Cleaning Validation - The Definitive Guide in 2022 - Pharma GXP

1/27/23, 2:58 PM Cleaning Validation: The Definitive Guide in 2022 - Pharma GxP
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Cleaning Validation: The Definitive Guide in 2022

By Saket Yeotikar January 19, 2021

 Manufacturing multiple drugs in the same facility is an efficient way to run the business. Yet, it involves risk of cross-
 contamination.
To avoid this, previous product traces must be completely removed before changing over the product.
This is called Product-to-Product cleaning.
Not only this but also a same product facility requires effective residue removal from batch to batch to avoid the
carry over of impurities.
Well, cleaning validation is a scientific technique that ensures:
Previous product traces have been removed
Contamination-free operations
Safe batch-to-batch transitions
In recent years, cleaning validation guidelines have become as complex as process validation due to raising
concerns over the quality of the cleaning.
This article discusses the what, why, when, and how of this technique and the broad classification of available
cleaning mechanisms.
Page Contents
What is Cleaning Validation?
Why Perform Cleaning Validation?
What is Contamination?
What is Cross-Contamination?
When to Perform Cleaning Validation?
https://pharmagxp.com/quality-management/cleaning-validation/#What-is-Cleaning-Validation 1/22
Cleaning Classifications
3 Ways of Cleaning
2 Types of Cleaning
Different Cleaning Mechanisms
List of Cleaning Agents
Cleaning Validation Program
Critical Process Parameters (CPPs) for Cleaning
Critical Quality Attributes (CQAs) For Cleaning
Pre-Requisites to Begin Cleaning Validation
Cleaning Validation Process Flowchart
Cleaning Validation Protocol and Report
Selecting a Proper Way of Cleaning
Selection of Analytical Methods and Their Validation
Sampling Methods for Cleaning Validation
Defining Equipment’s Dirty Hold Time and Clean Hold Time
Worst-Case Conditions in Cleaning Validation Program
Establishing Cleaning Limits and Requirements
Grouping Strategies FYI (Outdated Approach)
Regulatory Concerns
Conclusion
What is Cleaning Validation?
Establishing documented, scientific and risk-based evidence that provides a high degree of assurance that a
typical cleaning method or procedure will consistently clean the equipment or a medical device in compliance
with its predetermined specifications and quality attributes, taking the patient’s safety into consideration. In
a nutshell, it is a technique of developing effective cleaning processes that’ll not harm the end-user.
Essence taken from various guidelines
 Obviously, cleaning validation is a lesser concern for disposable systems such as single-use fermenters as they don’t
 get consumed in the next batch.

Cleaning validation, especially in India, is a trending topic for drug-makers due to increasing regulatory
observations and market complaints related to cleaning.
Why Perform Cleaning Validation?

When equipment is used to manufacture a product, it leaves behind traces of raw material, cleaning agents, and the
product itself. For product change-over, these traces may contaminate or cross-contaminate the next product.
To ensure your cleaning process effectively eliminates such traces, a cleaning validation program is outlined,
executed, and assessed.
Until the quality unit approves the cleaning validation report, firms don’t indulge in the new product campaign.
So, the cleaning validation is a regulatory requirement to ensure:
1. Product safety
2. Patient safety
Defining a cleaning validation program is one thing. But it needs to have systematic integration with QMS and QRM
systems as it helps in:
Understanding and identifying the risks to the patients
Performing its impact assessment
Outlining risk mitigation strategy
Mitigating those risks
Assuring finished product safety
What is Contamination?
The product that is adulterated with the residue of the previous batch of the same product in particular
equipment is called Contamination OR A new product that is adulterated with the residue of raw materials of
the previous product is also called Contamination.
What is Cross-Contamination?
A new product that is adulterated with the left behind traces of the previous product in particular equipment is
called Cross-Contamination.
Successful cleaning validation is that which…
1. Assures patient safety through risk-based studies conducted in the development of the cleaning processes.
2. Avoid product adulteration and achieve a contamination-free product.

3. Satisfies regulatory requirements.
4. Allow us to re-use the same equipment for different products.

5. Optimize processes and costs due to a systematic product change-over.
Now, we’ll look into…
Ways and types of cleaning processes
How to develop a cleaning validation program, and
The expectations of regulatory bodies.
 When to Perform Cleaning Validation?

 The following situations require a proper cleaning validation study.

When establishing a fresh commercial process
When reusing the existing facility for a different product every time
Major changes in raw materials based on impact assessment
Significant modifications in cleaning procedures
Introduction of new equipment for the already established process
Changes in cleaning agent
Changes that might affect the CPPs and CQAs of already approved cleaning validation
Cleaning Classifications
Cleaning processes based on industrial practices can be differentiated into three ways and two types.
3 Ways of Cleaning
Cleaning can be performed in 3 different ways using cleaning agents such as purified water, WFI (Water for
Injection), or chemical solvents.
1. Cleaning In Place (CIP)
1. CIP Skid to Clean the Equipment
2. Automated CIP of the Equipment
2. Cleaning Out of Place (COP)
1. Washers like Tray Washers, Dish Washers, etc.
2. Sub-systems of equipment hard to approach in CIP
3. Manual Cleaning
1. Components that are difficult to clean during COP and hence cleaned using tools such as Cleaning
Brushes, Scrubbers, etc.
Not a thumb rule but in general:
Equipment is preferred for automated cleaning in place i.e., CIP.
Components and sub-systems not being feasible for CIP are preferred for COP.
Critical components or locations of the equipment that are hard to reach during CIP and COP are preferred for
Manual Cleaning.
2 Types of Cleaning
As per the common understanding among pharma professionals, there are two types of cleaning.
1. Batch To Batch
1. Cleaning of the process equipment in between two batches for ongoing manufacturing campaign of the
same product.
2. Product to Product
1. Cleaning of the process equipment in between the two different products i.e. after finishing the previous
product campaign and before initiating a new product campaign.
Different Cleaning Mechanisms

Residues from equipment can be removed either physically or chemically. It is chosen by consistency and
performance-based selection criteria.
 Physical
1. Mechanical or Manual
 2. Emulsification

3. Dissolution
Chemical
1. Solubilization Using Solvent
2. Chemicals
3. Detergents
Mechanical Cleaning
This cleaning involves the mechanical application of scrubbers, brushes, wipes, etc. for removing residue or previous
product traces.
Let us see one by one.
Brushing or Scrubbing
Detergent solutions are prepared with a slightly alkaline pH in hot water, typically NLT 50°C.
The loose components are disassembled from the equipment and dipped in detergent solutions allowing
sufficient soaking time.
A brush, scrubber, or scrapper as suitable is applied on the surface and rinsed under hot or cold water for
sufficient time.
Advantages Disadvantages
Simple and flexible Inconsistency due to manual action
Requires exhaustive training Involves additional man-power
Water Spray
This involves a high-pressure water spray that easily disintegrates the residue from loose and dirty components of
the equipment.
Moreover, when water alone is insufficient to do this job, a suitable surfactant is considered for further scrubbing or
brushing solutions.
Wiping
Lint-free cloths are commonly used to clean visible equipment surfaces with wiping actions defining:
Wiping directions, patterns, and number of times to repeat the wiping
Solvent and cleaning agent concentrations
Quantity of cleaning solution to apply to the wipes
Emulsification
Hydrophobic residue suspended in an aqueous cleaning solution is called Emulsion. This method is typically
considered while dealing with insoluble liquid residues and is rarely applicable in pharmaceutical industries.
However, firms that follow detergent-based washing cycles may still find this method effective. Though considered
a physical cleaning mechanism, it may also fall under Detergents.
Surfactants are introduced in the equipment to form an emulsion. When agitated, break down the residue into
small droplets and either float or sink based on the density.
 Practically speaking, enough variations are possible in this method due to the uncertainty of the holding time of the
 residue.
 Dissolution
In this mechanism, a residue is dissolved with a suitable solvent. The common solvent readily available is water
which is aqueous in nature.
Non-aqueous solvents are also preferred in specific cases. However, water is non-toxic, cheap, environmentally
friendly, does not contribute to chemical degradation, and is easy to remove. Hence water is the primary choice.
But choosing either of them depends on the drug residue solubility characteristics.
Chemicals
This mechanism involves the application of chemical reactions for cleaning purposes and generally includes
oxidation and hydrolysis.
Oxidation
Strong oxidizing agents are used to break carbon-carbon bonds resulting in smaller molecules and increasing the
water solubility of the residue.
Hydrolysis mentioned below too has the same impact but on a more specific level. Whereas oxidation is a universal
term and hence puts challenges in choosing a specific analytical method to detect unoxidized residue.
Examples of oxidizing agents include Peracetic Acid (CH3CO3H), Hydrogen Peroxide (H2O2), and Sodium
Hypochlorite (NaClO), etc.
Hydrolysis
This method improves the solubility of solvents resulting in hydrolyzed residue with lower molecular weights.
For aqueous solutions, hydrolysis is carried out at elevated temperatures using acids or alkalis. The rate of hydrolysis
depends on the nature and quantity of residue and temperature.
It is important to consider the most appropriate analytical methods to test the efficiency of the cleaning process
independently.
Detergents
Wetting
This method lowers the surface tension of residue with the help of surfactant addition in water. Wetting results in
two actions.
Wet residue reduces its surface tension and improves the rate of dissolution
Wet equipment surface promotes residue disintegration
Dispersion
Dispersion is the same as that of emulsification except for the use of solid particles.
Solid particles are wetted and broken down using anionic surfactants and vigorous agitation to form a suspension
pool. More importantly, this method is practiced in Oral Solid Dosages (OSD) such as power blending and tablet
manufacturing.
Emulsification

Refer to the Emulsification Above.

 Solubilization
In some cases, acids or alkalis are used for proper dissolution, yet they require excess removal times to bring them
down to neutral pH ranges.
For example, bringing down the pH should be checked at the “drain point” rather than “in-place” to ensure
complete residue removal from the equipment during cleaning.
These methods can either be used in combination or sequence depending upon the feasibility and nature of
residue. It is highly advised to properly conduct a residual study to determine an effective cleaning mechanism.
List of Cleaning Agents

Organic Solvents
Generally, organic solvents are used in the bulk manufacturing of Active Pharmaceutical Ingredients (APIs).
When cleaned with water, reactors with higher volumes may not dissolve the bulk residue stuck to the surface of
reactors.
An organic solvent used in manufacturing the same drug usually dissolves the API and hence the most suitable
choice for cleaning purposes.
However, addressing cost optimization and solvent recovery are crucial aspects while designing the cleaning
processes. Examples of commonly used solvents are Methanol, Toluene, Acetone, and Ethyl Acetate.
Aqueous Agents
Water is used as a stand-alone cleaning agent or in combination with the following classifications.
Commodity Chemicals Specialty Cleaners
Surfactants (Based on the charge on the polar end)

Inorganic Chemicals – Nonionic (no charge)
– Ortho-Phosphoric Acid (H3PO4) – Anionic (+ve)
– Nitric Acid (HNO3) – Cationic (-ve)
– Amphoteric (+/- based on pH)
Organic Chemicals
– Acetic Acid (CH3COOH) Other Cleaners like Chelants, Dispersants, etc.
– Sodium Hydroxide (NaOH)
Table: Types of Aqueous Cleaning Agents
What we’ve understood so far was related to cleaning mechanisms and their commercially available options. You
can visit this link for a list of cleaning agents. For now, that’s all about the cleaning philosophy.
Cleaning Validation Program

This is the most critical part of your manufacturing activity.
Since if the cleaning is inadequate, it may compromise the patient’s safety. Hence, cleaning processes should be
designed and developed considering this as the 1st worst-case.
Identifying the core risks associated with the cleaning philosophy is the next important challenge. Risk
identification requires systematic study instead of experience-based predictions.

 Following are the most common CPPs and CQAs for a typical cleaning process.

Critical Process Parameters (CPPs) for Cleaning
Temperature
Pressure
Contact time
Concentration of the cleaning agent
Surface Roughness (More roughness means more difficult to clean)
Flow rate
Proper mixing RPMs
Dirty Hold Time for Equipment
Clean Hold Time for Equipment
Critical Quality Attributes (CQAs) For Cleaning

Product residue
Cleaning agent residue
Required concentration of cleaning agent
Microbial residue
Drain ability
Conductivity
Number of rinses
Time for cleaning
Pre-Requisites to Begin Cleaning Validation

Before commencing cleaning validation, the following pre-requisites should be met:
Cleaning Validation Strategy and Protocols are approved and ready
Equipment used for most of the products should be identified
SOP for Equipment Cleaning has been established (draft)
Sampling and Analytical Methods are validated
A list of CPPs and CQAs is available
Drug toxicity data is available
Product contact surface area is calculated
Training is given to the personnel involved in cleaning validation activity
Drug characteristics are evaluated for cleaning difficulty
Cleaning Validation Process Flowchart

Below is a flow diagram showing the overall strategic activities in cleaning validation in the pharmaceutical industry.



Cleaning Validation Process Flow
You may cascade the items as per the suitability of your cleaning process.
A risk-based approach would help identify the risks associated with:
Concerned residue
Priority of selecting sampling locations
Determining and justifying product/equipment groups
Defining acceptance criteria
A sequence of protocol execution
Product change-over SOPs
Cleaning Validation Protocol and Report

Instead of following any protocol template, it is important to understand its key technical aspects. A protocol should
be prepared explaining technical cleaning validation activities that contain:
Scope and Objective
Cleaning SOP Draft
Possible ways of contamination
Sampling plan and rationale including prioritized sampling locations
Worst-case conditions
Selection of analytical methods and their validation
Equipment Dirty and Clean Hold Time Study
Acceptance criteria
Technically sound deviation management strategy
Data monitoring Annexures (if Applicable)
Successful execution of the protocol would be incomplete without a report. A report should be prepared to
summarize the key achievements of the cleaning validation study, including a clear statement of
acceptance/rejection.
Selecting a Proper Way of Cleaning

As the manual cleaning and COP are already discussed, let us only see CIP.
Clean In Place (CIP)
To meet the regulatory expectations and a promising cleaning, this is the most suitable way of cleaning the
equipment. Equipment is cleaned at its existing location with a suitable cleaning agent.
It is recommended to develop and implement an automated cleaning sequence to better control the potential
variations. This helps to achieve cleaning consistency and adapt to an identical cleaning pattern.
 For Process Vessels and Integrated systems, a static or dynamic spray ball is preferred to ensure complete coverage
of 360° including dead spaces near nozzles (one of the major worst-case locations).

A Riboflavin test is conducted to conclude that the spray ball is effectively reaching remote spaces of equipment at

a defined pressure and flow rate. The Riboflavin solution acts as a speck of dirt and can be seen under Ultra-Violet
(UV) light.
A typical CIP cycle generally includes the following rinses:
Pre-rinse with PW or WFI
Alkali and Acid Wash (if product demands)
Final Rinse with PW or WFI
A proper air flushing mechanism should also be incorporated to remove stagnant water from the system avoiding
chances of microbial growth.
Selection of Analytical Methods and Their Validation

Two fundamental types of analytical methods exist.
1. Specific
2. Non-Specific
The selection of these methods requires a science- and risk-based approach. Inappropriate evaluation and selecting
any of these methods may invite regulatory objections.
For example, the FDA states that companies should determine the specificity of their analytical method. Most
professionals misunderstand that the FDA expects to use only specific methods. On the contrary, this also means
the selection of analytical methods requires proper evaluation.
However, the EU-GMP mentioned, “the analytical method must be specific for the target residue“. This may be
interpreted in two ways.
Only specific methods are acceptable OR
Any of the methods must be specific to that particular target residue even with the non-specific method.
However, the second one sounds more logical and that’s the reason European drugmakers generally practice it.
Needless to say, there is much depth to it. Hence, a correct assessment of the method selection is very important to
establish a scientifically meaningful cleaning process.
For easy understanding:
Specific Methods Non-Specific Methods
Gives us the exact quantification of the target Related to the target residue but doesn’t provide its direct
residue measurement or quantification
Recommended after cleaning validation OR also complement

Recommended during cleaning validation
specific methods during cleaning validation
Can detect interference in substances other Itself can falsify the measurement of the target residue
than residue like cleaning agents because of the presence of other substances
Examples: HPLC, RP-HPLC with UV, Ion

Examples: pH, Conductivity, Visual Detection, and TOC
Chromatography
Difference Between Specific and Non-Specific Analytical Methods


To bridge the gap, many pharmaceutical manufacturers follow the general practice i.e. a combination of both
methods. Specific methods for primary cleaning validation while using non-specific methods for subsequent
 cleaning verification.
These methods can also be selected based on the stage of manufacturing. Initial stages such as bulk drugs or
intermediates, excluding toxic APIs, may only use non-specific methods that may suffice the requirement. Whereas
formulation and downstream processing may require both.
But the correct way is to conduct scientific studies and then choose the analytical method/s that accurately
detects the compound of interest.
Analytical Method Validation
Upon successful selection of the analytical method, it is important to validate it for the intended use. All non-
pharmacopeial analytical methods require validation.
However, if you want to use any of them even when a pharmacopeial method exists, you’ve to provide a rationale
for doing so.
Just to clarify, methods described in the monograph of different pharmacopeias are called Pharmacopeial
methods, and selecting those methods is evidence-based and need not require a formal method validation.
Anyway, the following characteristics should be covered during the analytical method validation.
Specificity OR Selectivity
Ability to use analytical methods to accurately measure analytes and interferences such as cleaning agents.
Selectivity is checked with blank samples (without an analyte) examined in the anticipated time range of
the peak that contains the analyte.
Accuracy(% Recovery)
Degree of agreement of the test results produced by the analytical method to the true value. Accuracy is
generally established for a complete specified range of the procedure.
A known concentration of analyte standard spikes the sample matrix and measures the accuracy using the
specified analytical method.
Precision
The degree of agreement between the individual test results for the repeatedly applied analytical
procedure to multiple samplings.
It can be calculated by different methods like Statistical, Horwitz equation, etc.
Limit of Detection
The lowest concentration at which the instrument detects an analyte but does not necessarily quantify it.
The noise to signal ratio should be 1:3.
Limit of Quantitation
The lowest concentration at which the instrument both detects and quantifies an analyte. The noise to
signal ratio should be 1:10.
Linearity
The capability of the analytical method to obtain the outcome is directly proportional to the concentration
of the analyte within a given range.
5 concentrations at a minimum are preferred from 50% to 150% across the working range and are injected
with a mobile phase to produce a linear relationship.
Range
It is the concentration range and an interval between the upper and lower limit shown using precision,
linearity, and accuracy.
Stability of Solution
 The time duration of the sample for which it can be stored before the final analysis after extraction.
 Ruggedness
 It is a measure to determine the robustness and reliability of the analytical method to deliver linear,
accurate, and precise results in all anticipated conditions.
Sampling Methods for Cleaning Validation

According to the FDA guidelines, there are 3 types of sampling. Out of that, 2 are commonly followed for cleaning
validation.
Direct Surface Sampling (Swab Sampling)
Direct surface sampling (swab sampling) is the most preferred sampling method for hard-to-reach but reasonably
accessible areas of the equipment.
A sterile swab made of cotton is attached to a compatible stick just like earbuds.
The challenge is to use the solvent along with the swab comfortably without interfering with the analytical test.
Swabs may contain certain adhesives that can alter the results.
These swabs are stored and dipped in a buffer like a phosphate solution or as appropriate to soak the cotton.
During sampling, swabs are removed and then applied gently on the equipment surface in one verticle and one
horizontal direction without rubbing to and fro.
Once done for at least 5 to 6 sampling locations, they are put back into the buffer solution and sent to the
Quality Unit for evaluating and establishing an acceptable residue content per given surface area as CFU/cm2
or as appropriate.
Swab Unit
Though this method is more specific in terms of hard-to-reach areas, it has one major disadvantage i.e. the small
surface area for a given sample.
Rinse Sampling
Unlike swab sampling, rinse sampling has the advantage of covering a large surface area of the equipment in a
particular instance, including systems that are hard to disassemble frequently.
The required amount of cleaning solvent with the help of a suitable spray ball preferably with 360° coverage
 used to rinse the equipment.
 Rinsed samples are then collected from sample points located near drain lines for physical and microbiological
inspection.

One of the major disadvantages of rinse samples is when rinsed, the residue may incompletely solubilize in the rinse
solvent like WFI or PW and remain clogged to the equipment surface. In this case, just checking downstream water
for compendial requirements is illogical and hence unacceptable.
Instead, the system should be in place to identify the direct measurement of the residue in the rinse sample such as
Infrared sensors or visual inspection, etc.
Indirect Testing or Monitoring Method
Although it is a sampling method or more specifically a monitoring method, it is also an indirect measurement that
does not specifically provide us with exact quantification of the residue.
Hence not acceptable as a stand-alone sampling method during cleaning validation. Instead, it should either be
used as complementary to the actual sampling method or should be routinely verified after the cleaning validation
program.
It is more specific in cases like bulk drug manufacturing where sampling can be most easily performed through
rinsing. The best examples are pH, conductivity, and TOC (Total Organic Carbon) measurements.
However, in special cases where other methods fail to detect any presence, this method can be scientifically
justified.
Defining Equipment’s Dirty Hold Time and Clean Hold Time

Everything in the world comes with an expiry and cleaning is not an exception to this. Therefore, the timeframe for
the cleaning validity and dirty conditions becomes crucial. But what do they mean?
The equipment’s idle time between the end of the last batch and the start of the cleaning process is called
Dirty Hold Time.
The equipment’s idle time between the end of the cleaning process and the start of manufacturing is called
Clean Hold Time.
Dirty Hold Time
Dirty hold times are the most crucial aspect of a cleaning validation program as they directly impact the efficiency
of the cleaning process.
When equipment is left uncleaned for longer durations, the residue attached to the surface may become rigid and
dry over a period of time, ultimately challenging the cleaning process.
Establishing dirty hold times for a particular production process depends on the nature of the product, associated
processing materials, and cycle times.
The general practice is to conduct 3 consecutive runs of cleaning procedure considering maximum dirty hold time
as per the requirement (in most cases around 72 hrs.).
These runs should demonstrate the cleaning procedure effective in removing the residue at the considered
maximum dirty hold times. Obviously, through bioburden testing.
According to one of the FDA’s 483 observations, cleaning validation and dirty hold times should be
established for dedicated as well as non-dedicated equipment. This should also include hard-to-clean
equipment to obtain overall confidence in cleaning validation.
 Clean Hold Time
 Just like dirty hold times, the FDA also expects to define clean hold times during the cleaning validation program.

Clean Hold time study generally includes a sampling of clean equipment at a regular time interval of around 6 to 8
hrs. till the equipment completes 24 hrs.
After 24 hrs., the sampling is done once per day. Sampling is performed immediately after cleaning and thereafter
at specified intervals.
It is better to have a data recording sheet that captures the necessary information when the samples are sent to the
QC lab for bioburden testing (microbiological proliferation).
Data Recording Sheet Example:
Cleaning Hold Time Nature of Analysis Acceptance Criteria
Depends on the application for example,

Microbial: CFU/Swab
0 hrs. Microbial: NMT 10 CFU/Swab
Chemical: PPM/Swab
Chemical: NMT 10PPM/Swab
6 hrs. —“— —“—
12 hrs. —“— —“—
18 hrs. —“— —“—
24 hrs. (Day 1) —“— —“—
Day 2 —“— —“—
Till the required time —“— —“—
Data Monitoring Sheet for Clean Equipment Hold Time
Worst-Case Conditions in Cleaning Validation Program

Conditions that may critically impact cleaning validation efforts or even cause a failure should be identified with the
most specific challenges.
Following are the challenges considered for establishing the worst-case conditions.
Drugs with the lowest solubility in their cleaning agent
Swab locations that are difficult to clean
Lower therapeutic doses for effective cleaning measurement
Equipment catering for the largest number of products
Drugs with higher toxicity
Establishing Cleaning Limits and Requirements

When it comes to cleaning validation, defining the incomplete acceptance criteria compromises your cleaning
efforts. The two concepts commonly talked about are NOEL and MACO.
Maximum Allowable Carryover (MACO) tells you mathematically how much of your previous product will carry over
to the next product.
Whereas, the No Observed Effect Level (NOEL) tells the drug quantity that has no observable effect on human
health when provided with a 50% Lethal Dose.
a) Calculating NOEL
NOEL can be calculated as:



 No Observed Effect Level (NOEL)
Where LD50 – Lethal Dose is at 50% reduction in mg or kg and NOEL is generally measured in “mg”.
However, this approach of risk identification is pointless to carry forward. According to one of the European
Medicines Agency (EMA) Question and Answer documents, the use of LD50 to determine Health-Based Exposure
Limits (HBEL) for drug products is an inadequate point of departure.
b) MACO Based on Therapeutic Daily Dose and Safety Criteria
Based on the above calculated NOEL values, the MACO values can be calculated as:
Maximum Allowable Carryover (MACO): Safety Criteria
As per this criterion, no more than 0.1% normal therapeutic dose of the previous product shall appear in the
maximum daily dose of the next product.
Here, the min. batch size is considered for the next product.
c) MACO Based on 10 PPM Criteria
As per this, no more than 10 ppm of the previous product shall appear in the next product.
MACO can be calculated as:
MACO: 10ppm Criteria
d) Calculating MACO Using Toxicity Data
This approach is generally considered during the early stages of drug manufacturing such as Intermediates or APIs.
Additionally, this technique is used to calculate MACO for cases that don’t have information regarding the
therapeutic dose.
MACO: Toxicity Data
HBEL is another concept that is gaining popularity within different regulatory bodies due to its risk-based approach
(This section is under review and will be updated with a thorough explanation).
Grouping Strategies FYI (Outdated Approach)

Calling this an outdated approach because of some recent arguments and facts that I had with the SMEs including
the following key points.
The main aim of grouping in the early 2000s was to ease the cleaning validation efforts for the multiple
equipment or products based on their groups, cleaning procedures, and types. At that time it was a concern to
clean the same type of equipment, products, etc., to save time and increase productivity.
But as per recent FDA and other audit observations, SMEs understood that the grouping didn’t serve its
purpose and that the justifications behind the grouping were unfit. The cleaning efforts ultimately became
 inadequate and endangered the patient’s health due to cross-contamination issues concluded through audits.
Firms are getting frequent observations and are now allocating these issues to personnel rather than
 investigating their cleaning scientifically. And guess what, the FDA is not satisfied with this justification.
 In short, it causes more harm than good regarding the patient’s safety and regulatory approvals.
Many healthcare manufacturers have discontinued grouping practices based on this approach and are now focusing
on the development of more robust cleaning processes that are risk- and science-based.
After all, instead of saving time and effort, the safety of the patient is more important.
Indian healthcare manufacturers also need to adopt these improvisations and leave behind practices that are not
fundamental to the purpose of their manufacturing.
Anyway, let us see what the traditional grouping strategy is.
Validating one representative operation to demonstrate its effectiveness on all similar types of operations is
called a grouping strategy.
Successful cleaning validation of that representative operation would establish that all the associated grouped
operations are also validated.
This strategy minimizes cleaning validation efforts i.e. cleaning identical equipment and products. The FDA does not
have a specific policy for considering grouping strategies, but the FDA recommends a scientific rationale (a big
exercise to worry about) for such grouping strategies.
Grouping mostly can be of two types.
1. Product Grouping
2. Equipment Grouping
Product Grouping
Product grouping can be performed based on 3 different criteria. Instead of going theoretical here, let’s look at this.
Please zoom in or open the image in a new tab for better reading.
 Product Grouping Strategy

Equipment Grouping

Unlike Product Grouping, this technique is used to perform cleaning on one representative piece of equipment.
The first and foremost condition of equipment grouping is that all similar equipment follow the same cleaning
procedure.
Additionally, it is not acceptable to group different equipment with the same cleaning mechanism and application
e.g., Vacuum Tray Dryer and Roto-Cone Vacuum Dryer. Though the ultimate purpose and cleaning philosophy is the
same, the structure and dimensions of the two pieces of equipment are completely different.
Equipment must be similarly designed to fall under equipment grouping. And that similarity has to be established.
A simple example of equipment grouping is process vessels of different working capacities. Here, “similar design”
should indicate different aspects of equipment design such as MOC, Geometry, sub-components, and so on. Simply
put, one cannot group the equipment of Stainless Steel (SS) and Glass Lined Reactors (GLR).
However, a major challenge in the example above is selecting a representative vessel based on worst-case
conditions.
How would you justify a small capacity vessel as harder to clean than a large-capacity vessel?
In such cases, the combination of equipment should be selected for cleaning validation. That is, performing
cleaning on the equipment group with one smaller volume vessel and one larger volume vessel. Otherwise,
one can select two pieces of equipment separately for multiple cleaning runs individually.
Both scenarios are assumed to establish an overall degree of assurance for the effectiveness of the cleaning
procedure.
Practicality of Using Grouping Strategies
Grouping strategies, here, are discussed only for understanding purposes. The development of cleaning processes
requires a risk- and science-based agenda.
When identifying risks (not superficial but fundamental), systematic risk mapping is very important instead of
gathering experienced anticipations. Firms have to conduct studies in assessing and identifying the potential risks of
the facility being unclean. Then they set their action plan accordingly.
Regulatory Concerns
Auditors are not supposed to provide spoon-feeding. In fact, they don’t have much time to learn your complete
cleaning philosophy.
They just try to realize the rationales behind your decisions and that the documents should speak for themselves.
For example, choosing a method of analysis, cleaning agent, cleaning mechanism, etc.
The following are some of the regulatory audit observations and give us more clarity on their expectations.
The company’s overall policy, intentions, and approach to validation, including the validation of production
processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems,
and persons responsible for design, review, approval, and documentation of each validation phase, should be
documented – EU Guide To Good Manufacturing Practice Part II – Section 12.1 Validation Policy.
Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate
design to facilitate operations for its intended use and for its cleaning and maintenance. [21 CFR § 211.63] For
example, CP-2 packaging line was modified in a manner that made it difficult for employees to remove the line
cover. As a result, the line cover is not removed during line clearance operations and is only removed during
 preventative maintenance. Per firm personnel, unit dose strips can become caught in this area and are routinely
found during maintenance – FDA warning letter 06-NWJ-14 (July 2006)
 The analytical methods should be challenged in combination with the sampling methods used, to show that
 the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the
consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A
negative result may also be the result of poor sampling techniques – EU Guide To Good Manufacturing
Practice Annexure-15, Section 4.10.3.
Validated analytical methods having sensitivity to detect residues or contaminants should be used. The
detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable
level of the residue or contaminant – ICH Q7A.
The specificity of test methods should be documented. For example, instructions for the identification and
quantification of peaks when using integrators should be provided, and integrated peaks in the swab samples
taken during cleaning validation run eluting close to the retention time of the standard peak should be
identified or quantified during the validation exercise – FDA 483 Warning.
Cleaning validation studies for multiple use equipment were inadequate in that the validation protocol did not
identify the cleaning procedure, the total surface area was not considered during the validation study, recovery
studies were not done to validate the swab sampling method or filtering of rinse samples, some rinse samples
were not analyzed, dates of analyses were inaccurate, and analytical data on rinse samples were not checked by
a second person – FDA 483 Warning.
Pipework systems, valves, and vent filters should be properly designed to facilitate cleaning and sterilization –
EU GMP Guide, Annexure 2, Premises and Equipment.
Tanks, containers, pipework and pumps should be designed and installed so that they may be readily cleaned
and if necessary sanitised. In particular, equipment design should include a minimum of dead-legs or sites
where residues can accumulate and promote microbial proliferation – PIC/S GMP Guide PE 009-5, Guide to
Good Manufacturing Practices For Medicinal Products, Annexure 9, Premises and Equipment.
Washing and cleaning equipment should be chosen and used in order not to be a source of contamination –
PIC/S GMP Guide PE 009-5, Guide to Good Manufacturing Practices For Medicinal Products, Chapter
3/3.37.
The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be
identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP)
systems – EU GMP Guide, Annexure 15, Section 4.6.1.
With regard to transfer lines, they are generally hard piped and easily cleaned and sanitized. In some cases
manufacturers have used flexible hoses to transfer product. It is not unusual to see flexible hoses lying on the
floor, thus significantly increasing the potential for contamination. Such contamination can occur by operators
picking up or handling hoses, and possibly even placing them in transfer or batching tanks after they had been
lying on the floor. It is also a good practice to store hoses in a way that allows them to drain rather than be
coiled which may allow moisture to collect and be a potential source of microbial contamination. Observe
manufacturing areas and operator practices, particularly when flexible hose connection are employed – FDA
Guide to Inspections of Oral Solutions and Suspensions 1994.
Conclusion
Considering both cleaning complexity and regulatory importance, defining and measuring your cleaning goals
clearly is all that matters when it comes to establishing smart cleaning procedures.
Apart from the cleaning procedures, the selection of the analytical method and its validation carry equal
importance.
Upon successful completion of cleaning validation activities, firms should consolidate all the observations
noted during cleaning validation.
A report should be prepared to demonstrate that the predefined goals are met and summarized. Deviations
and NCs should be summarized to show how they’re closed.
Investigate your cleaning procedures to determine potential opportunities for improvement and consistency.
The document should properly capture the activities with a clear statement of “Pass/Fail” for your cleaning
 validation activities.
 To make the cleaning validation efforts robust, you’ll have to consider enough approaches from the development
including risks, science, and statistics, to the fundamentals of contamination or cross-contamination.

I’d like to turn it over to you. How did you find this article helpful? What challenges do you face in cleaning
validation? Comment below.
Saket Yeotikar
LinkedIn | facebook | twitter
PREVIOUS NEXT
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Good Manufacturing Practices – ICH Q7 Highlights

Updated December 1, 2021
20 Comments
Alex
It’s really very useful information to better understand the process. Can you please make one on equipment qualification as well?
Reply
 AUTHOR
Saket Yeotikar

Thanks, Alex for your kind words. I already have one published for Process Validation that includes the
 qualification part.
Here are the links for quick access:
https://pharmagxp.com/quality-management/process-validation/
https://pharmagxp.com/quality-management/qualification-and-validation/
Rama Krishna Atmakuri
Wow… Great job… Excellent Material… Thanks very much!
Reply
AUTHOR
Saket Yeotikar
Glad you found this excellent, Rama! Best of luck.
Mahesh Urdhwareshe
It’s very useful, well explained with observations received from FDA. Thank You for such an article on cleaning validation…
Reply
AUTHOR
Saket Yeotikar
Glad you liked it, Mahesh!
HEBA MOHAMED
Clear and interesting. Can you please let me know which guidelines clearly states the cleaning level type?
Reply
AUTHOR
Saket Yeotikar
Thanks, Heba for admiring the content. However, I don’t think if such types of levels are mentioned in any
guidelines. Rather, regulations like FDA do mention the types of sampling, methods of analysis, and establishment
of limits.
Mona Shamshe from Iran
The content was great. I enjoyed it and thank you
Reply
AUTHOR
Saket Yeotikar
Glad you find it helpful.

 Vilas Alte

The article written by you gives the great information collectively. It is very informative and helpful to everyone.
I really enjoyed reading this article.
Reply
AUTHOR
Saket Yeotikar
Thanks, Vilas. Glad you find the content informative! 😊
R Srinivasa Rao
I enjoyed a lot while reading the article. Good theory. Thank you for sharing such data with us…
Reply
AUTHOR
Saket Yeotikar
Pleasure all mine, Srinivasa 😊
Luis
Exceptional work, thoroughly enjoyed reading it.
Reply
AUTHOR
Saket Yeotikar
Appreciate your words Luis 🙂
Rakesh Jakkashetty
Really an excellent effort Mr. Saket. I can say you are the library of your profession! 😊 I relished the reading.
Reply
AUTHOR
Saket Yeotikar
Super satisfied with your feedback Rakesh 😊 Best wishes!
Musbau Lasisi
I enjoyed the write-up on Cleaning Validation. More power to your elbow.
Reply
 AUTHOR
Saket Yeotikar
 Glad you found the content useful 🙂

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Home » Quality Management

Cleaning Validation: The Definitive Guide in 2022

This is called Product-to-Product cleaning.

Well, cleaning validation is a scientific technique that ensures:

Previous product traces have been removed

Safe batch-to-batch transitions

What is Cleaning Validation?

Essence taken from various guidelines

Why Perform Cleaning Validation?

So, the cleaning validation is a regulatory requirement to ensure:

Understanding and identifying the risks to the patients

Performing its impact assessment

Outlining risk mitigation strategy

Mitigating those risks

Assuring finished product safety

Successful cleaning validation is that which…

2. Avoid product adulteration and achieve a contamination-free product.

4. Allow us to re-use the same equipment for different products.

Now, we’ll look into…

Ways and types of cleaning processes

How to develop a cleaning validation program, and

The expectations of regulatory bodies.

 When to Perform Cleaning Validation?

Major changes in raw materials based on impact assessment

Significant modifications in cleaning procedures

Introduction of new equipment for the already established process

Changes in cleaning agent

1. Cleaning In Place (CIP)

1. CIP Skid to Clean the Equipment

2. Automated CIP of the Equipment

2. Cleaning Out of Place (COP)

1. Washers like Tray Washers, Dish Washers, etc.

2. Sub-systems of equipment hard to approach in CIP

Not a thumb rule but in general:

Equipment is preferred for automated cleaning in place i.e., CIP.

Different Cleaning Mechanisms

1. Solubilization Using Solvent

Let us see one by one.

Simple and flexible Inconsistency due to manual action

Requires exhaustive training Involves additional man-power

Wiping directions, patterns, and number of times to repeat the wiping

Solvent and cleaning agent concentrations

Quantity of cleaning solution to apply to the wipes

Wet equipment surface promotes residue disintegration

List of Cleaning Agents

Commodity Chemicals Specialty Cleaners

Surfactants (Based on the charge on the polar end)

Table: Types of Aqueous Cleaning Agents

Cleaning Validation Program

Concentration of the cleaning agent

Surface Roughness (More roughness means more difficult to clean)

Proper mixing RPMs

Dirty Hold Time for Equipment

Clean Hold Time for Equipment

Critical Quality Attributes (CQAs) For Cleaning

Cleaning agent residue

Required concentration of cleaning agent

Time for cleaning

Pre-Requisites to Begin Cleaning Validation

Cleaning Validation Strategy and Protocols are approved and ready

Equipment used for most of the products should be identified

SOP for Equipment Cleaning has been established (draft)