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 − 17

Standard Guide for

Science-Based and Risk-Based Cleaning Process
Development and Validation1
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 Impacts the Design, Development, and Operation of PAT

1.1 This guide applies the life-cycle approach to cleaning Processes for Pharmaceutical Manufacture
process validation, which includes the development, 2.2 ICH Standards:4
qualification, and verification of cleaning processes. It is Q8 Pharmaceutical Development
applicable to pharmaceuticals (including active pharmaceutical Q9 Quality Risk Management
ingredients (APIs); dosage forms; and over-the-counter, Q10 Pharmaceutical Quality System
veterinary, biologics, and clinical supplies) and is also appli- Q11 Development and Manufacture of Drug Substances
cable to other health, cosmetics, and consumer products. 2.3 ISO Standards:5
1.2 This guide is focused only on the cleaning of equipment ISO 9000 Quality Management Systems—Fundamentals
product contact surfaces and does not cover disinfection or and Vocabulary
non-product contact surfaces (which are covered under another 2.4 Federal Standards:6
existing guide (1)2). 21 CFR 211.67 Equipment Cleaning and Maintenance
1.3 The values stated in SI units are to be regarded as
standard. No other units of measurement are included in this 3. Terminology
standard. 3.1 Definitions:
1.4 This standard does not purport to address all of the 3.1.1 acceptable daily exposure, ADE, n—represents a dose
safety concerns, if any, associated with its use. It is the that is unlikely to cause an adverse effect if an individual is
responsibility of the user of this standard to establish appro- exposed, by any route, at or below this dose every day for a
priate safety, health, and environmental practices and deter- lifetime.
mine the applicability of regulatory limitations prior to use. 3.1.1.1 Discussion—This is the term used in the ISPE
1.5 This international standard was developed in accor- Risk-MaPP Guide (1) and is equivalent to the acceptable daily
dance with internationally recognized principles on standard- intake (ADI) but is associated with any route of administration.
ization established in the Decision on Principles for the 3.1.2 acceptable daily intake, ADI, n—measure of the
Development of International Standards, Guides and Recom- amount of a specific substance (originally applied for a food
mendations issued by the World Trade Organization Technical additive, later also for a residue of a veterinary drug or
Barriers to Trade (TBT) Committee. pesticide) in food or drinking water that can be ingested
(orally) on a daily basis over a lifetime without an appreciable
2. Referenced Documents health risk. Ref (2)
2.1 ASTM Standards:3 3.1.2.1 Discussion—This term is more commonly associ-
E1325 Terminology Relating to Design of Experiments ated with food and the oral route of administration.
E2476 Guide for Risk Assessment and Risk Control as it 3.1.3 clean-in-place, CIP, n—method of cleaning without
dismantling equipment.
1
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of
4
Subcommittee E55.03 on General Pharmaceutical Standards. Available from International Conference on Harmonisation of Technical
Current edition approved Dec. 1, 2017. Published May 2018. DOI: 10.1520/ Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH
E3106-17. Secretariat, 9, chemin des Mines, P.O. Box 195, 1211 Geneva 20, Switzerland,
2
The boldface numbers in parentheses refer to a list of references at the end of http://www.ich.org.
5
this standard. Available from American National Standards Institute (ANSI), 25 W. 43rd St.,
3
For referenced ASTM standards, visit the ASTM website, www.astm.org, or 4th Floor, New York, NY 10036, http://www.ansi.org.
6
contact ASTM Customer Service at [email protected]. For Annual Book of ASTM Available from U.S. Government Printing Office, Superintendent of
Standards volume information, refer to the standard’s Document Summary page on Documents, 732 N. Capitol St., NW, Washington, DC 20401-0001, http://
the ASTM website. www.access.gpo.gov.

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3.1.4 cleanability, n—relative difficulty for cleaning a piece 3.1.14 coupon, n—representative surface that is typically a
of equipment or product. rectangular piece of a material of construction in which a
3.1.5 cleaning control strategy, n—planned set of controls known amount of a compound is deposited to simulate a
derived from the risk assessment and current cleaning process process residue.
understanding that ensures reliable and consistent cleaning 3.1.15 design space, n—multidimensional combination and
process performance. ICH Q10 interaction of input variables (for example, material attributes)
3.1.5.1 Discussion—The controls can include parameters and process parameters that have been demonstrated to provide
and attributes related to materials and tools used for cleaning, assurance of quality. ICH Q8
cleaning procedure(s), equipment operating conditions, and the 3.1.16 exposure, n—process by which a human or animal
associated sampling plans, methods for validation, and routine can come into contact with a hazard.
monitoring. 3.1.16.1 Discussion—Exposure may occur through any
3.1.6 cleaning design space, n—multidimensional combina- route (oral, inhalational, dermal, and so forth). Exposure may
tion and interaction of cleaning input variables (for example, be short-term (acute exposure), of intermediate duration, or
product cleanability, equipment design, and so forth) and long-term (chronic exposure).
cleaning process parameters (for example, solvent/cleaning 3.1.17 grouping strategy, n—strategy of using groups of
agent concentration, temperature, time, and so forth) that have products or equipment to simplify cleaning validation.
been demonstrated to provide assurance of achieving accept- 3.1.17.1 Discussion—Products or equipment or both are
able cleaning outputs (for example, active pharmaceutical placed into groups and one or more representatives from the
ingredients (API) residues, cleaning agent residues). ICH Q8 group are chosen for cleaning process performance studies. A
3.1.7 cleaning input variables (parameters), n—those fac- grouping strategy shall be scientifically justified.
tors or settings whose values constitute the cleaning process 3.1.18 manual cleaning, v—cleaning of equipment, either in
and affect the cleaning output variables. place or out of place, by hand and with the aid of brushes,
3.1.7.1 Discussion—These independent variables include cloths, detergents, and so forth.
product cleanability, equipment size/groups, process residue
3.1.19 margin of safety, n—difference between the cleaning
load, holding times, cleaning agent concentration, cleaning
acceptance limit (based on ADE) and the process residue data.
agent type, rinse volume, pH, time, temperature, velocity,
pressure, surface coverage, location and cleaning cycle, and so 3.1.19.1 Discussion—This value can be used as a measure
forth. of the overall risk to patient safety presented by the cleaning
process. The margin of safety can be measured a number of
3.1.8 cleaning output attributes, n—these attributes include ways including the process capability index (Cpk) and the
product and cleaning agent residues remaining on the equip- process performance index (Ppk).
ment surfaces after cleaning.
3.1.20 maximum allowable carryover, MAC or MACO,
3.1.8.1 Discussion—Bioburden/endotoxin levels and opera- n—maximum amount of carryover from one product to the
tional considerations such as total cleaning time, holding times next.
and costs may also be cleaning output attributes.
3.1.20.1 Discussion—The MAC is calculated as a fraction
3.1.9 cleaning process, n—any process designed to remove of the lowest therapeutic dose (usually 1/1000) or as a fraction
process residues from product contact surfaces of manufactur- of a lethal dose (LD50) (usually 1/100 000 or 1/1 000 000).
ing equipment to levels that ensure patient safety and product
3.1.21 maximum safe carryover, MSC, n—maximum
quality.
amount of carryover of a residual process residue (API,
3.1.10 cleaning process parameters, n—cleaning agent cleaning agent, degradant, and so forth) into the next product
concentration, temperature, time, and so forth. manufactured without presenting an appreciable health risk to
3.1.11 cleaning validation, n—collection and evaluation of patients.
data, from the cleaning process design stage through cleaning 3.1.21.1 Discussion—The MSC is calculated from the ADE
at commercial scale, which establishes scientific evidence that and the total number of doses in a subsequent batch.
a cleaning process is capable of consistently delivering clean 3.1.22 permitted daily exposure, PDE, n—represents a
equipment. Ref (3) substance-specific dose that is unlikely to cause an adverse
3.1.12 cleaning verification, n—confirmation, through the effect if an individual is exposed at or below this dose every
provision of objective evidence, that specified cleaning re- day for a lifetime.
quirements have been fulfilled. ISO 90000 3.1.22.1 Discussion—This is the term used by the European
Medicines Agency (EMA) and is equivalent to both the ADE
3.1.13 clean-out-of-place (COP) system, n—automated sys-
and ADI.
tem usually used to clean large pieces of equipment or parts of
equipment that are disassembled, but too large to clean 3.1.23 probability, n—likelihood of occurrence of harm.
manually. 3.1.24 cleaning process residue, n—any residue, including,
3.1.13.1 Discussion—COP systems can range from elabo- but not limited to, APIs, cleaning agents, degradation products,
rate washing cabinets with automatic control systems to simple intermediates, excipients, and microbes remaining after a
dishwasher type units. cleaning process.

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3.1.25 qualified statistician, n—individual with a working 5. Science-Based, Risk-Based, and Statistics-Based
knowledge and education, training, or background in statistics Cleaning Process Development and Validation
who can apply statistical analysis to data from cleaning and 5.1 Science-based approaches should be applied throughout
cleaning validation studies. the cleaning process development and validation process.
3.1.26 qualified toxicologist/pharmacologist, n—individual 5.2 Quality risk management should be applied throughout
with specific education and training in toxicology/ the cleaning process development and validation process.
pharmacology that can apply the principles of toxicology to
deriving an ADE or PDE value for required process residues. 5.3 Appropriate statistical analysis should be applied
throughout the cleaning process development and validation
3.1.27 quality by design, n—systematic approach to devel- process.
opment that begins with predefined objectives and emphasizes
product and process understanding and process control based 6. Risk Assessment
on sound science and quality risk management. ICH Q8
6.1 Under ICH Q9, risk assessment is broken into three
3.1.28 representative surface, n—surrogate surface that may stages: risk identification, risk analysis, and risk evaluation.
be actual processing equipment or has characteristics similar to
that of processing equipment and is used for spiking studies. 6.2 Risk can be defined as: risk = f (probability of occur-
rence of harm and the severity of that harm).
3.1.29 visual inspection, n—process of using the human
eye, alone or in conjunction with various aids, as the sensing 6.3 For the purposes of cleaning, risk can be further defined
mechanism from which judgments may be made about the as a function of the severity of the hazards of process residues,
condition of the surface to be inspected. likelihood and level of process residues, and detectability of
process residues.
3.1.30 visual limit of detection, n—lowest level of a process
residue on a surface (in µg/cm2 or µg/in.2) that is visible to a 6.4 For a reliable assessment of risk, scientific means (for
qualified inspector under defined viewing conditions. example, risk management tools) should be used to identify the
hazard presented by a process residue (for example, API,
3.2 Definitions of Terms Specific to This Standard: degradation products, intermediates, cleaning agent,
3.2.1 CIP system, n—in this standard, CIP systems include bioburden/endotoxin, and so forth), the ability of a cleaning
the manufacturing equipment itself (mix tanks, transfer piping, process to remove process residues to levels that are
and so forth) as well as the equipment used for cleaning acceptable, and the ability to detect and quantify the presence
(detergent tanks, rinse tanks, pumps, and so forth). of process residues after cleaning.
3.2.2 cleaning failure modes and effects analysis, FMEA, 6.5 Risk Identification—Risk identification should encom-
n—a procedure to identify all possible failures of a cleaning pass the identification of process residue hazards, equipment
process or procedure, their effects on cleaning, the likelihood design hazards, and procedural hazards.
of occurrence, and the probability that the failure will go 6.5.1 Process Residue Hazard Identification:
undetected. 6.5.1.1 The hazard presented by a potential process residue
3.2.2.1 Discussion—The cleaning FMEA can also identify may be determined from a toxicological review performed by
ways to minimize the failures, decrease their likelihood, and a qualified toxicologist or qualified pharmacologist. For an
improve their detectability. API, this involves a thorough review of all relevant toxicologi-
cal data available for the process residue under study (4). When
4. Significance and Use preclinical and clinical data on APIs are available to review, an
ADE can be determined and used as a measure of the severity
4.1 Application of the approach described within this guide of hazard presented by a compound. For further information,
applies risk-based concepts and principles introduced in ICH see the ISPE Risk-MaPP Guide (1) or the EMA Guideline on
Q9. As stated in ICH Q9, the level of effort, formality and Setting Health Based Exposure Limits for Use in Risk Identi-
documentation for cleaning should also be commensurate with fication in the Manufacture of Different Medicinal Products in
the level of risk. Shared Facilities (4).
4.2 Application of the approach described within this guide 6.5.1.2 When an ADE is not available, such as for
applies many of the science-based, risk-based, and statistical intermediates, degradation products, or compounds in early
concepts and principles introduced in the FDA’s Guidance for development, alternative approaches such as the threshold of
Industry Process Validation: General Principles and Practices toxicological concern (TTC) may be justified (4, 5). Although
(3). compounds in early development may not have sufficient
safety data to perform a complete analysis, useful information
4.3 This guide supports, and is consistent with, elements
can be found in the chemical structure of a compound to help
from ICH Q8, ICH Q9, ICH Q10, and ICH Q11.
determine a provisional ADE for the compound. “In silico”
4.4 Key Concepts—This guide applies the following key (computer-assisted) toxicological assessment or a structure
concepts: (1) quality risk management, (2) science-based activity relationship can be used to determine provisional
approach, (3) statistics-based approach, (4) process ADEs for a compound (6, 7). For example, a compound in the
understanding, and (5) continued improvement as described in same structural series of a known API from a given therapeutic
the ICH Q series. class can be treated in the same way as that API, for example,

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a compound with a propylamine structure would be expected to design considerations may include: materials of construction,
share properties of this class of antihistamines (8). Where data presence of dead legs or other areas in which material could
are available on comparative potency, these can be used to become trapped, or drainability.
adjust the estimated ADE. 6.6.6.2 Where satisfactory cleaning results cannot be
6.5.1.3 The hazard of possible bioburden from a previous achieved because of limitations in the equipment design, the
product and the possibility of microbial proliferation after a equipment may need to be modified, dedicated, or replaced.
cleaning process and the hazards this presents should also be 6.6.7 Evaluation of Historical Cleaning Data—The history
considered. For example, the hazard(s) presented by holding of cleanings (along with any deviations, investigations, and
equipment either in a dirty state or in clean state should be
corrective actions) should be reviewed. This cleaning process
considered.
understanding and knowledge can provide useful information
6.5.2 Equipment Hazard Identification—The potential haz-
in a risk analysis and may help identify cleaning process
ards presented by equipment design should also be considered,
parameters to be used in cleaning process development studies
such as the possibility of product buildup. Equipment should
and determine the likelihood of a cleaning failure (ICH Q10).
be designed to facilitate cleaning, inspection, and monitoring.
6.5.3 Procedural Hazard Identification—Before use, clean- 6.6.8 Levels of Cleaning—Manufacturing equipment may
ing procedures should be subjected to risk assessments, for require different levels of cleaning and validation under differ-
example, cleaning FMEA or other risk management tools, to ent circumstances. To determine the appropriate cleaning level,
minimize risk of failure (for example, to ensure that product the type of product manufactured on the equipment (for
buildup is avoided),, improve the cleaning procedures, and example, intermediates, APIs, finished products) should be
make the cleaning procedures more reliable and robust. considered and the risks to patient safety and product quality
should be understood. A cleaning process can then be devel-
6.6 Risk Analysis: oped to achieve the necessary results. There may be several
6.6.1 After identifying the hazards posed, the risks associ- levels of cleaning based on the level of risk, for example:
ated with them should be analyzed. This risk analysis should
6.6.8.1 Cleaning between different products,
involve the cleaning process development, facility/equipment
design review, cleaning procedure review, and the selection of 6.6.8.2 Cleaning between similar products,
analytical methods. The analysis should also determine what 6.6.8.3 Cleaning during campaigning (cleaning between
steps can be taken to mitigate the identified risks. batches of the same product),
6.6.2 The risk analysis should show how cleaning may 6.6.8.4 Cleaning of dedicated equipment,
affect the patient safety and quality of the next product. 6.6.8.5 Cleaning after equipment maintenance,
6.6.3 The impact of the different factors (process residue, 6.6.8.6 Cleaning after elapse of permissible storage/hold
cleaning/rinsing agents, equipment engineering, and so forth) time of clean equipment,
on the outcome of the cleaning process should be analyzed.
6.6.8.7 Cleaning after sampling, and
6.6.4 The cleaning process risk analysis can help to deter-
mine the necessary cleaning qualifications and identify appro- 6.6.8.8 Cleaning after non-routine operations.
priate risk control mechanisms. 6.6.9 Cleaning Process Development—Cleaning processes
6.6.5 Process Residue Characterization: should not be adopted randomly or chosen based on past use.
6.6.5.1 The chemistry of process residues should be under- Cleaning processes should be developed to reduce process
stood to design an effective and efficient cleaning cycle, for residues levels as low as practical and determine the appropri-
example, cleanability of process residues (for example, highly ate cleaning agents for this purpose. Cleaning processes that
insoluble or strongly adhesive residues) and potential interac- have been optimized through the selection of the most appro-
tions (for example, staining, corrosion) of process residues priate cleaning agents and cleaning parameters can offer the
with equipment. greatest ability to reduce process residues in the shortest time
6.6.5.2 The chemistry and potential interactions between to the lowest level of risk. The output of the cleaning process
process residues and chemicals used as part of cleaning development should be used to create the cleaning standard
processes should also be understood, for example, the solubil- operating procedure (SOP).
ity of process residues in cleaning agents or rinsing agents 6.6.9.1 Bench-Scale Studies:
should be considered to avoid situations in which process (1) Laboratory scale or “bench-scale” studies can provide
residues are not removed or whether degradation products may valuable sources of cleaning process knowledge and cleaning
be formed that may be harder to clean or more toxic than the process understanding (9). The studies may be conducted by
original process residue. spiking the process residue(s) on coupons and then subjecting
6.6.6 Equipment Design for Cleanability: the coupons (after drying) to varying cleaning conditions. The
6.6.6.1 The design of equipment has an impact on its studies could also be conducted in small-scale equipment
cleanability. Equipment design should be considered as part of designed to simulate the actual manufacturing equipment.
the risk analysis taking into consideration the likely type of (2) Bench-scale studies can be quick, economical, and
cleaning process that will be applied to that equipment. The provide information on how difficult a product is to clean,
variables and attributes related to equipment design should be which cleaning agent provides optimal cleaning, which clean-
identified and linked to the cleaning critical attributes using the ing input variables are critical, and whether dirty hold time
appropriate risk assessment tool(s). Examples of equipment studies may be necessary. Cleaning process knowledge and

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cleaning process understanding gained from bench scale stud- 6.6.10.2 A documented risk assessment should determine
ies may be directly applicable to full-scale cleaning processes the level of risk presented by the cleaning equipment and the
but differences between full scale and bench scale should be controls that should be established to mitigate risks.
considered. 6.6.11 Risk Analysis of Written Cleaning Procedures
6.6.9.2 Cleaning Parameter Determination—The effects (SOPs)—A risk analysis on legacy SOPs, or SOPs being
and the interactions of input variables affecting cleaning should developed, can determine if there are any gaps that may
be evaluated. The variables typically associated with cleaning contribute to failures in the cleaning process execution or cross
are: time, temperature, cleaning agent chemistry, mechanical contamination. Risk analysis on SOPs being developed can
action, product cleanability, and amount of process residue. further determine adequacy and agreement with the develop-
6.6.9.3 Design of Experiments (DoE) and “Cleaning Design ment studies.
Space:” 6.6.12 Manual Cleaning—A risk assessment should be done
(1) To improve or optimize cleaning processes, experi- to determine the effects of operator variability on manual
ments can be designed to examine the effects of cleaning input cleaning. Depending on the level of risk, steps should be taken
parameters on cleaning output variables. These inputs can be to mitigate these risks or automated procedures should be
assigned as factors in a DoE (Terminology E1325) and the considered. Operators should be qualified to perform these
effects and interactions of varying these factors on the outputs procedures.
can be measured as responses. 6.6.13 Automated Cleaning Systems:
(2) Typical cleaning input parameters include product 6.6.13.1 Automated cleaning systems can potentially pro-
cleanability, equipment size/groups, process residue vide a lower level of risk than manual cleaning but should be
concentration, holding times, cleaning agent type and analyzed for potential sources of cross contamination.
concentration, wash/rinse temperature/time/volume, flow, 6.6.13.2 COP cleaning solutions may be a source of con-
pressure, and spray ball type/location. tamination.
(3) The typical cleaning output variables are the product 6.6.13.3 Equipment in CIP systems not being disassembled
and cleaning agent residues. Bioburden levels and operational may lead to buildup and cross contamination.
considerations such as cleaning times, holding times, and costs 6.6.13.4 CIP systems should be capable of controlling,
may also be considered. monitoring, and recording critical operating/process param-
(4) DoE are used for determining a “cleaning design eters.
space”7 that provides many benefits including justification of 6.6.13.5 Cleaning coverage, risk of system failure, and its
product or equipment grouping and process change control potential impact on cleaning efficiency and cleanability of the
strategies. If changes to the cleaning process or equipment are system itself should be considered during the design and
considered, the results of a risk review can provide information qualification of CIP systems.
regarding the impact on cleaning design space and the need for 6.6.14 Grouping Strategies—A “group” is a collection of
additional studies or testing. products or equipment that share a common cleaning design
(5) “Cleaning design space” also provides important input space and a common cleaning procedure to minimize cleaning
into the cleaning control strategy. process performance studies and reduce the number of runs and
6.6.9.4 Cleaning Agent Selection: samples required. Such a group may also share a common
(1) Cleaning agents should be selected based on scientific cleaning control strategy. Any groupings should be scientifi-
principles and the level of hazard they pose. This selection cally justified based on a risk assessment and from knowledge
should also be based on cleaning process development studies gained from cleaning development studies. Groupings may
(for example, bench-scale studies), compatibility with the also be used as the basis for factors in a DoE.
materials of construction of the equipment, and should not be 6.6.15 Hold Time Studies:
based simply on availability or only for harmonization pur- 6.6.15.1 There are generally two types of hold time studies:
poses. dirty hold times and clean hold times. The maximum time
(2) The composition of a cleaning agent and its variability interval between equipment use and cleaning is known as the
should be known. The ability to detect residues of the cleaning dirty hold time (DHT). The maximum time interval between
agent should also be considered. the last step of the cleaning procedure to the start of next
6.6.10 Cleaning Equipment Design and Qualification: equipment use for manufacturing is known as clean hold time
6.6.10.1 Equipment used to support cleaning should be (CHT). Expired equipment hold time (EEHT) occurs when the
designed with the same attention to detail as directed to maximum time interval in the DHT or CHT has been exceeded.
manufacturing equipment. Equipment design specifications 6.6.15.2 A cleaning risk assessment can be performed to
should be capable of meeting the required cleaning specifica- determine the potential impact or effect of these time periods
tions from bench scale and cleanability studies. This equipment on the ability to clean the equipment or maintain its cleanli-
should be suitably located to facilitate proper cleaning during ness. The cleaning risk assessment can be used to justify the
operations. criticality level of the hold time period and number of cleaning
exercises to support its qualification. If the conclusion of the
cleaning risk assessment is that the hold time period does not
7
Note that under ICH Q8 Design Space is submitted in the filing but this is not have an impact on the cleaning process, then this hold time
the case for cleaning. period should not need to be qualified.

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6.6.16 Cleaning Control Strategy—A cleaning control strat- considerations may include; swab type, number of swabs,
egy should be developed based on the overall outcome of the swabbing pattern used, swabbing solvents required, and any
risk assessment, which includes cleaning process knowledge special requirements for specific areas or equipment. The area
and understanding obtained during cleaning process develop- to be swabbed should be defined.
ment and includes the results of cleaning data collected and 6.6.18.5 Surface Scanning Sampling—Technologies such as
evaluated during cleaning qualification runs in the risk evalu- Fourier transform infrared (FTIR), near infrared (NIRS),
ation step. The cleaning control strategy should be refined and Raman, fluorescence and ultraviolet (UV) spectroscopy that
continually improved as new knowledge is gained from peri- are used in various in-line/at-line applications may have
odic assessment and monitoring of cleaning processes. application to cleaning verification. These technologies should
6.6.17 Operator Training: be qualified for their intended use.
6.6.17.1 The suitability of initial and ongoing training 6.6.18.6 Indirect Surface Sampling: Rinse Sampling—Rinse
should be determined based on the education and experience of sampling allows sampling of residues from a greater surface
operators as well as a periodic assessment of effectiveness of area than swab sampling. Rinse sampling is usually the
the training program. technique of choice where equipment surfaces are not readily
6.6.17.2 The level and frequency of training should be accessible, there are physical limitations, or it is undesirable to
based on risk and the training program should be appropriate open or enter a closed system for process safety or occupa-
for each operator to ensure that they perform tasks reliably. tional exposure considerations and when the design of equip-
Assessment of training effectiveness or qualification should be ment has been carefully reviewed to ensure that locations in
considered to help reduce variation in the performance of equipment that cannot be cleaned have been eliminated from
cleaning processes. the design. The rinse solution selection should be based
6.6.18 Sampling—In statistics, the purpose of sampling is to primarily on product solubility. The use of rinse sampling
select a representative subset of individuals from a population should be justified in a risk assessment.
that can reliably characterize the whole population. In cleaning,
6.6.18.7 Qualification of Sampling—The ability of sampling
this means selecting representative samples from cleaned
techniques to recover process residues of interest should be
equipment that can reliably characterize the cleanliness of the
determined and documented. This qualification typically in-
equipment.
volves a recovery study. The sampling technique should be
6.6.18.1 Sampling Strategy—The risk assessment and prior
standardized and well defined to ensure consistency and
experience should be used to determine the sampling locations,
reproducibility. Training for the sampling technique is essential
number of samples, and sampling methods for each piece of
to obtain reliable results. Statistical techniques can be used to
equipment. Sampling locations should consider the equipment
determine the accuracy, precision, and robustness of the
design, accessibility, and materials of construction. Sampling
sampling technique.
locations should include those determined to be most difficult
to clean and where there is a likelihood of contamination or 6.6.19 Selection of Analytical Methods—The choice of
carryover to the next product. Sampling strategies should have methods should be science and risk based. The goal should be
a statistical basis. to use the simplest technique that is appropriate and can be
6.6.18.2 Sampling Techniques—The cleaning risk assess- justified. Analytical methods fall into two general categories:
ment should be used to determine the selection of the appro- specific and non-specific.
priate sampling technique. The risk associated with the process 6.6.19.1 Specific Analytical Methods—Specific methods,
residues and the equipment design and accessibility to the area such as high performance liquid chromatography (HPLC), are
to be sampled will determine the type of sampling method capable of identifying and quantifying specific process residues
needed. Process residues with a low risk may be candidates for in the presence of potential contaminants. Specific methods
visual inspection only, while process residues with a high risk should be considered for high-hazard products or high-risk
may require swab sampling using specific analytical methods. situations.
6.6.18.3 Visual Inspection—The most basic tool for inspect- 6.6.19.2 Non-Specific Analytical Methods—Non-specific
ing equipment for cleanliness as in accordance with 21 CFR methods, such as total organic carbon (TOC), UV, conductivity,
211.67(b)(6) has typically been visual inspection, and it should pH, and visual inspection detect the presence of multiple
be the foundation technique for all cleaning assessment ingredients which can be acceptable in certain situations.
programs, including cleaning process development, and should 6.6.20 Using Risk Analysis for Master Planning—The mas-
be a part of the validation. A risk assessment should be ter plan for cleaning should be developed based on the hazard
performed to determine the critical parameters for visual identification of the process residues and the risk analysis of
inspection. Using visual inspection alone for validation may be the equipment design and cleaning procedures as a minimum
acceptable (10) only when the risk is low and 100 % of the and provide the basis for the cleaning control strategy.
equipment surface can be inspected under appropriate viewing
conditions. 6.7 Risk Evaluation:
6.6.18.4 Direct Surface Sampling: Swab Sampling—Swab 6.7.1 Risk evaluation for cleaning compares the cleaning
sampling offers direct physical sampling of residues from data collected against the acceptance criteria for the identified
surfaces. Swab sampling is usually the technique of choice hazards. Risk evaluations should consider the probability of
where equipment surfaces are readily accessible. Points to patient exposure to the hazard.

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6.7.2 Risk reduction steps should be considered if the adjusted to a statistically appropriate level and be representa-
evaluation of the data for the cleaning process indicates the risk tive of the equipment.
is a concern. This can be determined using one or more risk 7.3.3 Statistical Process Control (SPC) Limits—Data that
analysis tools. has been collected in the risk evaluation or risk control stages
6.7.3 Evaluation of Cleaning Data: can have SPC limits calculated from these data. These SPC
6.7.3.1 One approach for this assessment is the maximum limits should then be used for monitoring cleaning processes
safe surface residue (MSSR) based on the ADE for that process and in place of the MSSR limits used for the risk analysis in
residue (11-13). The comparison of process residue to MSSRs risk evaluation.
can demonstrate whether process residues on equipment prod- 7.3.4 Use of PAT in Cleaning Validation:
uct contact surfaces pose significant risk to patients and show 7.3.4.1 PAT can be used as a system for designing,
what the margin of safety is for that process residue (13). analyzing, and controlling cleaning processes. This includes
6.7.3.2 A similar procedure can be used for assessing timely measurements of critical cleaning input/output variables
microbial risk (14, 15). identified and documented during risk assessment and during
6.7.3.3 The results of all cleaning runs should be collected cleaning process development with the goal of ensuring patient
in a database for the validation of the cleaning process. safety and product quality.
7.3.4.2 It is recommended that cleaning processes use tech-
7. Risk Control
nologies to measure, control, and record these variables to
7.1 Risk control encompasses activities around reducing detect critical failures and ensure reliable and consistent
risks with periodic assessments and monitoring to identify process performance.
problems before they occur. 7.3.4.3 The data from these approaches can be evaluated
7.2 Risk Reduction—After identifying the risks that are statistically. Models can be developed and subsequent runs can
significant enough that reduction steps should be taken, the be compared to the model to determine whether the cleaning is
next step is to attempt reducing the level of risk presented. This equivalent to the model or used for real-time release of
could include steps to reduce the severity of the hazard, reduce equipment.
the likelihood of occurrence, and increase the detectability of 7.3.4.4 On-line and in-line sampling have the most applica-
the risk. Aspects of risk reduction could include, but are not bility for continuous monitoring of critical cleaning input/
limited to, the examples in Table 1. output variables such as temperature, flow rate, TOC,
7.3 Risk-Based Monitoring: conductivity, and so forth.
7.3.1 Risk-based continued monitoring (levels and fre- 7.3.4.5 At-line sampling may include TOC, conductivity,
quency of routine sampling) of cleaning process parameters and visual inspection. Information collected during or after a
and sampling of critical cleaning quality attributes should be cleaning process is complete can enable parametric release of
based on the data collected during cleaning process develop- equipment and improve manufacturing process efficiency
ment and qualification runs. (Guide E2476).
7.3.2 Monitoring and sampling do not have to continue at 7.4 Risk Acceptance—After risk reduction steps on the
the level used during the cleaning process development and cleaning processes have been completed, an evaluation of the
qualification runs and can be modified based on the data and success of these efforts should be made. It is at this point that
level of risk. The level of monitoring and sampling can be the residual risk is either accepted or rejected and scheduled for
further reduction efforts. Risk acceptance can also occur after
risk evaluation when there is no need to take further risk
TABLE 1 Examples of Risk Reduction reduction. These decisions should be documented in the
Risk Reduction
Examples of Risk Reduction Steps
corresponding cleaning risk assessment.
Elements
Reduce severity Hazard removal 8. Risk Review
Hazard replacement (for example, move to safer
cleaning agents) 8.1 The results of cleaning and monitoring should be
Equipment dedication
formally reviewed on a periodic basis based on a risk assess-
Reduce likelihood Cleaning process improvements ment. Based on the risk review, a new risk control strategy and
Cleaning optimization (DoE) a new risk assessment may be required. The level of any
Operator training
SOP improvements (for example, poka-yoke) mitigation or corrective actions should be commensurate with
Equipment dedication the risk identified or reviewed. Note that the result of the risk
Modifications of equipment design review may tighten or relax controls that were instituted in the
Improvements in equipment storage practices
Selection of new equipment course of the original risk assessment.
Product campaigning 8.1.1 New Product Introduction:
Increase detectability Analytical method improvement (lower DL) 8.1.1.1 Before introducing a product new to a shared manu-
Sampling method improvement (increased recovery) facturing facility, a decision should be made and documented
Cleaning process monitoring about the appropriateness of manufacturing this product in the
Statistical process control
Introduction of PAT (for example, at-line release) facility (see Ref (1)). This would include an evaluation of all
relevant toxicological data (pre-clinical, clinical, and after

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 E3106 − 17
market) by a qualified toxicologist or pharmacologist to Communications might include those within a company, be-
determine an ADE (4). tween companies and contract manufacturers, with regulatory
8.1.1.2 At this point, if the new product is acceptable, the authorities, and so forth. The information should consider the
cleanability of the product should be determined. If the new severity (ADE/PDE), probability (prior cleaning results), de-
product is not cleanable with the existing cleaning process, tectability (analytical methods), control (cleaning procedures/
cleaning process development would be necessary including cleaning agents), or other aspects of risks to patient safety and
qualification studies for the new cleaning process. Otherwise, product quality that may result from inefficient or ineffective
no additional cleaning process development or qualification cleaning procedures.
studies would be necessary.
9. Risk Communication 10. Keywords
9.1 Risk communication is the sharing of information about 10.1 acceptance limits; CIP; cleaning development; clean-
cleaning risk and its management between the relevant parties. ing validation; PAT; risk-based; science-based

REFERENCES

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RELATED MATERIAL

ASTM E2363 Terminology Relating to Process Analytical Technology in

the Pharmaceutical Industry

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