
21 CFR 211.67 Current Good Manufacturing Practice for
3.1.7 cleaning design space, n—multidimensional combina-
Finished Pharmaceuticals—Equipment Cleaning and
tion and interaction of cleaning input variables (for example,
Maintenance
product cleanability, equipment design, and so forth) and
2.5 European Regulation:
cleaning process parameters (for example, solvent/cleaning
European Commission Directorate for Health and Food
agent concentration, temperature, time, and so forth) that have
Safety EudraLex Volume 4, EU Guidelines for Good
been demonstrated to provide assurance of achieving accept-
Manufacturing Practice for Medicinal Products for Hu-
able cleaning outputs (for example, active pharmaceutical
man and Veterinary Use Annex 15: Qualification and
ingredients (API) residues, cleaning agent residues). ICH Q8
Validation
2.6 USP Standards:
3.1.8 cleaning effectiveness factor, CEF, n—fraction of con-
USP <1072> Disinfectants and Antiseptics taminant removed, or remaining, from an initially contami-
nated test coupon and determined by gravimetric or other
3. Terminology
analytical techniques (for example, total organic carbon
3.1 Definitions:
analysis, and so forth). G122
3.1.1 acceptable daily exposure, ADE, n—dose that is un-
3.1.8.1 Discussion—The CEF is a laboratory bench-scale
likely to cause an adverse effect if an individual is exposed, by
measurement of the relative difficulty of a compound/product
any route, at or below this dose every day for a lifetime.
to be cleaned that can be compared to other compounds/
3.1.1.1 Discussion—This is the term used in the ISPE
products using standardized conditions for temperature,
Risk-MaPP Guide (1) and is equivalent to the permitted daily
agitation, type of cleaning agent, and cleaning agent concen-
exposure (PDE). The ADE is associated with any route of
tration. The tests can be performed using Manual Cleaning
administration. Toxicity scales can be used to evaluate severity
Models, Clean-Out-of-Place (COP) Models, or Clean-in-Place
of the hazard posed by product being cleaned.
(CIP) Models.
3.1.2 cleaning agent, n—chemical or mixture of chemicals
3.1.8.2 Discussion—The method can also be customized to
for the removal of residual material (for example, drug
use existing parameter settings of a cleaning process as
substance, drug product, machining oil, and so forth) from
specified by a company.
equipment surfaces or other critical objects (such as a medical
3.1.9 cleaning input variables (parameters), n—those fac-
device).
tors or settings whose values constitute the cleaning process
3.1.3 clean-in-place, CIP, n—manual, semi-automated, or
and affect the cleaning output variables.
automated methods of cleaning equipment in situ without
3.1.9.1 Discussion—These independent variables include
dismantling equipment.
product cleanability, equipment size/groups, process residue
3.1.4 clean-out-of-place (COP) system, n—semi-automated load, holding times, cleaning agent concentration, cleaning
or automated system used to clean large pieces of equipment or agent type, rinse volume, pH, time, temperature, velocity,
parts of equipment that are disassembled but too large to clean pressure, surface coverage, location and cleaning cycle, and so
manually. forth.
3.1.10 cleaning margin of safety, n—difference between the
Available from American National Standards Institute (ANSI), 25 W. 43rd St.,
cleaning acceptance limit (based on HBEL) and the process
4th Floor, New York, NY 10036, http://www.ansi.org.
residue data.
Available from U.S. Government Printing Office, Superintendent of
3.1.10.1 Discussion—This value can be used as a measure
Documents, 732 N. Capitol St., NW, Washington, DC 20401-0001, http://
www.access.gpo.gov.
of the overall risk to patient safety presented by the cleaning
Available from the European Commission, https://ec.europa.eu/health/
process. The margin of safety can be measured a number of
documents/eudralex/vol-4_en.
ways including the process capability index (Cpk) and the
Available from U.S. Pharmacopeial Convention (USP), 12601 Twinbrook
Pkwy., Rockville, MD 20852-1790, http://www.usp.org. process performance index (Ppk).
E3106 − 22
3.1.11 cleaning output attributes, n—these attributes in- 3.1.22 grouping strategy, n—approach of using groups of
clude product and cleaning agent residues remaining on the products or equipment that share materials of construction and
equipment surfaces after cleaning. share a common cleaning procedure as representative of the
group to simplify cleaning validation.
3.1.11.1 Discussion—Bioburden/endotoxin levels and op-
erational considerations such as total cleaning time, holding 3.1.22.1 Discussion—Products or equipment (or both) or
times, and costs may also be cleaning output attributes. families of products (medical devices ISO 17664-1, Section
4.3) are placed into groups and one or more representatives
3.1.12 cleaning process, n—any process designed to remove
from the group are chosen for cleaning process performance
process residues from product contact surfaces of manufactur-
studies. A grouping strategy shall be scientifically justified.
ing equipment to levels that ensure patient safety and product
quality.
3.1.23 hardest to clean equipment or device, n—equipment
or device that has been shown empirically to be the most
3.1.13 cleaning process capability, n—statistical analysis
difficult to remove process residues from.
that is used to find out how well a given cleaning process meets
3.1.23.1 Discussion—This is a piece of equipment or device
a set of specification limits, including a measure of how well a
that is used as representative of other equipment or devices in
process performs. E2281
a group to simplify cleaning validation studies.
3.1.13.1 Discussion—Process capability scales are used to
3.1.24 hardest to clean product, n—product (or API) that
measure the probability of an occurrence and are a component
has been shown empirically to be the most difficult to remove
of risk posed by cleaning processes. (2)
from manufacturing or medical device surfaces.
3.1.14 cleaning process parameters, n—temperature, time,
3.1.24.1 Discussion—This is determined by laboratory
cleaning agent concentration, and others as identified.
analysis following Practice G121 and Test Method G122 and
3.1.15 cleaning validation, n—collection and evaluation of
comparing the CEF results among the compounds to determine
data, from the cleaning process design stage through cleaning
which has the highest CEF (remaining).
at commercial scale, which establishes scientific evidence that
3.1.25 health-based exposure limit, HBEL, n—substance-
a cleaning process is capable of consistently delivering clean
specific dose that is unlikely to cause an adverse effect if an
equipment. Ref (3)
individual is exposed at or below this dose every day for a
3.1.16 cleaning verification, n—confirmation, through the
lifetime.
provision of objective evidence, that specified cleaning re-
3.1.25.1 Discussion—The procedure for calculating an
quirements have been fulfilled. ISO 9000
HBEL proposed by the EMA in their guideline is the same
3.1.17 coupon, n—representative surface that is typically a
method for establishing the Permitted Daily Exposure (PDE) as
rectangular piece of a material of construction in which a
described in Appendix 3 of ICH Q3C (R4) and Appendix 3 of
known amount of a compound is deposited to simulate a
VICH GL 18.
process residue.
3.1.26 manual cleaning, v—cleaning of manufacturing
3.1.18 critical quality attributes, n—physical, chemical,
equipment/medical devices, either in place or out of place, by
biological, or microbiological property or characteristic that
hand and with the aid of brushes, cloths, detergents, and so
should be within an appropriate limit, range, or distribution to
forth.
ensure the desired product quality. ICH Q8
3.1.26.1 Discussion—Medical devices manually cleaned
can involve both process and devices to the extent of the
3.1.19 design of experiments, DoE, n—experimental ap-
defined validated cleaning process.
proach to determine what factors (that is, cleaning process
parameters) have a main effect on the output (critical quality
3.1.27 maximum daily dose, MDD, n—highest dose that a
attributes) of a process and which factors interact with other
patient may be administered in one day (24 h); for example, for
factors and affect the output.
a 100 mg tablet that can be administered up to four times in a
3.1.19.1 Discussion—A large number of cleaning process
day, the MDD is 400 mg.
parameters can be studied in a relatively small experiment
3.1.27.1 Discussion—MDDs can often be found on the
using definitive screening designs that prevent the confounding
package insert of the drug product.
of main effects with interactions and can also detect non-
3.1.28 maximum safe carryover, MSC, n—maximum
linearity.
amount of carryover of a residual process residue (API,
3.1.20 design space, n—multidimensional combination and
cleaning agent, degradant, and so forth) into the next product
interaction of input variables (for example, material attributes)
manufactured without presenting an appreciable health risk to
and process parameters that have been demonstrated to provide
patients.
assurance of quality. ICH Q8
3.1.28.1 Discussion—The MSC is calculated from the
3.1.21 exposure, n—process by which a human or animal
HBEL and the total number of doses in a subsequent batch. It
can come into contact with a hazard.
is total mass amount of material (μg or mg) that can be safely
3.1.21.1 Discussion—Exposure may occur through any carried over into the next batch of product. The total number of
route (oral, inhalational, dermal, and so forth). Exposure may doses in a batch is determined by dividing the maximum daily
be short-term (acute exposure), of intermediate duration, or dose (MDD) of the next product into the batch size of the next
long-term (chronic exposure). product.
E3106 − 22
3.1.29 maximum safe surface residue, MSSR, n—maximum 3.1.38 visual limit of detection, n—lowest level of a process
2 2
amount of process residue that can remain on equipment residue on a surface (in μg/cm or μg/in. ) that is visible to a
surfaces or devices and still be safe to patients. qualified inspector under defined viewing conditions. E3263
3.1.29.1 Discussion—The MSSR is mathematically calcu-
3.2 Definitions of Terms Specific to This Standard:
lated dividing the maximum safe carryover (MSC) by the total
3.2.1 CIP system, n—in this standard, CIP systems include
area of contact (MSC/total equipment surface area). The
the manufacturing equipment itself (mix tanks, transfer piping,
MSSR is not used as a limit and is only used for risk
and so forth) as well as the equipment used for cleaning
assessment. The comparison of process residues to MSSRs can
(detergent tanks, rinse tanks, pumps, and so forth).
demonstrate whether the process residues on equipment prod-
3.2.2 cleaning failure modes and effects analysis, FMEA,
uct contact surfaces pose significant risk to patients and shows
n—procedure to identify all possible failures of a cleaning
what the margin of safety is for that process residue.
process or procedure that could result in process residue levels
3.1.30 permitted daily exposure, PDE, n—represents a
that could put a patient at risk, the toxicity of those cleaning
substance-specific dose that is unlikely to cause an adverse
process failures, the likelihood of those cleaning process
effect if an individual is exposed at or below this dose every
failures leaving significant levels of process residue, and the
day for a lifetime.
probability that the failure or process residues will go unde-
3.1.30.1 Discussion—This is the term used by the European
tected.
Medicines Agency (EMA) and is equivalent to the ADE.
3.2.2.1 Discussion—The CFMEA can also identify ways to
3.1.31 probability, n—likelihood of occurrence of harm.
minimize the failures, decrease their likelihood, and improve
ICH Q9
their detectability. Scales have been developed that can be
specifically used for cleaning FMEAs and to measure the risk
3.1.32 process capability, n—statistical estimate of the out-
come of a characteristic from a process that has been demon- of cleaning failures (2, 4). If criticality of the medical device is
strated to be in a state of statistical control. E2281 known, then cleaning failure modes effects and criticality
analysis (CFMECA) may be used.
3.1.33 process residue, n—any residue, including, but not
limited to, APIs, cleaning agents, degradation products,
3.2.3 cleaning process capability score, n—value obtained
intermediates, excipients, and microbes remaining after a by taking the reciprocal of the process capability index (upper)
cleaning process.
and multiplying by 10 (2).
3.1.33.1 Discussion—Guide F3127 defines residue as a
3.2.4 statistical subject matter expert, n—individual with a
substance present at the surface of an implant or embedded
working knowledge and education, training, or experience in
therein that is not explicitly recognized and defined as part of
statistics who can apply statistical analysis to data from
the implant specification. It includes processing-based residues
cleaning and cleaning validation studies.
as well as contamination by environmental factors (adsor-
3.2.5 recovery study, n—laboratory study evaluating a sam-
bates).
pling method (for example, swab, rinse, visual examination,
3.1.34 qualified expert, n—individual with specific educa-
and so forth) in combination with an analytical method (for
tion and training in toxicology/pharmacology/
example, TOC, HPLC, visual inspection, and so forth) to
pharmacotherapy and risk assessment methods that can apply
determine the quantitative recovery of a specific residue.
the principles of toxicology to deriving an HBEL. E3219
3.2.5.1 Discussion—Recovery studies are performed by
3.1.34.1 Discussion—The European Medicines Agency
spiking specific residues onto a defined surrogate surface
states that health-based exposure limits should be determined
(coupon) or onto surfaces of actual processing equipment or
by a person who has adequate expertise and experience in
onto actual medical devices and sampling these surfaces.
toxicology/pharmacology, familiarity with pharmaceuticals, as
3.2.6 toxicity score, n—value obtained by taking their
well as experience in the determination of health-based expo-
sure limits such as occupational exposure levels (OEL) or negative logarithm of the HBEL (in units of grams per day) (4).
permitted daily exposure (PDE). For medical devices, this
person should be familiar with medical devices and the 4. Significance and Use
determination of HBEL.
4.1 Application of the approach described within this guide
3.1.35 quality by design, n—systematic approach to devel-
applies risk-based concepts and principles introduced in ICH
opment that begins with predefined objectives and emphasizes
Q9. As stated in ICH Q9, the level of effort, formality, and
product and process understanding and process control based
documentation for cleaning should also be commensurate with
on sound science and quality risk management. ICH Q8
the level of risk.
3.1.36 surrogate surface, n—part that is used as a substitute
4.2 Application of the approach described within this guide
for a piece of manufacturing equipment or a medical device
applies many of the science-based, risk-based, and statistical
surface.
concepts and principles introduced in the FDA’s Guidance for
3.1.37 visual inspection, VI, n—process of using the human Industry Process Validation: General Principles and Practices
eye, alone or in conjunction with various aids, as the sensing (3) and Quality Management Maturity for Finished Dosage
mechanism from which judgments may be made about the Forms Pilot Program for Domestic Drug Product Manufactur-
condition of the surface to be inspected. E3263 ers; Program Announcement.
E3106 − 22
4.3 This guide supports, and is consistent with, elements and the ability to detect and quantify the presence of process
from ICH Q8, ICH Q9, ICH Q10, ICH Q11, and ICH Q12. residues after cleaning and in the case of medical devices, the
level of its criticality.
4.4 This guide supports and is consistent with the content
and intent of ISO 14971.
7. Risk (Hazard) Identification
4.5 Key Concepts—This guide applies the following key
7.1 Risk identification should encompass the identification
concepts: (1) quality risk management, (2) science-based
of process residue hazards, equipment design hazards, and
approach, (3) statistics-based approach, (4) process
procedural hazards.
understanding, (5) continued improvement, and (6) life-cycle
7.2 Chemical Hazard Identification—The hazard presented
management as described in the ICH Q series.
by a potential process residue may be determined from a
toxicological review performed by a qualified expert. This
5. Science-, Risk-, and Statistics-Based Cleaning Process
involves a thorough review of all relevant toxicological data
Development and Validation
available for the process residue under study. When preclinical
5.1 Science-based approaches should be applied throughout
and clinical data on APIs are available to review, an HBEL can
the cleaning process development and validation process.
be determined and used as a measure of the hazard presented
by a compound (Guide E3219).
5.2 Quality risk management should be applied throughout
7.2.1 HBELs are used to calculate MSCs, MSSRs, and swab
the cleaning process development and validation process.
and rinse limits for use in risk evaluation. See 9.4.4 for setting
5.3 Appropriate statistical analysis should be applied
limits based on SPC.
throughout the cleaning process development and validation
7.2.2 Chemicals identified as process residues that are
process.
known hazards should be scheduled for elimination or reme-
diation steps.
6. Risk Assessment
7.3 Microbiological Hazard Identification—The hazard of
6.1 Under ICH Q9, risk assessment is broken into three
possible bioburden from a previous product or cleaning process
stages: risk identification, risk analysis, and risk evaluation.
and the possibility of microbial proliferation after a cleaning
6.2 Risk can be defined as: risk = f (probability of occur-
process and the hazards this presents, including the need for
rence of harm and the severity of that harm).
subsequent disinfection, should be considered. For example,
microbiological hazard(s) presented by holding equipment
6.3 For the purposes of cleaning, risk can be further defined
either in a dirty state or in clean state should be considered. The
as: risk = f (toxicity of process residues, exposure to process
impact of bioburden levels on subsequent sterilization or
residues, and detectability of process residues).
endotoxin and the need for subsequent depyrogenation should
6.4 Fig. 1 shows the continuum of risk in cleaning as a
be considered.
function of the toxicity of process residues, the level of
7.3.1 Microbiological agents identified as process residues
potential exposure to the process residues and the detectability
that are known hazards should be scheduled for elimination or
of the process residues (5).
remediation steps.
6.5 Fig. 2 shows the continuum of risk in cleaning as a
7.4 Equipment Design Hazard Identification—The potential
function of the criticality for medical device manufacturing.
hazards presented by equipment design should also be
6.6 For a reliable assessment of risk, scientific means (for considered, such as the possibility of product buildup. Equip-
example, risk management tools) should be used to identify the ment should be designed to facilitate cleaning, inspection, and
hazard presented by a process residue (for example, API, monitoring. Cleanability should be a requirement in User
degradation products, intermediates, cleaning agent, process Requirement Specifications prior to purchase of equipment,
aids, bioburden/endotoxin, and so forth), the ability of a including determination of Materials of Construction of prod-
cleaning process to remove process residues from manufactur- uct contact surfaces, instructions on disassembly, and equip-
ing equipment or medical devices to levels that are acceptable, ment manufacturer’s recommendation on cleaning.
FIG. 1 Continuum of Cleaning Risk based on Toxicity, Exposure, and Detectability
E3106 − 22
Med devices follow FDA Definitions and ISO of Med Device Classes to determine level of risk to patient.
FIG. 2 Continuum of Medical Device Risk
7.4.1 Equipment designs identified as known hazards (staining, corrosion, and so forth) of process residues with
should be scheduled for elimination or remediation steps. equipment should be understood.
(1) Cleanability should be demonstrated through bench
7.5 Procedural Hazard Identification—During development
scale testing (Practice G121 and Test Method G122). In the
and before use, cleaning procedures should be analyzed using
case of API manufacturing, the solubility of the active in the
a risk assessment, for example, cleaning FMEA or other risk
process solvent may be used as a measure of cleanability.
management tools, to minimize risk of failure (for example, to
8.5.1.2 The chemistry and potential interactions between
ensure that product buildup is avoided), improve the cleaning
process residues and chemicals used as part of cleaning
procedures, and make the cleaning procedures more reliable
processes should also be understood. For example, the solu-
and robust. Legacy cleaning procedures should also be sub-
bility of process residues in cleaning agents or rinsing agents
jected to risk assessments to minimize the risk of cleaning
should be understood to ensure that process residues are
failures, including review of legacy cleaning data.
removed or whether degradation products could be formed that
7.5.1 Procedural steps identified as known hazards should
may be harder to clean or more toxic than the original process
be scheduled for elimination or remediation steps.
residue.
8.5.2 Equipment Design for Cleanability:
8. Risk Analysis
8.5.2.1 The design of equipment has a critical impact on its
8.1 Risk analysis is the estimation of the risk associated
cleanability. User Requirement Specifications (URS) for equip-
with the identified hazards in Section 7 and is the qualitative or
ment design should include requirements for the equipment to
quantitative process of linking the likelihood of occurrence and
be cleanable as per 21CFR21 such as material of construction,
severity of harms.
total surface areas, manufacturer’s suggested cleaning
8.2 After identifying the hazards posed in Section 7, the
procedures, and so forth (Guides E2500 and F3127). These
risks associated with them should be analyzed. This risk specifications should be considered before purchase.
analysis should involve the cleaning process development,
(1) Guide F3357 has useful guidance on designing medical
facility/equipment design review, cleaning procedure review devices for cleanability.
(including legacy cleaning data review), and the selection of
8.5.2.2 Equipment design should be included as part of the
analytical methods. The analysis should also determine what risk assessment, taking into consideration the likely type of
steps can be taken to mitigate the identified risks.
cleaning process that will be applied to that equipment. The
input variables related to equipment design should be identified
8.3 The risk analysis should focus on how cleaning may
and evaluated to the critical cleaning attributes using appropri-
affect the patient safety and quality of the next product or
ate risk assessment tool(s). Examples of equipment design
device functionality.
considerations may include materials of construction,
8.4 The impact of the different factors (process residue
drainability, presence of dead legs, or other areas in which
cleanability (Test Method G122), cleaning/rinsing agents,
material could become trapped.
equipment engineering, and so forth) that have an impact on
8.5.2.3 Where equipment design is not found to be satisfac-
the outcome of the cleaning process should be analyzed.
tory in the risk (hazard) identification stage, or where cleaning
8.5 The cleaning process risk analysis is used to determine results cannot be achieved because of limitations in the
the necessary cleaning qualifications and identify appropriate equipment design, the equipment may need to be modified,
risk control mechanisms. dedicated, or replaced.
8.5.1 Process Residue Characterization: 8.5.3 Evaluation of Legacy Cleaning Data—The history of
8.5.1.1 The chemistry of process residues should be under- cleanings (along with any deviations, investigations, and cor-
stood to design an effective and efficient cleaning cycle. For rective actions) should be reviewed. This cleaning process
example, the cleanability of process residues (highly insoluble understanding and knowledge can provide useful information
or strongly adhesive residues) and potential interactions in the risk analysis and may help identify cleaning process
E3106 − 22
parameters to be used in cleaning process development studies studies are directly applicable to full-scale cleaning processes
and determine the likelihood of a cleaning failure (ICH Q10). but differences between full scale and bench scale should be
This evaluation should include statistical analysis of the data. considered.
(2) These studies are conducted by spiking the product(s)
8.5.3.1 These legacy data can also be used to facilitate new
or other residue(s) onto surrogate surfaces (for example,
product introduction including evaluation of new product
coupons) and then subjecting the surrogate surfaces (after
HBELs for acceptability into the facility. (HBEL-based accep-
drying) to varying cleaning conditions. The studies can also be
tance limit calculations can be found in 8.6.2.)
conducted in small-scale equipment designed to simulate the
8.5.4 Degree of Cleaning Based on Risk—Manufacturing
actual manufacturing equipment (Practice G121 and Test
equipment may require different degrees of cleaning effort,
Method G122).
formality and documentation for and validation based on the
8.5.5.2 Cleaning Parameter Determination—The effects
level of risk under different circumstances. To determine the
and the interactions of input variables affecting cleaning should
appropriate degree of cleaning, the type of product manufac-
be evaluated. The variables typically associated with cleaning
tured on the equipment (for example, intermediates, APIs,
are:
finished products) should be considered and the risks to patient
(1) Time,
safety and product quality should be understood. A cleaning
(2) Temperature,
process can then be developed to achieve the necessary results.
(3) Cleaning agent chemistry,
There may be several different types of cleaning based on the
(4) Mechanical action,
level of risk, for example:
(5) Product (that is, cleanability), and
8.5.4.1 Cleaning between different products,
(6) Amount of process residue.
8.5.4.2 Cleaning between similar products,
8.5.5.3 Design of Experiments (DoE) and “Cleaning Design
8.5.4.3 Cleaning during campaigning (cleaning between
Space”:
batches of the same product),
(1) To improve or optimize cleaning processes, experi-
8.5.4.4 Cleaning of dedicated equipment,
ments can be designed to examine the effects of cleaning input
8.5.4.5 Cleaning after equipment maintenance,
parameters on cleaning output variables. These inputs can be
8.5.4.6 Cleaning after elapse of permissible storage/hold assigned as factors in a DoE (Terminology E1325) and the
time of clean equipment, effects and interactions of varying these factors on the outputs
can be measured as responses. These experiments can be
8.5.4.7 Cleaning after sampling (for example, environmen-
initially performed using bench scale procedures.
tal monitoring or cleaning validation), and
(2) Typical cleaning input parameters include those listed
8.5.4.8 Cleaning after non-routine operations (for example,
in 8.5.5.2 and may also include for example, equipment
placebo runs during equipment qualifications).
size/groups, holding times, flow, pressure, and spray ball
8.5.5 Cleaning Process Development—Cleaning processes
type/location.
should be developed for each individual product to provide
(3) The typical cleaning output variables are the product,
optimal cleaning and not simply adopted based on past use
cleaning agent or other residues. Bioburden levels and opera-
(unless demonstrated). Cleaning processes should be devel-
tional considerations such as cleaning times, holding times,
oped to reduce process residue levels below the MSSR and as
reduction of manufacturing costs, and environmental impact
low as practical and determine what the appropriate cleaning
may also be considered.
agents are for this purpose. Cleaning processes that have been
(4) DoE can be used for determining a “cleaning design
optimized through the selection of the most appropriate clean-
space” (see Note 1) that can provide many benefits including
ing parameters (for example, temperature, time, mechanical
justification of product or equipment grouping and process
action, concentration, and so forth) can offer the greatest ability
change control strategies. If changes to the cleaning process or
to reduce process residues in the shortest time to the lowest
equipment are considered, the results of a risk review can
level of risk with the least impact on the system (for example,
provide information regarding the impact on cleaning design
cleaning with only water or other solvents based on the nature
space and whether any additional studies or testing are neces-
of the manufacturing process). Laboratory scale or bench-scale
sary.
studies provide valuable sources of cleaning process knowl-
(5) “Cleaning design space” also provides important input
edge and cleaning process understanding for the development
into the cleaning control strategy.
of commercial scale cleaning processes. The output of the
NOTE 1—Note that under ICH Q8, design space is submitted in the
cleaning process development should be used to create the
filing, but this is not the case for cleaning.
cleaning standard operating procedure (SOP) or cleaning
records or both.
8.5.5.4 Cleaning Agent Selection—Cleaning agents should
8.5.5.1 Bench-scale Studies: be selected based on scientific principles, the level of hazard
(1) Bench-scale studies are quick, economical experiments they pose, the ability to detect their residues and their environ-
that provide information on how difficult a product is to clean, mental impact. This selection should also be based on cleaning
which cleaning agent provides optimal cleaning, which clean- process development studies (for example, bench-scale
ing input variables are critical, and whether dirty hold time studies), compatibility with the materials of construction of the
studies may be necessary (6-8). Cleaning process knowledge equipment or products, and should not be based simply on
and cleaning process understanding gained from bench scale legacy use (ISO 10993-1, Ref (7)). The composition of a
E3106 − 22
cleaning agent should be known for methods to detect residues 8.5.7.1 Cleaning FMEAs/FMECAs are very useful tools for
of the cleaning agent to be developed where required. identifying potential failure modes in cleaning procedures and
8.5.6 Equipment Used for Cleaning—Design and Qualifica- prevent cleaning failures.
tion: 8.5.8 Manual Cleaning:
8.5.6.1 Equipment used for cleaning should be designed 8.5.8.1 Manual cleaning processes shall be validated using a
with the same attention to detail as directed to manufacturing science- and risk-based approach.
equipment and complying with appropriate regulations (21 8.5.8.2 Qualified visual inspection is required for release of
CFR 21). Equipment design specifications should be capable of parts or devices cleaned using manual cleaning processes.
meeting the required cleaning specifications derived from the 8.5.8.3 A risk assessment should be done to determine the
bench scale and cleanability studies. This equipment should be effects of operator variability on manual cleaning. Depending
conveniently located and appropriately stored in the facility to on the level of risk, steps should be taken to mitigate these risks
facilitate proper cleaning during operations. or automated procedures should be considered. Operators
8.5.6.2 The level of risk presented by the cleaning equip- should be qualified to perform these procedures.
ment and the controls that should be established to mitigate 8.5.8.4 Design of experiments can be useful in identifying
risks should be documented as part of the risk assessment (see which cleaning parameters pose the highest risk.
Fig. 3). 8.5.8.5 The level of risk presented by the manual cleaning
8.5.7 Risk Analysis of Written Cleaning Procedures and the controls that should be established to mitigate risks
(SOPs)—A risk analysis on legacy SOPs, or SOPs being should be documented as part of the risk assessment (see Fig.
developed, can determine if there are any gaps that may 3).
contribute to failures in the cleaning process execution or cross 8.5.9 Automated Cleaning Systems:
contamination. Risk analysis on SOPs being developed can 8.5.9.1 Automated cleaning systems can potentially provide
further determine adequacy and agreement with the develop- a lower level of risk compared to manual cleaning but should
ment studies. be assessed for potential sources of cross contamination.
This diagram also follows the cleaning maturity model (9).
FIG. 3 Cleaning Risk Assessment based on ICH Q9
E3106 − 22
8.5.9.2 The following could be considered automated clean- assessment (see Fig. 3). If the conclusion of the cleaning risk
ing systems: assessment is that the hold time period does not have an impact
(1) Clean-out-of-place (COP): on the cleaning process, then this hold time period should not
(a) Examples of COP system include glassware/parts need to be qualified.
washers, jet manifolds, trough cleaners, ultrasonic cleaners,
8.5.12 Operator Training:
and so forth;
8.5.12.1 The effectiveness of the training program shall be
(b) COP processes must be validated using a science and
demonstrated through the qualification of the operators
risk-based approach;
(1) This is especially important for manual cleaning com-
(c) COP processes require load configurations that should
bined with visual inspection programs (Practice E3263).
be qualified;
8.5.12.2 The content and structure of the training program
(d) COP operations can be carried out without interrup-
should be commensurate with level of risk involved with the
tion of the manufacturing process; and
cleaning process.
(e) COP cleaning solutions may be a source of contami-
8.5.12.3 The suitability of initial and ongoing training
nation; and
should be determined by a periodic assessment of effectiveness
(2) Clean-in-placeCIP processes shall be validated using a
of the training program.
science- and risk-based approach.
8.5.12.4 The frequency of training should be based on the
8.5.9.3 Equipment in CIP systems not being disassembled
level of risk and the training program should ensure that
may lead to buildup and cross contamination.
operators perform tasks reliably.
8.5.9.4 CIP systems should be capable of controlling,
8.5.12.5 Periodic assessment of training programs should be
monitoring, and recording critical operating/process param-
performed to reduce variation in the cleaning processes.
eters.
8.5.13 Sampling—The purpose of sampling is to select a
8.5.9.5 Cleaning coverage, risk of system failure, and its
representative subset of individuals from a population that can
potential impact on cleaning efficiency and cleanability of the
reliably characterize the whole population. In cleaning, this
system itself should be considered during the design and
means selecting representative samples from cleaned equip-
qualification of CIP systems.
ment that can reliably characterize the cleanliness of the
8.5.10 Grouping Strategies—A “group” is a collection of
equipment.
products, devices, or equipment that share a common cleaning
8.5.13.1 Any sampling and testing plans shall be described
design space and a common cleaning procedure to minimize
in written procedures that shall include the method of sampling
cleaning process performance studies and reduce the number of
and the number of samples to be tested; such written procedure
runs and samples required. Such a group may also share a
shall be followed [21CFR 211.165(c)].
common cleaning control strategy. Any groupings should be
8.5.13.2 Acceptance criteria for the sampling and testing
scientifically justified based on a risk assessment and from
shall be adequate to assure that cleaning processes meet each
knowledge and understanding gained from bench scale clean-
appropriate specification and as appropriate statistical quality
ing development studies.
control criteria as a condition for release of equipment or
8.5.10.1 Grouping strategies may be compared to the
devices [21CFR 211.165(d)].
knowledge and understanding of operators to confirm their
8.5.13.3 Statistical quality control criteria shall include as
experience with the cleaning process.
appropriate acceptance levels and/or appropriate rejection
8.5.10.2 Grouping strategies should be verified during rou-
levels [21CFR 211.165(d)].
tine monitoring.
8.5.13.4 Samplings Strategy—The risk assessment and prior
8.5.10.3 Groupings may also be used as the basis for factors
experience should be used to determine the sampling locations,
in a DoE.
number of samples (see 8.5.13.2), and sampling methods for
8.5.11 Hold Time Studies: each piece of equipment. Sampling locations should consider
the equipment design, accessibility, and materials of construc-
8.5.11.1 There are generally two types of hold time studies:
dirty hold times and clean hold times. tion.
(1) The maximum time interval between the end of product 8.5.13.5 Sampling strategies should have a statistical basis
processing or device processing and the cleaning is known as
(see 8.5.13.2).
the dirty hold time (DHT) (FDA, 1993). Swab or rinse samples (1) Sampling locations should also include those deter-
or both are taken from the equipment or device to demonstrate
mined to be most difficult to clean (based on prior experience
that acceptable cleaning (chemical or microbiological residues or studies) and where there is a l
...

This document is not an ASTM standard and is intended only to provide the user of an ASTM standard an indication of what changes have been made to the previous version. Because
it may not be technically possible to adequately depict all changes accurately, ASTM recommends that users consult prior editions as appropriate. In all cases only the current version
of the standard as published by ASTM is to be considered the official document.
´1
Designation: E3106 − 18 E3106 − 22
Standard Guide for
Science-Based and Risk-Based Cleaning Process
Development and Validation
This standard is issued under the fixed designation E3106; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
ε NOTE—Corrections were made editorially to 3.1.13 in October 2018.
1. Scope
1.1 This guide applies the life-cycle approach to cleaning process validation, which includes the development, qualification, and
verification of cleaning processes. It is applicable to pharmaceuticals (including active pharmaceutical ingredients (APIs); (APIs));
all dosage forms; and over-the-counter, veterinary, biologics, and clinical supplies) over-the-counter medicinal and neutraceutical
products, veterinary products, biologics, clinical supplies, advanced therapy medicinal products (ATPM), medical device
manufacturing; and is also applicable to other health, cosmetics, and consumer products.
1.2 This guide is focused only on the cleaning of equipment product contact surfaces and medical device surfaces and does not
cover disinfection disinfection, sterilization, or non-product contact surfaces (which are covered under other existing guides: Ref
(1), USP <1072>, Guide E2614, ISO 14698, and ISO 14698).14937).
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.
1.4 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility
of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of
regulatory limitations prior to use.
1.5 This international standard was developed in accordance with internationally recognized principles on standardization
established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued
by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
2. Referenced Documents
2.1 ASTM Standards:
E1325 Terminology Relating to Design of Experiments
E2281 Practice for Process Capability and Performance Measurement
E2476 Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes
for Pharmaceutical Manufacture
E2500 Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and
Equipment
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of
Subcommittee E55.03 on General Pharmaceutical Standards.
Current edition approved Sept. 1, 2018Nov. 1, 2022. Published September 2018December 2022. Originally approved in 2017. Last previous edition approved in 20172018
ɛ1
as E3106 – 17.18 . DOI: 10.1520/E3106-18E01.10.1520/E3106-22.
The boldface numbers in parentheses refer to a list of references at the end of this standard.
For referenced ASTM standards, visit the ASTM website, www.astm.org, or contact ASTM Customer Service at [e-mail]. For Annual Book of ASTM Standards
volume information, refer to the standard’s Document Summary page on the ASTM website.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E3106 − 22
E2614 Guide for Evaluation of Cleanroom Disinfectants
E3219 Guide for Derivation of Health-Based Exposure Limits (HBELs)
E3263 Practice for Qualification of Visual Inspection of Pharmaceutical Manufacturing Equipment and Medical Devices for
Residues
F3127 Guide for Validating Cleaning Processes Used During the Manufacture of Medical Devices
F3357 Guide for Designing Reusable Medical Devices for Cleanability
G121 Practice for Preparation of Contaminated Test Coupons for the Evaluation of Cleaning Agents
G122 Test Method for Evaluating the Effectiveness of Cleaning Agents and Processes
2.2 ICH Standards:Guidelines:
Q8 Pharmaceutical Development
Q9 Quality Risk Management
Q10 Pharmaceutical Quality System
Q11 Development and Manufacture of Drug Substances
Q12 Implementation Considerations for FDA-Regulated Products
2.3 ISO Standards:
ISO 9000 Quality Management Systems—Fundamentals and Vocabulary
ISO 10993-1 Biological evaluation of medical devices—Part 1: Evaluation and testing within a risk management process
ISO 14698 Guide for Evaluation of Cleanroom Disinfectants, Parts 1–3.
ISO 14937 Sterilization of Health Care Products—General Requirements for Characterization of a Sterilizing Agent and the
Development, Validation and Routine Control of a Sterilization Process for Medical Devices
ISO 17664 Processing of health care products
2.4 Federal Standards:Regulations:
21 CFR 211.67 Equipment Current Good Manufacturing Practice for Finished Pharmaceuticals—Equipment Cleaning and
Maintenance
2.5 European Regulation:
European Commission Directorate for Health and Food Safety EudraLex Volume 4, EU Guidelines for Good Manufacturing
Practice for Medicinal Products for Human and Veterinary Use Annex 15: Qualification and Validation
2.6 USP Standards:
USP <1072> Disinfectants and Antiseptics
Available from International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH Secretariat, 9,
chemin des Mines, P.O. Box 195, 1211 Geneva 20, Switzerland, http://www.ich.org.
Available from American National Standards Institute (ANSI), 25 W. 43rd St., 4th Floor, New York, NY 10036, http://www.ansi.org.
Available from U.S. Government Printing Office, Superintendent of Documents, 732 N. Capitol St., NW, Washington, DC 20401-0001, http://www.access.gpo.gov.
Available from the European Commission, https://ec.europa.eu/health/documents/eudralex/vol-4_en.
Available from U.S. Pharmacopeial Convention (USP), 12601 Twinbrook Pkwy., Rockville, MD 20852-1790, http://www.usp.org.
E3106 − 22
3. Terminology
3.1 Definitions:
3.1.1 acceptable daily exposure, ADE, n—represents a dose that is unlikely to cause an adverse effect if an individual is exposed,
by any route, at or below this dose every day for a lifetime.
3.1.1.1 Discussion—
This is the term used in the ISPE Risk-MaPP Guide(1) and is equivalent to the acceptable daily intake (ADI) but permitted daily
exposure (PDE). The ADE is associated with any route of administration. Toxicity scales can be used to evaluate severity of the
hazard posed by product being cleaned.
3.1.2 acceptable daily intake, ADI, n—measure of the amount of a specific substance (originally applied for a food additive, later
also for a residue of a veterinary drug or pesticide) in food or drinking water that can be ingested (orally) on a daily basis over
a lifetime without an appreciable health risk. Ref (2)
3.1.2.1 Discussion—
This term is more commonly associated with food and the oral route of administration.
3.1.2 cleaning agent, n—a chemical or mixture of chemicals for the removal of residual material (for example, drug substance,
drug product, machining oil, etc.) and so forth) from equipment surfaces or other critical objects (such as a medical device).
3.1.3 clean-in-place, CIP, n—method of cleaning manual, semi-automated, or automated methods of cleaning equipment in situ
without dismantling equipment.
3.1.4 clean-out-of-place (COP) system, n—semi-automated or automated system used to clean large pieces of equipment or parts
of equipment that are disassembled but too large to clean manually.
3.1.4.1 Discussion—
COP systems can range from elaborate washing cabinets with automatic control systems to simple dishwasher type units. Many
medical devices may be cleaned in these types of systems (for example, mechanical washers, ultrasonic baths, and so forth).
3.1.5 cleanability, n—relative difficulty for cleaning a piece of equipment equipment, product, or product.device. G122, F3357
3.1.6 cleaning control strategy, n—planned set of controls derived from the risk assessment and current cleaning process
understanding that ensures reliable and consistent cleaning process performance. ICH Q10
3.1.6.1 Discussion—
The controls can include parameters and attributes related to materials and tools used for cleaning, cleaning procedure(s),
equipment operating conditions, and the associated sampling plans, methods for validation, and routine monitoring.
3.1.7 cleaning design space, n—multidimensional combination and interaction of cleaning input variables (for example, product
cleanability, equipment design, and so forth) and cleaning process parameters (for example, solvent/cleaning agent concentration,
temperature, time, and so forth) that have been demonstrated to provide assurance of achieving acceptable cleaning outputs (for
example, active pharmaceutical ingredients (API) residues, cleaning agent residues). ICH Q8
3.1.8 cleaning effectiveness factor, CEF, n—fraction of contaminant removed, or remaining, from an initially contaminated test
coupon and determined by gravimetric or other analytical techniques (for example, total organic carbon analysis, and so forth).
G122
3.1.8.1 Discussion—
The CEF is a laboratory bench-scale measurement of the relative difficulty of a compound/product to be cleaned that can be
compared to other compounds/products using standardized conditions for temperature, agitation, type of cleaning agent, and
cleaning agent concentration. The tests can be performed using Manual Cleaning Models, Clean-Out-of-Place (COP) Models, or
Clean-in-Place (CIP) Models.
3.1.8.2 Discussion—
The method can also be customized to use existing parameter settings of a cleaning process as specified by a company.
3.1.9 cleaning input variables (parameters), n—those factors or settings whose values constitute the cleaning process and affect
the cleaning output variables.
3.1.9.1 Discussion—
E3106 − 22
These independent variables include product cleanability, equipment size/groups, process residue load, holding times, cleaning
agent concentration, cleaning agent type, rinse volume, pH, time, temperature, velocity, pressure, surface coverage, location and
cleaning cycle, and so forth.
3.1.10 cleaning margin of safety, n—difference between the cleaning acceptance limit (based on HBEL) and the process residue
data.
3.1.10.1 Discussion—
This value can be used as a measure of the overall risk to patient safety presented by the cleaning process. The margin of safety
can be measured a number of ways including the process capability index (Cpk) and the process performance index (Ppk).
3.1.11 cleaning output attributes, n—these attributes include product and cleaning agent residues remaining on the equipment
surfaces after cleaning.
3.1.11.1 Discussion—
Bioburden/endotoxin levels and operational considerations such as total cleaning time, holding times, and costs may also be
cleaning output attributes.
3.1.12 cleaning process, n—any process designed to remove process residues from product contact surfaces of manufacturing
equipment to levels that ensure patient safety and product quality.
3.1.13 cleaning process capability, n—statistical analysis that is used to find out how well a given cleaning process meets a set
of specification limits, including a measure of how well a process performs. E2281
3.1.13.1 Discussion—
Process capability scales are used to measure the probability of an occurrence and are a component of risk posed by cleaning
processes. (2)
3.1.14 cleaning process parameters, n—temperature, time, cleaning agent concentration, temperature, time, and so forth.and
others as identified.
3.1.15 cleaning validation, n—collection and evaluation of data, from the cleaning process design stage through cleaning at
commercial scale, which establishes scientific evidence that a cleaning process is capable of consistently delivering clean
equipment. Ref (3)
3.1.16 cleaning verification, n—confirmation, through the provision of objective evidence, that specified cleaning requirements
have been fulfilled. ISO 9000
3.1.14 clean-out-of-place (COP) system, n—automated system usually used to clean large pieces of equipment or parts of
equipment that are disassembled, but too large to clean manually.
3.1.14.1 Discussion—
COP systems can range from elaborate washing cabinets with automatic control systems to simple dishwasher type units.
3.1.17 coupon, n—representative surface that is typically a rectangular piece of a material of construction in which a known
amount of a compound is deposited to simulate a process residue.
3.1.18 critical quality attributes, n—physical, chemical, biological, or microbiological property or characteristic that should be
within an appropriate limit, range, or distribution to ensure the desired product quality. ICH Q8
3.1.19 design of experiments, DoE, n—experimental approach to determine what factors (that is, cleaning process parameters)
have a main effect on the output (critical quality attributes) of a process and which factors interact with other factors and affect
the output.
3.1.19.1 Discussion—
A large number of cleaning process parameters can be studied in a relatively small experiment using definitive screening designs
that prevent the confounding of main effects with interactions and can also detect non-linearity.
3.1.20 design space, n—multidimensional combination and interaction of input variables (for example, material attributes) and
process parameters that have been demonstrated to provide assurance of quality. ICH Q8
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3.1.21 exposure, n—process by which a human or animal can come into contact with a hazard.
3.1.21.1 Discussion—
Exposure may occur through any route (oral, inhalational, dermal, and so forth). Exposure may be short-term (acute exposure),
of intermediate duration, or long-term (chronic exposure).
3.1.22 grouping strategy, n—strategyapproach of using groups of products or equipment that share materials of construction and
share a common cleaning procedure as representative of the group to simplify cleaning validation.
3.1.22.1 Discussion—
Products or equipment or both (or both) or families of products (medical devices ISO 17664-1, Section 4.3) are placed into groups
and one or more representatives from the group are chosen for cleaning process performance studies. A grouping strategy shall be
scientifically justified.
3.1.23 hardest to clean equipment or device, n—equipment or device that has been shown empirically to be the most difficult to
remove process residues from.
3.1.23.1 Discussion—
This is a piece of equipment or device that is used as representative of other equipment or devices in a group to simplify cleaning
validation studies.
3.1.24 hardest to clean product, n—product (or API) that has been shown empirically to be the most difficult to remove from
manufacturing or medical device surfaces.
3.1.24.1 Discussion—
This is determined by laboratory analysis following Practice G121 and Test Method G122 and comparing the CEF results among
the compounds to determine which has the highest CEF (remaining).
3.1.25 health-based exposure limit, HBEL, n—substance-specific dose that is unlikely to cause an adverse effect if an individual
is exposed at or below this dose every day for a lifetime.
3.1.25.1 Discussion—
The procedure for calculating an HBEL proposed by the EMA in their guideline is the same method for establishing the Permitted
Daily Exposure (PDE) as described in Appendix 3 of ICH Q3C (R4) and Appendix 3 of VICH GL 18.
3.1.26 manual cleaning, v—cleaning of equipment, manufacturing equipment/medical devices, either in place or out of place, by
hand and with the aid of brushes, cloths, detergents, and so forth.
3.1.26.1 Discussion—
Medical devices manually cleaned can involve both process and devices to the extent of the defined validated cleaning process.
3.1.20 margin of safety, n—difference between the cleaning acceptance limit (based on ADE) and the process residue data.
3.1.20.1 Discussion—
This value can be used as a measure of the overall risk to patient safety presented by the cleaning process. The margin of safety
can be measured a number of ways including the process capability index (Cpk) and the process performance index (Ppk).
3.1.27 maximum allowable carryover, MAC or MACO, daily dose, MDD, n—maximum amount of carryover from one product to
the next.highest dose that a patient may be administered in one day (24 h); for example, for a 100 mg tablet that can be
administered up to four times in a day, the MDD is 400 mg.
3.1.27.1 Discussion—
The MAC is calculated as a fraction of the lowest therapeutic dose (usually 1/1000) or as a fraction of a lethal dose (LD50) (usually
1/100 000 or 1/1 000 000).MDDs can often be found on the package insert of the drug product.
3.1.28 maximum safe carryover, MSC, n—maximum amount of carryover of a residual process residue (API, cleaning agent,
degradant, and so forth) into the next product manufactured without presenting an appreciable health risk to patients.
3.1.28.1 Discussion—
The MSC is calculated from the ADEHBEL and the total number of doses in a subsequent batch. It is total mass amount of material
(μg or mg) that can be safely carried over into the next batch of product. The total number of doses in a batch is determined by
dividing the maximum daily dose (MDD) of the next product into the batch size of the next product.
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3.1.29 maximum safe surface residue, MSSR, n—maximum amount of process residue that can remain on equipment surfaces or
devices and still be safe to patients.
3.1.29.1 Discussion—
The MSSR is mathematically calculated dividing the maximum safe carryover (MSC) by the total area of contact (MSC/total
equipment surface area). The MSSR is not used as a limit and is only used for risk assessment. The comparison of process residues
to MSSRs can demonstrate whether the process residues on equipment product contact surfaces pose significant risk to patients
and shows what the margin of safety is for that process residue.
3.1.30 permitted daily exposure, PDE, n—represents a substance-specific dose that is unlikely to cause an adverse effect if an
individual is exposed at or below this dose every day for a lifetime.
3.1.30.1 Discussion—
This is the term used by the European Medicines Agency (EMA) and is equivalent to both the ADE and ADI.the ADE.
3.1.31 probability, n—likelihood of occurrence of harm. ICH Q9
3.1.32 process capability, n—statistical estimate of the outcome of a characteristic from a process that has been demonstrated to
be in a state of statistical control. E2281
3.1.33 cleaning process residue, n—any residue, including, but not limited to, APIs, cleaning agents, degradation products,
intermediates, excipients, and microbes remaining after a cleaning process.
3.1.33.1 Discussion—
Guide F3127 defines residue as a substance present at the surface of an implant or embedded therein that is not explicitly
recognized and defined as part of the implant specification. It includes processing-based residues as well as contamination by
environmental factors (adsorbates).
3.1.26 qualified statistician, n—individual with a working knowledge and education, training, or background in statistics who can
apply statistical analysis to data from cleaning and cleaning validation studies.
3.1.34 qualified toxicologist/pharmacologist,expert, n—individual with specific education and training in toxicology/
pharmacology toxicology/pharmacology/pharmacotherapy and risk assessment methods that can apply the principles of toxicology
to deriving an ADE or PDE value for required process residues. HBEL. E3219
3.1.34.1 Discussion—
The European Medicines Agency states that health-based exposure limits should be determined by a person who has adequate
expertise and experience in toxicology/pharmacology, familiarity with pharmaceuticals, as well as experience in the determination
of health-based exposure limits such as occupational exposure levels (OEL) or permitted daily exposure (PDE). For medical
devices, this person should be familiar with medical devices and the determination of HBEL.
3.1.35 quality by design, n—systematic approach to development that begins with predefined objectives and emphasizes product
and process understanding and process control based on sound science and quality risk management. ICH Q8
3.1.36 representative surrogate surface, n—surrogate surface that may be actual processing equipment or has characteristics
similar to that of processing equipment and is used for spiking studies.part that is used as a substitute for a piece of manufacturing
equipment or a medical device surface.
3.1.37 visual inspection, VI, n—process of using the human eye, alone or in conjunction with various aids, as the sensing
mechanism from which judgments may be made about the condition of the surface to be inspected. E3263
2 2
3.1.38 visual limit of detection, n—lowest level of a process residue on a surface (in μg/cm or μg/in. ) that is visible to a qualified
inspector under defined viewing conditions. E3263
3.2 Definitions of Terms Specific to This Standard:
3.2.1 CIP system, n—in this standard, CIP systems include the manufacturing equipment itself (mix tanks, transfer piping, and so
forth) as well as the equipment used for cleaning (detergent tanks, rinse tanks, pumps, and so forth).
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3.2.2 cleaning failure modes and effects analysis, FMEA, n—a procedure to identify all possible failures of a cleaning process or
procedure that could result in process residue levels that could put a patient at risk, the toxicity of those cleaning process failures,
the likelihood of those cleaning process failures leaving significant levels of process residue, and the probability that the failure
or process residues will go undetected.
3.2.2.1 Discussion—
The cleaning FMEA CFMEA can also identify ways to minimize the failures, decrease their likelihood, and improve their
detectability. Scales have been developed that can be specifically used for cleaning FMEAs and to measure the risk of cleaning
failures (4-82, 4). If criticality of the medical device is known, then cleaning failure modes effects and criticality analysis
(CFMECA) may be used.
3.2.3 cleaning process capability score, n—value obtained by taking the reciprocal of the process capability index (upper) and
multiplying by 10 (2).
3.2.4 statistical subject matter expert, n—individual with a working knowledge and education, training, or experience in statistics
who can apply statistical analysis to data from cleaning and cleaning validation studies.
3.2.5 recovery study, n—laboratory study evaluating a sampling method (for example, swab, rinse, visual examination, and so
forth) in combination with an analytical method (for example, TOC, HPLC, visual inspection, and so forth) to determine the
quantitative recovery of a specific residue.
3.2.5.1 Discussion—
Recovery studies are performed by spiking specific residues onto a defined surrogate surface (coupon) or onto surfaces of actual
processing equipment or onto actual medical devices and sampling these surfaces.
3.2.6 toxicity score, n—value obtained by taking their negative logarithm of the HBEL (in units of grams per day) (4).
4. Significance and Use
4.1 Application of the approach described within this guide applies risk-based concepts and principles introduced in ICH Q9. As
stated in ICH Q9, the level of effort, formality, and documentation for cleaning should also be commensurate with the level of risk.
4.2 Application of the approach described within this guide applies many of the science-based, risk-based, and statistical concepts
and principles introduced in the FDA’s Guidance for Industry Process Validation: General Principles and Practices (3).) and
Quality Management Maturity for Finished Dosage Forms Pilot Program for Domestic Drug Product Manufacturers; Program
Announcement.
4.3 This guide supports, and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, ICH Q11, and ICH Q11.Q12.
4.4 This guide supports and is consistent with the content and intent of ISO 14971.
4.5 Key Concepts—This guide applies the following key concepts: (1) quality risk management, (2) science-based approach, (3)
statistics-based approach, (4) process understanding, and (5) continued improvement improvement, and (6) life-cycle management
as described in the ICH Q series.
5. Science-Based, Risk-Based,Science-, Risk-, and Statistics-Based Cleaning Process Development and Validation
5.1 Science-based approaches should be applied throughout the cleaning process development and validation process.
5.2 Quality risk management should be applied throughout the cleaning process development and validation process.
5.3 Appropriate statistical analysis should be applied throughout the cleaning process development and validation process.
6. Risk Assessment
6.1 Under ICH Q9, risk assessment is broken into three stages: risk identification, risk analysis, and risk evaluation.
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6.2 Risk can be defined as: risk = f (probability of occurrence of harm and the severity of that harm).
6.3 For the purposes of cleaning, risk can be further defined as: risk = f (toxicity of process residues, exposure to process residues,
and detectability of process residues).
6.4 Fig. 1 shows the continuum of risk in cleaning as a function of the toxicity of process residues, the level of potential exposure
to the process residues and the detectability of the process residues (5).
6.5 Fig. 2 shows the continuum of risk in cleaning as a function of the criticality for medical device manufacturing.
6.6 For a reliable assessment of risk, scientific means (for example, risk management tools) should be used to identify the hazard
presented by a process residue (for example, API, degradation products, intermediates, cleaning agent, process aids, bioburden/
endotoxin, and so forth), the ability of a cleaning process to remove process residues from manufacturing equipment or medical
devices to levels that are acceptable, and the ability to detect and quantify the presence of process residues after cleaning and in
the case of medical devices, the level of its criticality.
7. Risk (Hazard) Identification
7.1 Risk identification should encompass the identification of process residue hazards, equipment design hazards, and procedural
hazards.
7.2 Chemical Hazard Identification—The hazard presented by a potential process residue may be determined from a toxicological
review performed by a qualified expert. This involves a thorough review of all relevant toxicological data available for the process
residue under study. When preclinical and clinical data on APIs are available to review, an HBEL can be determined and used as
a measure of the hazard presented by a compound (Guide E3219).
7.2.1 HBELs are used to calculate MSCs, MSSRs, and swab and rinse limits for use in risk evaluation. See 9.4.4 for setting limits
based on SPC.
7.2.2 Chemicals identified as process residues that are known hazards should be scheduled for elimination or remediation steps.
7.3 Microbiological Hazard Identification—The hazard of possible bioburden from a previous product or cleaning process and the
possibility of microbial proliferation after a cleaning process and the hazards this presents, including the need for subsequent
disinfection, should be considered. For example, microbiological hazard(s) presented by holding equipment either in a dirty state
or in clean state should be considered. The impact of bioburden levels on subsequent sterilization or endotoxin and the need for
subsequent depyrogenation should be considered.
7.3.1 Microbiological agents identified as process residues that are known hazards should be scheduled for elimination or
remediation steps.
7.4 Equipment Design Hazard Identification—The potential hazards presented by equipment design should also be considered,
FIG. 1 Continuum of Cleaning Risk based on Toxicity, Exposure, and Detectability
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Med devices follow FDA Definitions and ISO of Med Device Classes to determine level of risk to patient.
FIG. 2 Continuum of Medical Device Risk
such as the possibility of product buildup. Equipment should be designed to facilitate cleaning, inspection, and monitoring.
Cleanability should be a requirement in User Requirement Specifications prior to purchase of equipment, including determination
of Materials of Construction of product contact surfaces, instructions on disassembly, and equipment manufacturer’s recommen-
dation on cleaning.
7.4.1 Equipment designs identified as known hazards should be scheduled for elimination or remediation steps.
7.5 Procedural Hazard Identification—During development and before use, cleaning procedures should be analyzed using a risk
assessment, for example, cleaning FMEA or other risk management tools, to minimize risk of failure (for example, to ensure that
product buildup is avoided), improve the cleaning procedures, and make the cleaning procedures more reliable and robust. Legacy
cleaning procedures should also be subjected to risk assessments to minimize the risk of cleaning failures, including review of
legacy cleaning data.
7.5.1 Procedural steps identified as known hazards should be scheduled for elimination or remediation steps.
8. Risk AssessmentAnalysis
6.1 Under ICH Q9, risk assessment is broken into three stages: risk identification, risk analysis, and risk evaluation.
6.2 Risk can be defined as: risk = f (probability of occurrence of harm and the severity of that harm).
6.3 For the purposes of cleaning, risk can be further defined as a function of the severity of the hazards of process residues,
likelihood and level of process residues, and detectability of process residues.
6.4 For a reliable assessment of risk, scientific means (for example, risk management tools) should be used to identify the hazard
presented by a process residue (for example, API, degradation products, intermediates, cleaning agent, bioburden/endotoxin, and
so forth), the ability of a cleaning process to remove process residues to levels that are acceptable, and the ability to detect and
quantify the presence of process residues after cleaning.
8.1 Risk Identification—Risk identification should encompass the identification of analysis is the estimation of the risk associated
with the identified hazards in Section 7process residue hazards, equipment design hazards, and procedural hazards. and is the
qualitative or quantitative process of linking the likelihood of occurrence and severity of harms.
6.5.1 Process Residue Hazard Identification:
6.5.1.1 The hazard presented by a potential process residue may be determined from a toxicological review performed by a
qualified toxicologist or qualified pharmacologist. For an API, this involves a thorough review of all relevant toxicological data
available for the process residue under study (9). When preclinical and clinical data on APIs are available to review, an ADE can
be determined and used as a measure of the severity of hazard presented by a compound. For further information, see the ISPE
Risk-MaPP Guide(1) or the EMA Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the
Manufacture of Different Medicinal Products in Shared Facilities(9).
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6.5.1.2 When an ADE is not available, such as for intermediates, degradation products, or compounds in early development,
alternative approaches such as the threshold of toxicological concern (TTC) may be justified (9, 10). Although compounds in early
development may not have sufficient safety data to perform a complete analysis, useful information can be found in the chemical
structure of a compound to help determine a provisional ADE for the compound. “In silico” (computer-assisted) toxicological
assessment or a structure activity relationship can be used to determine provisional ADEs for a compound (11, 12). For example,
a compound in the same structural series of a known API from a given therapeutic class can be treated in the same way as that
API, for example, a compound with a propylamine structure would be expected to share properties of this class of antihistamines
(13). Where data are available on comparative potency, these can be used to adjust the estimated ADE.
6.5.1.3 The hazard of possible bioburden from a previous product and the possibility of microbial proliferation after a cleaning
process and the hazards this presents, including the need for subsequent disinfection, should also be considered. For example, the
hazard(s) presented by holding equipment either in a dirty state or in clean state should be considered or the possibility of
endotoxin and the need for subsequent depyrogenation should be considered.
6.5.2 Equipment Hazard Identification—The potential hazards presented by equipment design should also be considered, such as
the possibility of product buildup. Equipment should be designed to facilitate cleaning, inspection, and monitoring.
6.5.3 Procedural Hazard Identification—Before use, cleaning procedures should be subjected to risk assessments, for example,
cleaning FMEA or other risk management tools, to minimize risk of failure (for example, to ensure that product buildup is
avoided),, improve the cleaning procedures, and make the cleaning procedures more reliable and robust.
8.2 After identifying the hazards posed in Section 7, the risks associated with them should be analyzed. This risk analysis should
involve the cleaning process development, facility/equipment design review, cleaning procedure review (including legacy cleaning
data review), and the selection of analytical methods. The analysis should also determine what steps can be taken to mitigate the
identified risks.
8.3 The risk analysis should focus on how cleaning may affect the patient safety and quality of the next product or device
functionality.
8.4 The impact of the different factors (process residue cleanability (Test Method G122), cleaning/rinsing agents, equipment
engineering, and so forth) that have an impact on the outcome of the cleaning process should be analyzed.
8.5 Risk Analysis: The cleaning process risk analysis is used to determine the necessary cleaning qualifications and identify
appropriate risk control mechanisms.
6.6.1 After identifying the hazards posed, the risks associated with them should be analyzed. This risk analysis should involve the
cleaning process development, facility/equipment design review, cleaning procedure review, and the selection of analytical
methods. The analysis should also determine what steps can be taken to mitigate the identified risks.
6.6.2 The risk analysis should show how cleaning may affect the patient safety and quality of the next product.
6.6.3 The impact of the different factors (process residue, cleaning/rinsing agents, equipment engineering, and so forth) on the
outcome of the cleaning process should be analyzed.
6.6.4 The cleaning process risk analysis can help to determine the necessary cleaning qualifications and identify appropriate risk
control mechanisms.
8.5.1 Process Residue Characterization:
8.5.1.1 The chemistry of process residues should be understood to design an effective and efficient cleaning cycle, forcycle. For
example, the cleanability of process residues (for example, highly (highly insoluble or strongly adhesive residues) and potential
interactions (for example, staining, corrosion) (staining, corrosion, and so forth) of process residues with equipment.equipment
should be understood.
(1) Cleanability should be demonstrated through bench scale testing (Practice G121 and Test Method G122). In the case of
API manufacturing, the solubility of the active in the process solvent may be used as a measure of cleanability.
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8.5.1.2 The chemistry and potential interactions between process residues and chemicals used as part of cleaning processes should
also be understood, forunderstood. For example, the solubility of process residues in cleaning agents or rinsing agents should be
considered to avoid situations in which understood to ensure that process residues are not removed or whether degradation products
maycould be formed that may be harder to clean or more toxic than the original process residue.
8.5.2 Equipment Design for Cleanability:
8.5.2.1 The design of equipment has a critical impact on its cleanability. User Requirement Specifications (URS) for equipment
design should include requirements for the equipment to be cleanable as per 21CFR21 such as material of construction, total
surface areas, manufacturer’s suggested cleaning procedures, and so forth (Guides E2500 and F3127). These specifications should
be considered before purchase.
(1) Guide F3357 has useful guidance on designing medical devices for cleanability.
8.5.2.2 The design of equipment has an impact on its cleanability. Equipment design should be consideredincluded as part of the
risk analysisassessment, taking into consideration the likely type of cleaning process that will be applied to that equipment. The
input variables and attributes related to equipment design should be identified and linkedevaluated to the cleaning critical cleaning
attributes using the appropriate risk assessment tool(s). Examples of equipment design considerations may include:include
materials of construction, drainability, presence of dead legs, or other areas in which material could become trapped, or drainability.
trapped.
8.5.2.3 Where satisfactory equipment design is not found to be satisfactory in the risk (hazard) identification stage, or where
cleaning results cannot be achieved because of limitations in the equipment design, the equipment may need to be modified,
dedicated, or replaced.
8.5.3 Evaluation of HistoricalLegacy Cleaning Data—The history of cleanings (along with any deviations, investigations, and
corrective actions) should be reviewed. This cleaning process understanding and knowledge can provide useful information in athe
risk analysis and may help identify cleaning process parameters to be used in cleaning process development studies and determine
the likelihood of a cleaning failure (ICH Q10). This evaluation should include statistical analysis of the data.
8.5.3.1 These legacy data can also be used to facilitate new product introduction including evaluation of new product HBELs for
acceptability into the facility. (HBEL-based acceptance limit calculations can be found in 8.6.2.)
8.5.4 Levels of Cleaning—Degree of Cleaning Based on Risk—Manufacturing equipment may require different levelsdegrees of
cleaning and validation effort, formality and documentation for and validation based on the level of risk under different
circumstances. To determine the appropriate cleaning level, degree of cleaning, the type of product manufactured on the equipment
(for example, intermediates, APIs, finished products) should be considered and the risks to patient safety and product quality should
be understood. A cleaning process can then be developed to achieve the necessary results. There may be several levels different
types of cleaning based on the level of risk, for example:
8.5.4.1 Cleaning between different products,
8.5.4.2 Cleaning between similar products,
8.5.4.3 Cleaning during campaigning (cleaning between batches of the same product),
8.5.4.4 Cleaning of dedicated equipment,
8.5.4.5 Cleaning after equipment maintenance,
8.5.4.6 Cleaning after elapse of permissible storage/hold time of clean equipment,
8.5.4.7 Cleaning after sampling, sampling (for example, environmental monitoring or cleaning validation), and
8.5.4.8 Cleaning after non-routine operations.operations (for example, placebo runs during equipment qualifications).
8.5.5 Cleaning Process Development—Cleaning processes should not be adopted randomly or chosen be developed for each
individual product to provide optimal cleaning and not simply adopted based on past use. use (unless demonstrated). Cleaning
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processes should be developed to reduce process residues levels residue levels below the MSSR and as low as practical and
determine what the appropriate cleaning agents are for this purpose. Cleaning processes that have been optimized through the
selection of the most appropriate cleaning agents and cleaning parametersparameters (for example, temperature, time, mechanical
action, concentration, and so forth) can offer the greatest ability to reduce process residues in the shortest time to the lowest level
of risk. risk with the least impact on the system (for example, cleaning with only water or other solvents based on the nature of
the manufacturing process). Laboratory scale or bench-scale studies provide valuable sources of cleaning process knowledge and
cleaning process understanding for the development of commercial scale cleaning processes. The output of the cleaning process
development should be used to create the cleaning standard operating procedure (SOP).(SOP) or cleaning records or both.
8.5.5.1 Bench-ScaleBench-scale Studies:
(1) Laboratory scale or “bench-scale” studies can provide valuable sources of cleaning process knowledge and cleaning process
understanding (14). The studies may be conducted by spiking the process residue(s) on coupons and then subjecting the coupons
(after drying) to varying cleaning conditions. The studies could also be conducted in small-scale equipment designed to simulate
the actual manufacturing equipment.
(1) Bench-scale studies can be quick, economical, and are quick, economical experiments that provide information on how
difficult a product is to clean, which cleaning agent provides optimal cleaning, which cleaning input variables are critical, and
whether dirty hold time studies may be necessary.necessary (6-8). Cleaning process knowledge and cleaning process understanding
gained from bench scale studies may be are directly applicable to full-scale cleaning processes but differences between full scale
and bench scale should be considered.
(2) These studies are conducted by spiking the product(s) or other residue(s) onto surrogate surfaces (for example, coupons)
and then subjecting the surrogate surfaces (after drying) to varying cleaning conditions. The studies can also be conducted in
small-scale equipment designed to simulate the actual manufacturing equipment (Practice G121 and Test Method G122).
8.5.5.2 Cleaning Parameter Determination—The effects and the interactions of input variables affecting cleaning should be
evaluated. The variables typically associated with cleaning are: time, temperature, cleaning agent chemistry, mechanical action,
product cleanability, and amount of process residue.
(1) Time,
(2) Temperature,
(3) Cleaning agent chemistry,
(4) Mechanical action,
(5) Product (that is, cleanability), and
(6) Amount of process residue.
8.5.5.3 Design of Experiments (DoE) and “Cleaning Design Space:”Space”:
(1) To improve or optimize cleaning processes, experiments can be designed to examine the effects of cleaning input
parameters on cleaning output variables. These inputs can be assigned as factors in a DoE (Terminology E1325) and the effects
and interactions of varying these factors on the outputs can be measured as responses. These experiments can be initially performed
using bench scale procedures.
(2) Typical cleaning input parameters include product cleanability, equipment size/groups,those listed in 8.5.5.2 process
residue concentration, holding times, cleaning agent type and concentration, wash/rinse temperature/time/volume, and may also
include for example, equipment size/groups, holding times, flow, pressure, and spray ball type/location.
(3) The typical cleaning output variables are the product and product, cleaning agent or other residues. Bioburden levels and
operational consi
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