Article-4

Process Equipment Cleaning Validation

Part-1: Cleaning Process Design (PHASE-I)

Kiran Kota
[email protected]
Quality Head

Note: This is completely a knowledge sharing effort and no other intention on circulating any of my papers

Abstract: From the Guidelines & Regulations & related articles

Process Equipment Cleaning Validation:
CLEANING VALIDATION (POLICY) PHILOSOPHY
CLEANING VALIDATION MASTER PLAN (CVMP)
CVMP

CLEANING VALIDATION LIFE CYCLE

PHASE-II PHASE-III
PHASE-I
CLEANING PROCESS VALIDATION CONTINUAL CLEANING PROCESS
CLEANING DESIGN
/QUALIFICATION VERIFICATION

Cleaning process Development (Verification) Cleaning Validation Plan Continual monitoring of Cleaning process

Quality Risk Management

Change Control

Understanding the Equipment Scientific rationale

Analytical Method /
establishment
Technique (Development) Cleaning Process Qualification
Equipment train identification selection Cleaning results trending annually
Establishment of worst case
Specific
Non-Specific Establishment of cleaning process repeatability
Identification of Equipment
Cosmetic changes * Product grouping basis

Mitigation controls Solubility basis

Establishment of
Analytical Method Cleaning Alerts limit establishment
Identification of Critical to Equipment basis Batch to batch cleaning /
Verification
reach Area Product to product cleaning /
Common / unknown Campaign cleaning /
Identification of Hard to clean cleaning process basis Periodical cleaning /
Area Exposed equipment cleaning
Cleanability basis Analytical Method Validation

Fixed / Disassembly parts Investigation for crossing of alert limits (If any)
Cleaning agent selection

Sampling method Establishment of COQ / VRL

Recovery establishment
identification / VVR & Angle of view
(Plant / Lab)
Critical sampling point with Establishment of Efficiency of cleaning process / Sampling
scientific rationale technique / Analytical Method / Cleaning Operator /
Exposed equipment
Rinse Swab Analyst on the whole equipment train / CEHT#/ DEHT#
identification
Cleaning Method Re-visiting the cleaning process /technique / Method /
Identification Practice / Limits
Clean in place / Clean out of Sample solution stability /
Ancillary equipment &
place Sample solution storage
Utensils & Sampling aids
(Automatic / Semi-Automatic condition establishment
covering
/ Manual)
Report & Conclusion & Recommendations (If any)
Cleaning process establishment
Surface area calculation Re-validation (If necessary)based on
including all the equipment
Feasibility & Verification
train & Ancillary equipment
Analytical Residue limits
/ Utensils
Optimizing the flow rate / establishment
CPPs/CSPs/Temperature/
CQA's/CEHT#/DEHT# Introducing of Change in
Microbial Attributes Reestablishment of cleaning process if warranted based on Any major change
new product cleaning agent or
conclusion in the cleaning
which is found as concentration of
procedure
worst case cleaning agent
Training

Absence of residue (Product / Impurity) shall be proven. Specifically Genotoxic impurities / NDSRI /AZIDO, Byproducts (if any), Insitu stages (if any) etc. # CEHT / DEHT establishment shall be done either in Phase-I or Phase-II based on feasibility or requirement

This article has been designed with the concept on Equipment Cleaning approach to understand and deliver accordingly. In addition to this, it also
requires the cross functional involvement with practical RISK & TACT based to meet the compliance and regulations at each element defined in the
above tree and this article has made with the collective information from the guidelines and other references given at the end with my
experience.
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Process Equipment Cleaning Validation:

GUIDELINE REQUIREMENT OF CLEANING Cleaning Validation is a critical component of
VALIDATION: an effective GMP Compliance program at any
regulated drug manufacturing facility. In fact,
In general cleaning validation Cleaning Validation in pharmaceutical industry
should be directed to those has been one of the most evolving and debated
situations or process steps topic since years as the industry transitions
where contamination or took place recently towards a risk and science
carryover of materials poses the based validation from traditional V model and
great risk to API quality. towards Health Based Exposure Limits (HBEL)
from traditional methods.
Cleaning validation should be
performed in order to confirm Cleaning validation plays an important role in
the effectiveness of a cleaning reducing the possibility of product
procedure. contamination from pharmaceutical
manufacturing equipment. It demonstrates
that the cleaning process adequately and
The data should support a consistently removes product residues, process
conclusion that residues have residues and environmental contaminants from
been reduced to an acceptable the manufacturing equipment/system, so that
level. this equipment/system can be safely used for
the manufacture of specified subsequent
Cleaning validation should be products (which may be the same or a
performed in order to confirm different product). Principles and practices
the effectiveness of any given in this report may apply to a variety of
cleaning procedure for all manufacturing situations. It is incumbent on
product contact equipment. the reader to decide the appropriateness of
those principles and practices to his/her
Where similar types of equipment are grouped specific situation.
together, a justification of the specific
equipment selected for cleaning validation is Every major regulator has either revised the
expected. Cleaning Validation Guideline in the recent
years or in the process of revising as a result of
that the regulators are continuously finding the
Cleaning validation is
observations during their visits and it is
documented evidence that an
becoming a challenge to the industry to comply
approved cleaning procedure
with those observations as the Cleaning
will reproducibly remove the
activity needs to be addressed with the
previous product or cleaning
practical approach rather than the traditional
agents used in the equipment
approach. In this article, we take a look at the
below the scientifically set
current status of where the Cleaning Validation
maximum allowable carryover
Guidelines stand for all major regulators and
level.
organisations and the practice towards meeting
the regulations and its gap.

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

Cleaning is a process of removing the STAGE-I (CLEANING PROCESS DESIGN):
contaminants from process equipment and
monitoring the condition of the equipment such QUALITY RISK MANAGEMENT:
that equipment can be safely used for RISK ASSESSMENT:
subsequent product manufacturing. • Risk assessment is to identify different risks
Cleaning validation is document evidence that involved in cleaning and to evaluate the
an approved cleaning procedure will impact of the risk on the quality of the
consistently reduce API, process residue from product along with the corrective action
product contact surfaces to acceptable level for and preventive action for the risk assessed,
processing of drug products. as necessary.
WHY VALIDATE CLEANING? • Brief description of the Synthetic scheme
Greater emphasis has been placed on the and description of the Process shall be
development of validated and robust cleaning evaluated.
protocols in recent years due to concerns over • Risk assessment involves identification of
the safety of the drug supply. risk, describing the existing controls, risk
Growth in the outsourcing and off-shoring of assessment, proposing additional controls
pharmaceutical manufacturing has also and/or CAPA to bring down the level of
heightened US FDA concern over cleaning risk.
processes. Inadequate documentation, training, • Risk evaluation shall be conducted by
and validation of cleaning processes rank high analyzing each risk for its severity,
among the most cited problems in FDA Form likelihood and existing controls.
483 observation and warning letters. • Impact assessment shall be carried out to
FDA issued the Guide to inspections- validation identify the risk. Analysis shall be done to
of cleaning process in 1993. Since that time, confirm the risk.
the protocols surrounding cleaning processes in
• From the evaluation of severity, likelihood
pharmaceutical manufacturing environments
& existing controls and based on the impact
and sampling and filling suites have received
assessment, testing results a conclusion
increased attention. The primary regulatory
shall be dawn with any recommendations if
concern driving the need for cleaning validation necessary.
is contamination of the desired drug substance
• Proposed additional controls, monitoring
or drug product. Contamination may be either
mechanisms and CAPAs shall be reviewed
the same or other API from previous batch runs
every quarter for the progress and
or residual cleaning agents.
implementation of action points.
Cross contamination with extraneous residues
• The reassessment shall be done whenever
of any kind presents a safety risk to patients
there is a change to the existing approved
consuming the drug product. It threatens to
system.
alter the strength, chemical identity, purity
and integrity of the drug substance or product. ROLE OF QRM IN CLEANING VALIDATION:
Contaminants may elicit their own
• Risk assessment must be applied to
pharmacologic effect. The equipment and work
decide on the extent of cleaning
environments involved in drug manufacturing
validation studies.
processes must be cleaned according to defined
• Risk assessment based on product
and proven procedures at regular intervals to
exposure is required to determine the
prevent the possibility of cross contamination.
need for validation of facility cleaning
These cleaning processes must be validated in
procedures.
order to provide assurance that they do in fast
• The rationale for selecting limits of
serve their purpose to clean the surfaces to a
carryover of product residues, cleaning
level that avoids the possibility of cross
agents and microbial contamination
contamination. This activity also has the
must be based on scientific data and
beneficial effect of prolonging the useful life of
risk analysis procedures.
the equipment.

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

Application of ICH Q9:
ICH Q9 steps Corresponding cleaning development and validation elements
Risk Data collection Identify possible cleaning process residues-API cleaning agents, etc.
identification Collect historical cleaning data and other knowledge like equipment
aging and etc.
Methods for detection of process residues.
Hazard Determine PDE/ADEs for cleaning process residues
identification Calculate maximum safe carryover / maximum safe surface residues
/ maximum allowable carryover
Identify possible / potential failure modes of cleaning process
Risk analysis FMEA (Initial)
Severity Impact of cleaning process failures (e.g. toxicity, product quality /
Contamination)
Exposure Historical cleaning data and other cleaning knowledge
Bench scale analysis (Process residue characterization, cleanability,
cleaning agent selection, critical process parameter determination,
design of experiments, “design space” definition)
Cleaning process robustness
Detectability Detectability of cleaning process residues
VRL’s & ARL’s
Risk Collection and evaluation of cleaning data
evaluation Statistical evaluation of data (Cpk/Ppk)
Margin of safety measurement
Statistical process control limit determination & Product / Stability failures w.r.t
Contamination
Risk reduction Design of experiments
Define the cleaning “Design space”
Cleaning process optimization
Training
Risk FMEA (Final)
acceptance Severity Impact of cleaning process failures (e.g. toxicity, product quality)
Exposure Process capability determination (Cpk/Ppk)
Margin of safety measurement
Statistical process control limit determination
Detectability Statistical process control charting
Monitoring program / periodic evaluation
Visual inspection
PAT applications
Risk review Updates to PDE/ADEs based on new clinical / toxicological data
Cleaning failure investigations
New product introductions
Cleaning procedure improvements
Statistical process control charting
Monitoring program / periodic evaluation
Risk Facility cleaning risk assessment
communicati Hazard identification report
on ADE monographs
Risk analysis of cleaning procedures
Cleaning validation master plan
CV protocols & CV reports
Risk evaluation of cleaning procedures
Cleaning control strategy
Training records
New product risk review
Note: FMEA is used as an example in this table. Other RA tools may be equally appropriate.

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

UNDERSTANDING THE EQUIPMENT: MOCs
Material of construction of the equipment
plays a vital role in cleaning. Equipment
must be designed with the material of
construction that ensures that the product
contact surfaces are inert and does not
react with the materials of the
manufacturing and/or the cleaning process.

Product Contact Surfaces

Typically, SS 316L is the preferred material
Documentation: of construction for all product contact
All the major equipments should have a parts. Also commonly seen product contact
unique identification code or number, and parts consist of food grade plastics,
this must be recorded in the batch silicone material, etc. The product contact
manufacturing record (BMR). Separate surfaces of equipment in use in API
cleaning and maintenance logs must be manufacturing facilities are typically made
maintained for each of the major of SS surfaces or glass lined SS surfaces.
equipment, and any cleaning or
maintenance activity must be recorded in
these. Other Surfaces (non-product contact)
Other surfaces of equipment also are
Purchase Specifications for Equipment designed to facilitate cleaning and provide
Pharmaceutical industry equipment is quite strength along with being non-corrosive to
expensive and therefore, selecting the right material. Typically, all surfaces are made
equipment is a critical process. Some of the of SS 316 or SS 304.
most important factors to be considered in
making this decision are as follows: Dedicated and/or non-dedicated equipment
Based on the product characteristics, the
Ease of cleaning and maintenance: equipment might be required to be
dedicated, or they can be shared across
Equipment will require regular cleaning and
different products.
special, more thorough cleaning between
It is important to understand if the
batches of different products. The time equipment provides an opportunity for a
used for cleaning is time lost from the thorough and extensive cleaning of all its
production run. So equipment must be easy components on the basis of its design.
to clean (either in-place or by disconnecting
and taking to a special cleaning area). It When satisfactory cleaning results cannot
must also be easy to maintain and not be achieved due to limitation in equipment
require frequent maintenance activities design, the equipment should be modified
which again are a time consuming process. or replaced. Similarly, if certain product
contact parts are not feasible to dismantle
Equipment Characteristics and/or are difficult to clean because of
Equipment are typically designed to with their design factors, such as difficulty of
suitable material of construction (MOC) that access, presence of curved or grooved
does not interact with the material of the areas, hoses or tubing, etc., they need to
be considered for dedication.
manufacturing process and are also have
smooth surfaces in order to facilitate proper
Equipment parts, where preferential
cleaning. While designing the cleaning transfer may occur (filling needles,
process, the following equipment punches), should be considered for
characteristics are required to be evaluated. dedication.

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

At times, the product and/or material being An equipment train should be delineated to
used in process renders the part to be used separate those portions in which the
for a limited period, and continuing usage residue would be evenly (homogeneously)
for many batches could lead to corrosion of distributed in the next product (e.g.,
the contact part; in such cases, dedication blender, granulator) from those in which
must also be considered for such parts of the residue could be transferred to an
the equipment. individual dosage unit of the next product
Rationale for dedication of equipment (e.g., tablet press, vial filler).
should be available.
IDENTIFICATION OF EQUIPMENT COSMETIC
Age of Equipment CHANGES:
The age of equipment needs special focus
and attention. Aspects of equipment design, Staining on Glass lined Equipment
such as smoothness and finish to facilitate Some instances of ‘staining’ of the
proper cleaning, are directly influenced by Glasslined surface in Glasslined reactors
the age and usage of equipment. It is, have been reported from time to time.
therefore, necessary to review the Some of the reasons for the staining are as
equipment surfaces periodically for its finish follows
and adequacy and its impact on cleaning
efficiency. Caustic Corrosion: This occurs to the
addition of caustic at temperatures above
Dedicated Facility acceptable levels. Typical alkali attack
Manufacturers should give due consideration stains are as shown below.
for dedicating the facility with respect to
product category/dosage forms being
handled. Following are some examples:

1. Cytotoxic products.
2. Hormones.
3. Beta lactam, Penicillin.
4. Cephalosporins.
5. Radiopharmaceuticals.
6. Ectoparasiticides (e.g., substance for
the treatment of lice).
7. Highly active pharmaceutical
ingredients (PDE equal to or less than
10 microgram).

In such and similar cases, dedicated facility

should be considered, if actual limits are
not practical, achievable and verifiable.

EQUIPMENT TRAIN IDENTIFICATION:

Equipment train is the sequence of
equipment through which a product is
produced or processed.

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

Acid Attack: This occurs typically when
highly corrosive acids are added at possibly
adverse temperatures. This again causes
stains as shown below.

Another mechanism is mainly cosmetic in

nature. The lightening of the surface being due
to the processing taking place in the
Surface will show areas of etch and glossy equipment.
This is the result of a diffusion controlled ion
Superficial stains: These are stains that exchange, the rate of which would be
occur on the surface of the glass through a controlled by time, temperature and
mechanism of ionic exchange. The detailed concentration of materials present.
explanation is given below.
Typical Photographs showing cosmetic
Explanation of Surface Staining effect: It is staining:
not an effect caused by any residual
material on the glass surface but is the
result of a lightening or leeching of the glass
which can be explained as follows: As glass
is an amorphous material, it is not
crystallized but contains a bubble structure
and has properties similar to a liquid. The
bubble structure is shown in figure below: Cosmetic effect on General “staining”
side effect seen on the glass

Cover Coat

Ground Coat
Vessel side wall showing Close up of lightening
higher concentration of effect on the glass due
effect to ion exchangewall
Steel Stains on the glass lining surface must be
evaluated case by case and based on the
nature of staining identified as being caused by
When glass is corroded or abraded the smooth
the process and which has affected the glass
“fire polish” surface will be removed and the
and those stains that are purely cosmetic in
bubble structure will be exposed making the
nature. Those that are cosmetic in nature
surface feel rougher and under magnification
could be taken into service without causing any
the revealed open bubbles are visible.
adverse effect on the product.

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

Mechanical Polishing: Small chipping, marks Rouge Formation and Remediation”
on stains on the glass due to residual material Key objectives:
or small areas of cosmetic stains could be • Overview of Stainless Steel
removed with special diamond polishing. • Understand Rouge Generation
This is suitable only for very small locations • Impact of Rouge on System
and it is not practical to polish large stains.
• Rouge Remediation
• Predictive maintenance for vessels
Superficial stains: These are stains that occur
with corrosive buffers
on the surface of the SS due to aging of the
equipment on long run w.r.t the products & • Case Studies
temperature & Conc. of mass. Pictorials is
given below: OVERVIEW OF STAINLESS STEEL
Facts about Stainless Steel
– Named “Stainless”, it is really “stain
resistant”
– Chromium oxide rich passive layer
– Iron alloys with a minimum of 10.5%
chromium.
– Metals and non-metals are added to
enhance their structure and properties:
• Nickel
• Molybdenum
• Titanium
• Copper
• Carbon
• Nitrogen
Stains on SS surface
Types of Stainless Steel
• Depends on Microstructure
– Austenitic: Grades 304, 316, and 317.
These have the highest corrosion
resistance
– Ferritic: Grades 430 and 434. Less ductile
than Austenitic
– Martensitic: Grades 410 and 420. Highest
hardness.

ASI Carbon
Chromium Nickel
Type (max) Iron Silicon Molybdenum
304 18-20 8-10.5 0.08 65-71 1.0 --
304L 18-20 8-12 0.03 65-71 1.0 --
316 16-18 10-14 0.08 62-69 1.0 2-3
316L 16-18 10-14 0.03 62-69 1.0 2-3
Discoloration on SS316L
S = 0.03, Si = 1.0 and Mn = 2.0
Hence, Cleaning Risk assessment needs to be Passive layer: 3 Cr + 3 O2 à 2 Cr2O3 (thin,
performed on equipment perspective as well protective, tenacious and transparent film)
and these cosmetic changes has to be Thickness of passive layer: 3 to 5 nm thick
addressed and visual inspector should aware of (1nm = 1 x 10-6 mm).
those.

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

Stainless steel must contain > 10.5% Cr to Types of Rouge:
allow the formation of a “passive” layer on the • Type I
surface. – Oxidized metal particles generated from
Nature of Rouge: external sources by erosion or cavitation
of pump surfaces.
– Easier to remove, can often be wiped
off

Causes of Rouge:
• Destruction of the passive layer accelerated
by:
• Highly corrosive environments
• Rouge is a corrosion product on Stainless – Steam
steel composed of: – Chlorides, corrosive products
– Predominantly various forms of iron – High temperature, stress, erosion
oxides – Improper surface conditions
• Typical in water systems and processing – Improper welding
equipment – Surface defects
• Some wipe off easily; others are tenacious – Inadequate cleaning
and can be reddish brown to black. – Inadequate passivation
Types of Corrosion:
Challenges of Rouge: • Pitting corrosion:
• Industry challenge in pharmaceutical  Localized corrosion
manufacturing facilities  Small pits and hole
• Stainless steel corrosion, or rouge, is an • Stress cracking / Intergranular corrosion:
industry-wide problem that, left
 High temperature and corrosive
untreated, can cause product environment
contamination
 Chromium carbide deposits along grain
• Removing rouge and maintaining passive
boundary
layer of stainless steel equipment are
essential preventative maintenance Stress cracking /
Pitting corrosion
requirements for any manufacturing Intergranular corrosion
facility.
EFFECTS OF ROUGE:

Reduces
Increases cleanabilit Increases Product Reduces
surface y and microbial Contamina equipment
roughness Sanitizatio excursions tion life
n

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

Micro-pitting: • Galvanic corrosion:
• Micro pitting is a type of local corrosion  Electrically driven process
• Causes damage in the form of pits or
spots
• Can be due to presence of corrosive
buffers

White Stains Pitting • Crevice corrosion

 Shielded from full environment
exposure

• 300 Series Stainless Steel alloys are prone

to corrosion in the presence of chlorides

Pitting corrosion is an electrochemical

oxidation-reduction process, which occurs in
MITIGATION CONTROLS:
the absence of the passive layer
How to avoid / slow rouging effect?
 Stainless steel composition – 316L is the
best option
 Ni improve the stability of the passive
layer
 Mo improve micro pitting resistance
 Low carbon
 Surface finishing
Types of Corrosion:  Avoid corrosive contaminant / environment:
• Uniform corrosion:
 Chloride, Sulfide
 Uniformly distributed over entire
surface  Steam
 High temperature
 Residue
 Cleaning procedure:
 Remove efficiently residues
 Optimal frequency of sanitization
 Periodic Maintenance

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

De-rouging and Passivation Considerations:
• Passivation can be enhanced with the use
• Effective removal of any visible rouge of chemical treatments.
• Process constraints (e.g., temperatures,
flow rates, etc.) • Analytical techniques like x-ray
• Avoiding damage to surface finish caused photoelectron spectroscopy (XPS) are
by excessively aggressive chemistries commonly used to quantify the depth and
• Operator safety when handling hazardous quality of this passive layer by measuring
chemicals the chromium-to-iron ratio (Cr/Fe).
• Environmental concerns (e.g. phosphates, • Chemical methods can be used to enhance
volatile compounds, etc.) the nature of this passive layer
• Adherence to industry standards (e.g., –
Nitric acid, phosphoric acid, citric
ASTM A 967) acid, other proprietary chelant
• Use of chemicals that are not part of the formulations are typically used.
validated process cleaning operations. – Nitric acid and citric acid are ASTM
referenced
De-rouging: • Passivation goal:
• No single “recipe” for performing a  dissolve the free iron
successful de-rouging operation.
 acceleration Cr2O3 formation
• Example of model operating procedure:  smooth surface
– A laboratory-based assessment to – Regenerate the passive layer
establish effective de-rouging parameters
– A robust alkaline cleaning to remove Passivation Processes:
organic residues
– An acid treatment to remove iron oxides Process Reference Conditions
– Process monitoring to assess the Nitric acid
ASTM 10-40%,
effectiveness of the treatment. A380/A967 30-90 min
• Removal of metal oxides by solubilization Phosphoric ASME BPE 5-25%,
acid 2009 1-4 hrs
• Depends on concentration and temperature
Phosphoric
• Concentration of dissolved Fe increases ASME BPE 5-25%,
acid
2009 1-4 hrs
initially in the de-rouging solution blends
• Critical to remove any organic residue Citric acid ASTM A967 10%, 1-4 hrs
before the de-rouging step Chelant 3-10%,
ASTM A967
systems 1-4 hrs
• HACH test kit – Field tool to measure level
of Iron
Passivation: Type of De-rouging & Passivation:

• Stainless steel has the • Mechanical:

ability to resist – Electropolishing (ASTM A 380):
corrosion by forming a Electrochemical process. Metal ions are
relatively unreactive removed from surface
Cr enriched passive – Manually polished
film in the presence of
oxygen. • Chemical (ASTM A 967):

• Clean surface is a – Nitric acid

critical prerequisite to – Phosphoric acid
the formation of this – Citric acid
film. – Oxalic acid

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

IDENTIFICATION OF CRITICAL TO REACH ii. expertise and empirical knowledge from
AREA: the subject matter expert (SME) involved
in the processing and cleaning of the
First of all, an SME(s) should perform an equipment and parts; and
assessment to identify the iii. Recommendations from the equipment
surfaces/areas/sites of equipment/parts and manufacturer. The assessment should be
use a risk-based approach to classify difficulty performed and documented using
in cleaning. An assessment should be appropriate templates or forms for
performed separately for each piece of consistency and document control.
equipment; however, similar equipment (same These types of assessments are the basis
name, model, design, working principle, scale, for a successful cleaning validation
and manufacturer) may be grouped for a risk program.
assessment. There are two ways to perform a
risk assessment: IDENTIFICATION OF HARD TO CLEAN AREA:
• Determine difficult to clean areas by a When you have a new piece of equipment that
visual residue inspection. has not undergone any usage, you may not be
• Determine difficult to clean areas on able to assess it in a dirty state. This type of
clean equipment, by assessing the residue assessment should be rare. Similar to the
level that can be accumulated during the process described in the previous section, a
processing of the product. template can be used to document the
equipment name and number, the date the
IDENTIFICATION OF CRITICAL TO REACH equipment was cleaned, and the date the
AREA: pictures are taken.
The surfaces, areas, or sites of manufacturing
and packaging equipment that are cleaned The assessment for SCL (Surface Cleanability
upon completion of oral solid dosage Level) can be performed by following the steps
manufacturing production. As stated in the below.
FDA’s Guide to Inspections Validation of
Cleaning Processes (7/93), “the firm should Identify the surfaces, areas, or sites that
challenge the analytical method in become difficult to clean due to the nature
combination with the sampling method(s) used (material of construction), design, geometry,
to show that contaminants can be recovered and accessibility of the surfaces of equipment
from the equipment surface and at what level, and parts (where residue comes in contact or
i.e. 50% recovery, 90%, etc. This is necessary accumulates, and where residue does not come
before any conclusions can be made based on in contact). Identify these parts/areas/sites as
the sample results.” Therefore, for a cleaning DPC (Direct Product Contact), IPC (In-direct
validation program that will successfully Product Contact), and NPC (Non-Product
qualify and continually verify well-designed Contact), in accordance with the definitions
cleaning processes, meaningful and provided above. You can take pictures of these
methodical recovery studies need to be surfaces, areas, and sites with all the parts
conducted. disassembled and create a photo log of all the
The approach is based on thorough assessment pictures taken. Pictures can be arranged in the
and evaluation of all critical equipment that order of DPC parts followed by IPC and NPC
plays a major role in product manufacturing parts. Use arrows to point to the
and identification of difficult to clean or locations/areas/sites of interest in the picture.
inspect surfaces, areas, or sites, including: Label the identified surfaces, areas, and sites
i. visual inspection of the equipment and in the pictures of the photo log as described in
parts; the previous section.

Abstract: From the Guidelines & Regulations

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Process Equipment Cleaning Validation:

The SMEs, along with the quality team, should SAMPLING METHOD IDENTIFICATION CRITICAL
rate the SCL of each of the areas or sites in an SAMPLING POINT WITH SCIENTIFIC
increasing order of difficulty to clean. If a RATIONALE:
combination of different kind of surfaces is Selection of a sampling method depends on the
present on an equipment or part, consider the nature of the equipment, the nature of the
worst case and rate accordingly. If additional residue being measured, the residue limit, and
types of surfaces, areas, or sites are the desired analytical method. Sampling
present/identified (that are not listed in the methods discussed here are:
table), identify and rate them accordingly • Direct surface sampling
(this must be performed by an SME). • Rinse sampling
IPC areas/parts/sites and NPC area/parts/sites • Swabbing
can be combined and rated, if they are • Placebo sampling.
exposed to the same extent of the It should be noted that while regulatory
contaminant residue and/or are of the same documents refer to swabbing as “direct”
type of surfaces/areas. sampling and to rinse sampling as “indirect”
sampling, it is operationally more descriptive
The residue level (RL) assessment is performed to refer to those sampling methods as “swab
based on the knowledge of the product sampling” and “rinse sampling,” and reserve
processing and type of residue contact and the term “direct sampling” for techniques such
accumulation on each of the DPC, IPC, and as visual inspection.
NPC surfaces/areas/parts. Rate each of the Swab/wipe sampling, rinse sampling, and
surfaces/areas/sites, and assign each an RL in visual examination are listed as acceptable
an ascending order of difficulty to clean. sampling techniques in most regulatory
Once the SCL and VRL or RL have been documents. Each method has its advantages
assigned or determined for each area or site, and limitations. In a given protocol, multiple
calculate the risk level for each area or site sampling methods may be used, such as “both
using the risk level equation: rinse sampling and visual examination” or
“rinse sampling, swab sampling, and visual
Risk Level = Impact (Severity) x Occurrence examination,” as required to adequately
Probability, where: determine that the equipment is acceptably
clean.
Impact (Severity) = Surface Cleanability Level Direct Sampling Methods
(SCL)
Direct sampling methods (as used in this
Occurrence Probability = Visible Residue Level document) include both instrumental methods
(VRL) or Residue Level (RL) and visual inspection. It should be recognized
that direct surface sampling incorporates
Based on the risk level obtained for DPC, IPC, elements of both sampling and analytical
and NPC parts, independently categorize the methods
risk as low, medium, or high Visual Inspection
It is a well-accepted practice that a cleaning
FIXED / DISASSEMBLY PARTS: process should remove visible residues from
the production equipment surfaces. The visual
Equipment design must facilitate dismantling inspection of equipment has limitations in that
to the maximum extent possible so as to reach some equipment surfaces (e.g., piping) are
all the product contact surfaces while usually not accessible for viewing. The use of
performing cleaning operations. The level of optical equipment like mirrors or endoscopes,
dismantling directly determines the efficiency as well as the use of additional lighting, can
of the cleaning process. This is very important help to facilitate visual inspection. Ordinarily
for equipment that requires manual cleaning. surfaces that are visually examined should be
Dismantling of equipment is also important for dry, as this represents a worst-case condition
certification of cleaning by visual inspection. for visual inspection.

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Process Equipment Cleaning Validation:

Remote inspection techniques (e.g., with fiber
SAMPLING TECHNIQUES optic probes and a viewing screen) are utilized
when visual inspection by a trained inspector is
difficult to perform. Things that might make
visual inspection difficult include issues related
to tank entry, the hazards of a potential
residue, or inaccessibility of critical equipment
surfaces. Additionally, one might use remote
inspection techniques to supplement an
“unaided” visual inspection procedure.
• General accepted sampling methods in the Bore scopes, Fiberscopes, and Video scopes
pharmaceutical industry are two types for allow visual inspection of hard-to-reach areas.
cleaning validation: direct and indirect. Bore scopes have been used to view the
• Direct sampling for cleaning validation is interior of piping and tank welds. A benefit of
also known as the swab method, where the these scopes is that they typically can fit into
product is systematically rubbed across a confined spaces not accessible to operators.
surface to be analyzed for the presence of They are typically very maneuverable have
residue. additional lighting attached, and may come
• Indirect sampling for cleaning validation is with optional magnification and/or zooming
often referred to as rinse sampling, where a capabilities. The major drawbacks of these
solvent like water is rinsed in a specific scopes are the difficulty of use, controlling
area of clean surface and tested for traces lighting/brightness, and that the operator still
of contaminants. has to make the determination if the area
• While performing the Cleaning validation, viewed is visually clean
both the methods needs to be applied and
based on satisfactory results, it is A Remote Visual Camera allows operators to
acceptable to have Rinse sampling for wet view remote areas on a screen. The camera
equipment & Swab for Dry equipment. has most of the same strengths and weaknesses
as the scopes, but the added benefit that
operators can typically also record video or
take pictures. Multiple operators can, at the
same time, view what is on the screen. The
potential to record video and allow multiple
operators to view the screen may help support
a site’s visual inspection training program.
Pictures printed from the camera may distort
the actual amount of residue present since
operators will typically zoom in on a particular
area when taking a picture.

Examples of different swabs It should be noted that the basic regulatory

expectation is that the equipment be visually
clean by viewing with the unaided eye. Use of
aids to magnify or otherwise improve visibility
of residues should be seen as a more stringent
use of visual examination

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Process Equipment Cleaning Validation:

ISSUES WITH SAMPLING AND TESTING: Instrumental Methods
A considerable proportion of the testing Instrumental methods typically involve a
failures experienced in the industry are not surface probe connected to an analytical
related to the ability to clean the equipment instrument by a fiber-optic cable. For
or perform the analysis. They are solely example, this may involve an attenuated total
related to the skills of the person taking the reflection probe connected to an FTIR
swabs. It is easy to write and train a procedure instrument by a fiber-optic cable. The
on how to carry out a swab test but it is a advantage of this type of sampling is that it is
different thing being able to perform a test not necessary (as in swab and rinse sampling)
correctly and reproducibly. So what can be to remove the residue from the surface for
done to reduce this risk and help secure a analysis. It also therefore does not require a
successful validation outcome? separate sampling recovery study. The main
A number of issues can be identified related to disadvantages of this technique are limited
the swabbing procedure and this must be length of the fiber-optic probe and the
addressed if success is to be guaranteed. requirement that surfaces be relatively flat
(therefore, many worst-case locations may not
• Control of swab equipment – It is essential be sampled by this technique).
that all the equipment used to carry out a
swab test is reliably controlled. It is extremely Rinse Sampling
easy to contaminate a swab and put your Rinse sampling involves sampling the
whole cleaning validation exercise at risk of equipment by flowing solvent (which may be
failure. The swab material, the solvent used, water, an aqueous solution, an organic solvent,
any disposable gloves etc. must be very or a water/organic solvent mixture) over all
carefully controlled to reduce the risk of relevant equipment surfaces to remove
possible false results. residues, which are then measured in the rinse
Test the ability of the operator to perform not solvent. Collection of rinse samples should
only the swab procedure itself but also their consider solubility, location, timing and
skill in: volume. One type of rinse sampling technique
– Being able to determine the correct area to is to take a “grab” sample from the final
be swabbed even when they cannot visually portion of the rinse solvent during the final
see where the task is being performed. Failure rinse of the cleaning process. A “grab” sample
to swab the required area will result in either is a single sample collected from a rinse
a failed swab or worse still, from a cross solution that represents the composition of the
contamination viewpoint, a passed result rinse solution at that time. As used in this
which should really fail. document, a grab sample generally refers to a
– Their reproducibility in being able to repeat single sample withdrawn from the final portion
this exercise 4 times in exactly the same of a CIP rinse.
place.
A second type of rinse sampling is to utilize a
It has been demonstrated that a swab taken separate sampling rinse after completion of
using 4 wipes of the same area results in the process rinse. This separate sampling rinse
maximum recovery (>90%) from a given may involve filling the equipment to an
surface. However, the ability to do this appropriate level with solvent and agitating
requires considerable skill and training. that solvent to make the composition of the
All of the above require considerable skill and residue in the sampling rinse is homogeneous.
extensive training of the operator. However, Then a sample of that solvent is taken and
techniques have been developed that will test analyzed. This separate sampling rinse may
these skills and give assurance that the final alternatively be a separate CIP sampling rinse,
test results reflect the actual plant cleanliness which may involve a once-through sampling
and not the ability of the swab operator to rinse or a recirculating sampling rinse.
perform the task.

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Process Equipment Cleaning Validation:

For a once-through separate sampling rinse, it Swab and Wipe Sampling
is necessary to collect the entire volume of Both swab sampling and wipe sampling involve
the separate sampling rinse, agitate it until it wiping a surface with a fibrous material (most
is homogeneous, and analyze a sample from commonly). During the wiping procedure, the
the homogenous rinse. For a recirculating residue on the surface may be transferred to
separate rinse, homogeneity is generally the fibrous material. The fibrous material is
achieved by recirculation. then placed in a solvent to transfer the residue
Rationales for the use of rinse sampling to the solvent. The solvent is then analyzed for
include the following: the residue by an appropriate and validated
• Equipment not accessible for other analytical method. For swabs, the fibrous
types of sampling material is some kind of textile (knitted,
• The residue is volatile, so measuring it woven or nonwoven) attached to a plastic
on dried surfaces is not appropriate handle. Wipes are fibrous materials, usually
• Rinse sampling adequately measures woven or non-woven textiles, which are
residues on surfaces. applied to the sampled surface by hand. A
Extraction Rinse Sampling for Small Parts special case of swabs is the use of cotton balls
One special case of rinse sampling is sampling or pads, which are moved across a surface with
of small parts. Those parts may be sampled by forceps. The selection of swab or wipes to be
swabbing but there are two options for rinse used requires an evaluation of the swab
sampling. One type of rinse sampling is properties, such as extractable and shedding
extraction from small parts. In an extraction properties. Recovery of residues from surfaces
procedure, the extraction solvent is placed in also de- pends on the size and shape of the
a clean vessel large enough to hold the swab head or wipe, as well as the properties
sampled part. The small part is then placed in (such as flexibility and length) of the swab
the extraction solution and agitated or handle.
sonicated for a fixed time. The sampling
solution is then analyzed for potential In most cases, the swabs and wipes are wetted
residues. A second type of rinse sampling for with a solvent prior to sampling the surface.
small parts is typically used for items with an The solvent selected should be able to assist in
orifice, such as filling needles. In this dissolving the residue and also be compatible
procedure, a fixed volume of sampling solution with the analytical method. For example, for
is passed through the lumen and collected in a HPLC analysis, the solvent could be mobile
clean collection vessel. The sampling solution phase. For TOC and conductivity, the solvent is
is agitated for uniformity, and then analyzed almost always water. For sampling the same
for the potential residues. Because the surface site, companies may choose to sample the
area and sampling volume are precisely same surface area with multiple swabs or
known, limits can be accurately calculated for wipes in order to provide a higher percent
such situations. recovery of residue from the surface. In such
Solvent Reflux Sampling cases, the additional swab(s) or wipe(s)
A second special case of rinse sampling is utilized may be either dry or wetted with the
organic solvent reflux sampling. In this same solvent.
process, volatile organic solvent is added to
the reactor of a manufacturing vessel. The Wipes are typically larger pieces of textile
solvent is heated to vaporize it. The solvent material, and may be used to sample larger
vapors condense on various upper parts of the equipment areas. The swab or wipe that has
manufacturing equipment, dissolve any soluble been applied to the surface is then extracted
residues and carry it back to the reactor. with a suitable solvent to remove the analyte
While the technique for distribution of the from the swab into the extraction solvent for
solvent to the surfaces for sampling is analysis. The extraction solvent may be the
different, the principles of rinse sampling are same or different solvent as that used for
still present. wetting the swab.

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Process Equipment Cleaning Validation:

SWABBING Sampling for Microbial and Endotoxin
Often, insufficient time is invested in the Analysis:
actual swabbing regime, which can ultimately Sampling for bio burden may involve rinse-
lead to a less than robust final method. Each water sampling and/or swabbing, but may also
of the surface types identified (discussed involve contact plates. Consideration should be
previously) should be spiked with the API (at given to the sampling solution for swabbing
the calculated residue limit) and experiments and rinsing. For swabbing, a sterile solution,
performed to demonstrate that acceptable such as phosphate-buffered saline, should be
recovery is repeatedly obtained. This can used. For rinse sampling, it is generally not
involve the evaluation of a number of different practical to sample large equipment items with
swabbing solvents and swab types together sterile water; however, for extraction of small
with optimization of the actual swab parts, the use of sterile water or a sterile
technique. This, combined with the need to be solution is preferred. For large equipment,
able to repeatedly detect residues at very low rinse sampling is generally done with purified
levels, can contribute significantly towards the water or WFI, and results may be compared to
time required for successful method a blank taken from the same use point.
development and validation.
Rinse-water sampling for bio burden should
Typical Swabbing to achieve Recovery: involve use of sterile sample containers.
“Aseptic” sampling technique, much like is
used for cleanroom bio burden sampling, is
required for any microbial method to avoid
external contamination of the sample.
Sampling for endotoxin is almost always a rinse
water sample, preferably with low endotoxin
water.

CLEANING METHOD IDENTIFICATION:

Cleaning
Swabbing irregular surfaces in place
(CIP)
Product Clean
to out of
product place
cleaning (COP)
Cleaning
methods

Batch to Automat
batch ed
Swabbing inner surfaces of process pipes cleaning cleaning

Manual
cleaning

CIP

Spray Ball
Many other sprays are available to implement effective
cleaning in place

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Process Equipment Cleaning Validation:

CLEANING PROCESS ESTABLISHMENT: 1. Cleaning in place
3 Ways of Equipment Cleaning 2. Clean out of place
• Clean-in-place Method – CIP Skid to 3. Manual cleaning
Clean the Equipment, Automated CIP of 4. Semi-automated cleaning
the Equipment 5. Automated cleaning
• Clean-out-of-place Method – Washers 6. Solvent reflux cleaning
like Tray Washers, Dish Washers, etc., 7. Placebo batch cleaning
• Sub-systems of equipment hard to
Clean-in-place (CIP) systems:
approach in CIP
This refers to an automated system, which can
• Manual Cleaning – Using tools such as
be a single pass or a re-circulatory system. It
Cleaning Brushes, Scrubbers, etc.
generally utilizes a spraying device to provide
2 Types of Equipment Cleaning coverage and physical impingement on
1. Batch to Batch – Cleaning of the process equipment surfaces. Examples are
equipment in between two batches of the manufacturing tanks, blenders, fluid bed
same product. driers, reactors and fermentation tanks.
2. Product to Product – Cleaning of the
process equipment in between the two Clean-out-of-place (COP) systems: Smaller
different products equipment items or dismantled parts are
2 methods of Residue Removal transported to designated wash areas. These
1. Physical – Mechanical or Manual, are generally done manually and hence a
Emulsification, Dissolution detailed procedure and appropriate training is
2. Chemical– Solubilisation Using Solvent, required. It is important to ensure that the
Chemicals, Detergents equipment is protected during transfer in
Cleaning Spectrum: common corridors.
Automated cleaning Manual cleaning Manual cleaning processes: These are direct
Cleaning in place Clean out of place cleaning by trained operators using hand tools,
Dedicated Non-dedicated cleaning aids and cleaning agents. Important
equipment equipment cleaning parameters include volume of
Indirect product Product contact cleaning agent; volume of rinse water;
contact surfaces surfaces
temperature of wash and rinse solutions;
Low risk location High risk location sequence and duration of soaking wash and
Minor equipment Major equipment rinse steps; scrubbing actions; pressure of
Low risk drugs High risk drugs solutions; detergent concentration, etc.
Highly characterized Poorly characterized
residue residue It is important to detail the instruction in
Liquid formulations Solid formulations cleaning SOP the extent of equipment
Easy to clean Difficult to clean disassembly to ensure the reproducibility of
product product the cleaning process. Consistency of manual
Materials with cleaning over the time is accomplished by
smooth & non- Porous materials operator training, adequate supervision and
porous surface well defined and properly documented
Single product Multiple product cleaning procedure.
facility facility
Non-campaign Campaign Semi-automated processes: This type of
production production cleaning is an intermediate between a fully
automated and a fully manual cleaning
Based on the above assessment the following process, where some parts can be cleaned
different types of cleaning methods can be manually (by removing, dismantling, etc.) and
developed: the remaining through an automated cycle.

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Process Equipment Cleaning Validation:

Automated processes: This does not involve For automated cleaning processes, consistency
intervention (except perhaps to select a cycle shall be established by PLC control of cleaning
and start/stop of the operation). Such a parameters.
process is usually driven through a PLC or a
computer program, where the control system Procedures may be written for specific
equipment or for groups of equipment.
regulates the cleaning cycle, addition of
Procedures may be specific to one
cleaning agent, temperature, time and other
manufactured product or may apply to a group
critical cleaning parameters. The validation of
of manufactured products on the same
such a system is critical to the success of an
equipment and/or equipment group.
automated cleaning process.
Appropriate selection of analytical test
Solvent reflux cleaning: This is appropriate
method, sampling method, sampling locations,
for small molecule of API manufactured by
organic synthesis, which involves boiling with a finalization of limits, etc., shall be done and
draft SOPs with cleaning steps shall be
volatile solvent in a reactor vessel.
attached with the cleaning verification
Placebo batches as cleaning method: For protocol.
highly viscous ointments and products or
potent (hazardous) products, it may be FEASIBILITY & VERIFICATION:
feasible to use a placebo run as a method of “Cleaning verification” as used in this article
cleaning equipment. The approach requires refers to documentation which says that a one-
the use of a placebo that has no detrimental off cleaning event is effective for cleaning
effect on the next manufactured product in equipment so that the equipment can be used
the equipment. The disadvantages include the for subsequent manufacture of a product.
cost of cleaning and the difficulty in There may be a variety of other terms for this
demonstrating the effectiveness of the same concept that are used by various
process. companies. Examples of where cleaning
verification might be used include cleaning
For manual cleaning processes, consistency after manufacture of a clinical trial product or
shall be controlled by adequate specification cleaning after product manufacture where
of actions in the written cleaning procedure, there is a deviation (e.g., the dirty hold time is
by training of operators and identifying exceeded) that affects a validated cleaning
important steps which needs supervision processes.
during the cleaning operation.
Documentation for cleaning verification
Wherever manual cleaning is to be adopted, it purposes is similar to the documentation for
is recommended that the cleaning process is cleaning validation, except that the
developed by performing an FMEA on the verification data is specific to one cleaning
equipment in order to identify the possible event.
deposition of product residues. The outcome From a compliance perspective, the data
of this FMEA should help to determine the applies only to the one cleaning event
following: (although from a scientific perspective the
• Level of dismantling to be done data may suggest similar performance if the
• Identifying hard to clean surfaces cleaning event were repeated). Another
difference is that because cleaning verification
• Logical steps of cleaning
is typically performed on a unique cleaning
• Type of cleaning aids to be used
event, there may be limited cleaning design
• Important steps which needs and development before execution of that
supervision event. One approach is to utilize a cleaning
• Type of sampling aids SOP and a cleaning verification protocol.
• Type of visual inspection aids

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Process Equipment Cleaning Validation:

Alternatively, companies might use a concept SCIENTIFIC RATIONALE ESTABLISHMENT:
that defines explicit requirements for cleaning Validation Plan should include the following:
verification in an SOP and documents the  How clean is clean piece of equipment?
specific activities, sample positions and so on
• Setting limits should have a sound
in a form which will be approved. It is
scientific rational
generally not appropriate to consider three
cleaning verification runs as constituting a  An in-depth risk assessment on the cleaning
“validation” especially if the element of process.
appropriate design and development is absent.  Prospective, Concurrent, Retrospective
Validations as well as Re-validations.
OPTIMIZING THE FLOW RATE / CPPS/CSPS /  List of equipment (common vs. dedicated).
TEMPERATURE / CQAS / CEHT / DEHT:  List of product manufactured using the same
equipment.
Critical Process Parameters (CPP’s) for
 Product matrix
Cleaning:
• Temperature  Clearly define product and Non product
contact surfaces
• Pressure
• Contact time  Worst case sampling location based on the
• Concentration of the cleaning agent equipment design
• Surface Roughness (More roughness  If grouping strategy is applied, clear rational
means more difficult to clean) for this approach
• Flow rate  “Test until clean” not alternative to
• Proper mixing RPMs validation
• Dirty Hold Time for Equipment  Usually minimum three consecutive
• Clean Hold Time for Equipment successful PQ runs is acceptable, but it’s up
to the organization to decide (the end goal
Critical Quality Attributes (CQA’s) for is to have a stable, reproducible process
Cleaning: based on risk assessment)
• Product residue  Define CPP’s and CQA’s by risk FMEA based
• Cleaning agent residue assessment
• Required concentration of cleaning  Sampling / monitoring strategy
agent – Surface Swab (for small or worst
• Microbial residue location) Vs. Rinse water (large area)
• Drain ability – TOC Vs. Micro BCA
• Number of rinses – Testing for residual cleaning agent
• Time for cleaning (conductivity or pH)
– Endotoxin
DEHT & CEHT:
• The dirty equipment after cleaning – Microbial
should be evaluated for chemical as – Visual Inspection
well as microbiological quantity.  Stability and recovery studies for TOC
• Too long period is not acceptable.  Inclusion of Dirty Hold Time and Clean Hold
• Degradation aspect should also be Time
considered.
 Storage location and condition (must be dry
• The clean equipment after cleaning
and have minimal influence form the
should be evaluated for microbiological
storage area) – preferably closed storage
quality.

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Process Equipment Cleaning Validation:

ESTABLISHMENT OF WORST CASE:

Worst case determination-1

CALCULATING RESIDUE
SELECTION OF WORST SELECTING THE WORST
ACCEPTANCE LIMIT OF
CASE EQUIPMENT CASE PRODUCT
API

SELECTING SAMPLING SELECTING SUITABLE

METHOD ANALYTICAL METHOD

SELECTING WORST CASE EQUIPMENT

Small utensils like scoop The equipment

Cleaning validation and sampling thief Identical and inter with large
studies should take into should be grouped as changeable piece of surface area
account hard to clean one as they all have equipment shall be shall be taken
location very less surface area grouped together for worst case
and single design study

Worst case determination-2

WORST CASE EVALUATION

WORST CASE LIMIT WORST CASE MOLECULE

Water Molecule
Molecule
insoluble s which Molecule
Visually PDE / s which Molecule
10 ppm MDD MBL APIs are
are s which
s which
Clean ADE Aspect shall be having are
consider more are toxic
lower coloured
potent
ed doses

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Process Equipment Cleaning Validation:

Crucial step in defining contamination limits: Step 3: Determine NOAEL

 Based on step-1 & Step-2 evaluation

Product Batch
Potency Size  Requires toxicological expertise
 Defined as mg/kg/day
Product
solubility
Release
Step 4: Calculate PDE
Mechanism
Worst Case PDE (mg/day) = NOEL x Weight Adjustment
F1 x F2 x F3 x F4 x F5
Product
contact
area

Cleanability Product NOAEL: Expressed as mg/kg/day

Toxicity
Weight Adjustment: 50 kg
F1: A factor (values between 2 and 12) to
account for extrapolation between species
Establishing health based exposure limits: F2: A factor of 10 to account for variability
Step-1: Hazard Identification between individuals
First step of establishing health based F3: A factor 10 to account for repeat-dose
exposure limit is Hazard identification. toxicity studies of short duration
The following shall be considered while F4: A factor (1-10) that may be applied in
identifying the hazard. cases of severe toxicity
 Mechanism of action. F5: A variable factor that may be applied if the
 Re-productive toxicity no-effect level was not established.
 Genotoxicity
 Developmental Toxicity ADE (mg/day) = NOEL x Weight Adjustment
 Carcinogenicity UFc x MF x PK
 Repeat Dose Toxicity
 LD-50 NOAEL: Expressed as mg/kg/day
Weight Adjustment: 50 kg - 60 kg
UFc: Composite Uncertainty Factor similar to
Mechanis
m of
F1-F5 in PDE formula
action MF: Modifying Factor
Reproduct
LD-50 ive PK: Pharmacokinetic Adjustments
toxicity

MACO (mg) = PDE x MBS next

SF x TDD next
Repeat
Hazard
Genotoxici
Dose ty
Toxicity PDE: Obtained in Step 4
MBSnext: Min. Batch Size
Carcinoge Developm SF: Safety Factor
ental
nicity
Toxicity TDDnext: Standard Therapeutic Daily Dose
(mg/day)

Step 2: “Critical Effects” Safety factors:

Topicals 10 – 100
 Clinical & non-clinical studies Oral products 100 – 1000
 Therapeutic effects Parenterals 1000 - 10000
 Adverse effects

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Process Equipment Cleaning Validation:

Establishing Cleaning limits and Calculating NOEL
Requirements:
NOEL can be calculated as:
Permitted Daily Exposure (PDE) represents a
substance-specific dose that is unlikely to (LD50) * (Average Body Weight of an Adult i.e. 70 Kg)
cause an adverse effect if an individual is (Empirical constant i.e. 2000)
exposed at or below this dose every day for a
lifetime No Observed Effect Level (NOEL)

Acceptable Daily Exposure (ADE) represents a Where LD50 – Lethal Dose is at 50% reduction
dose that is unlikely to cause an adverse effect in mg or kg and NOEL is generally measured in
if an individual is exposed, by any route, at or “mg”.
below this dose every
c) Calculating MACO using Toxic data:
MACO represents a mathematically calculated
quantity of residue from a previous product This approach is generally considered during
when carried over into a different product the early stages of drug manufacturing such as
that CAN represent potential harm to the Intermediates or APIs. Additionally, this
patient. technique is used to calculate MACO for cases
that don’t have information regarding the
a) MACO Based on 10 ppm Criteria: therapeutic dose.
As per this, no more than 10 ppm of the
(PDE in mg/day) * (Min Batch size in mg) * (Swab surface Area in cm2)
previous product shall appear in the next (Product contact Surface area cm2) * (Maximum daily dose in mg)
product.
d) Calculating MACO using Purge factor (PF):
MACO values can be calculated as:
MACO= HBEL Previous x MBS next x PF
(10 ppm) * (Min Batch size in mg) * (Swab surface Area in cm2) TDD next x SF
(Product contact Surface area cm2)

Maximum Allowable Carryover (MACO): purge

Maximum Allowable Carryover (MACO): 10 ppm
factor
criteria
HBEL: Health-Based Exposure Limit (mg/day)
b) MACO Based on Therapeutic Daily Dose of the previous compound
and Safety Criteria:
MBS next: Minimum batch size for the next
MACO values can be calculated as: material(s) (where MACO can end up) (mg)
TDD next: Maximum Therapeutic Daily Dose for
(NOEL in mg) * (Min Batch size in mg) * (Safety Factor i.e. 0.001)
(Largest Daily Dose in mg)
the next material (mg/day)
SF: Safety factor
Maximum Allowable Carryover (MACO): Safety
Criteria
Purging Factor reflects the ability of a process
to reduce the level of the previous product in
As per this criterion, no more than 0.1%
the downstream synthetic route of the next
normal therapeutic dose of the previous
material (in case the next material is not yet
product shall appear in the maximum daily
dose of the next product. the final API). The default value is “1” unless
R&D can provide case-specific purging ability
Here, the min. batch size is considered for the
evidence (e.g. in case of control LOD
next product.
limitation.)

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Process Equipment Cleaning Validation:

PRODUCT GROUPING BASIS:
Grouping is a strategy whereby manufactured The use of products and equipment grouping
products and/or equipment are considered may be used to streamline cleaning validation
together, and a formal protocol is performed programs while ensuring sufficient data are
on a representative from the group. The available to sup- port the validation of
representative from the group is usually the procedures, processes, and equipment
worst case among products or equipment in a associated with cleaning. The grouping
group. Grouping is also called matrixing, family program for a given facility or company should
approach or bracketing. The rationale for be specified or referenced (e.g., by pointing to
grouping is to generate optimum value from a facility cleaning rationale) in a well-designed
cleaning validation tasks based on a risk validation program/validation master plan
approach. One requirement for grouping is that
product and equipment be cleaned by the
same cleaning process.

PRODUCT GROUPING BASIS:

Product Grouping

Product Belonging same Products manufactured on Products Cleaned with same

group same equipment cleaning procedure

 Cleaning procedures describe

 Here same equipment should different aspects such as
 Products that are relate with same size same cleaning methodology, cleaning
similar in nature can material of construction. agent, concentration, cleaning
share a common Different sizes would come time, temperature and
cleaning procedure on under Equipment grouping. completion.
the same equipment  Multiple runs on same  While choosing product from this
 Products with similar equipment with same criteria is hard to adjust because
solubility & high cleaning procedures will be all the above mentioned aspects
Toxicity less risky. Best example, should be intact for different
 Same API and same different products operated products.
excipient with on 4 vacuum driers of  For example, it would be
different identical construction. considered unacceptable to
compositions.  Remember, these clean the equipment for 2
 Different API and equipments should not be different products 2 different
same excipients. different in terms of cleaning time requirements. In
Different APIs and capacity too. Otherwise, such cases, overkill approach
best way to consider them would be helpful and acceptable
different excipients
under Equipment grouping. i.e. performing cleaning at
actual time for less time
required product.

• Finally choosing one representative of all similar product groups with sound justification
• Best way to select a product representative is by considering worst case justified by scientifically
sound rationale.

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Process Equipment Cleaning Validation:

Products may be grouped together if they are A qualification protocol on the representative
manufactured on the same or equivalent (worst-case) product is performed. The
equipment, and cleaned by the same cleaning acceptance criterion for that worst-case
procedure. Products may be assessed for their product is generally the most stringent
relative cleanability by several methods. acceptance criterion of all products in the
Relative cleanability may be affected by the group (that is, the lowest residue limit).
nature of the active ingredients, of the Successful cleaning validation of the
excipients, and/or of degradation products. representative (worst-case) product means the
One example of assessing relative cleanability cleaning of the other products in the group is
involves selecting the product with the least- also validated. Based on risk assessments
soluble active ingredient in the cleaning (addressing both quality risks and business
solution. This approach may be appropriate for risks), one approach is to perform a single
small-molecule API synthesis cleaned with a confirmatory validation run on every other
solvent or for finished drug product product in the group. Also based on a risk
manufacture involving water-soluble assessment, another approach is to perform
formulations. Such an approach may also be qualification protocols on both the most
possible for solid dosage drug products difficult to clean product and the product with
provided that the excipient portion of the the lowest limit.
different drug products has the same effect on
SOLUBILITY BASIS:
the difficulty of cleaning. Another approach
To understand the cleanability, solubility of
involves determining relative difficulty of
API and excipients used in the formulations
cleaning using laboratory studies. For
should be considered.
laboratory studies, cleanability is assessed on
coupons or small equipment parts using Typically, for manufacturers of finished
representative surfaces, with stainless steel products, cleaning procedures are equipment
being the most common because of its specific and are prepared targeting the
predominance in pharmaceutical equipment. insoluble components in the formulation.
For coupons, the roughness of the surface
should be the same or rougher (as a worst Solubility of the components in water and/or
case) than actual equipment surfaces. From the organic solvents is required to be
the lab results, the relative cleanability of evaluated and documented. The difficult to
each product is defined, typically by solubilize components in water, and
determining under proposed cleaning components which have the property of
parameters which product requires the longest adhering to surfaces because of their sticky
time to clean. Bioactivity and clinical effects nature, pose major challenges to cleaning;
may also be considered for the selection of a hence, methods such as using a detergent
representative product and/or cleaning at elevated temperatures are
generally adopted.
One option for product grouping is to use a
surrogate worst-case product. In this situation, EQUIPMENT BASIS:
the worst- case product is an artificially Equipment may be grouped together if they
constructed product (which may not be a are similar and can be cleaned by the same
commercial product) designed to be more cleaning procedure. Grouping of equipment is
difficult to clean than products expected to be an effective method for encompassing
routinely manufactured. One rationale for this equipment from a limited population of
approach is to maintain continuity of the systems undergoing cleaning validation without
worst-case product (in cases where a redundant testing. The grouping strategy is
commercial product might be discontinued). based on designating equipment as “identical”
Another rationale is to minimize situations in or “similar,” based on design, mode of
which new worst-case products are added. operation, and cleanability.

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Process Equipment Cleaning Validation:

Such a determination usually involves COMMON / UNCOMMON CLEANING PROCESS
evaluating the equipment qualification, with BASIS:
the stipulation that qualification differences
This is one of the criteria to select the cleaning
that do not affect the cleaning process may
process in considering the existing equipment
allow one to conclude that two equipment
cleaning process and grouping the common
items are identical for cleaning purposes.
cleaning process equipment to execute as per
Regulatory documents such as the U.S. FDA
the respective limits as established based on
SUPAC guidance may assist in that
the HBEL limits.
determination.
CLEANABILITY BASIS:
Once equipment has been placed within a
designation, the designation defines the Cleanability of a drug product, which is based
cleaning validation requirements. If it involves on the physical properties of the formulation
identical equipment, a protocol involving any components, plays a vital role in the selection
combination of identical equipment items in of a cleaning process. The assessment should
the group is performed. Provided an adequate look at physical properties including solubility
rationale is given for determining the in water and their composition percentage, in
equipment items are identical, there is no order to determine which formulations are
need to perform validation runs on every item considered the hardest to clean.
in the group. CLEANING AGENT SELECTION:

For similar equipment, the representative Cleaning agent selection should be based on a
equipment is the worst case or may involve scientific rationale. Cleaning agents should be
bracketing of the equipment. For example, for selected for their suitability to remove the
storage tanks that are of the same size but product residues; their compatibility with
different complexity due to the number of equipment; their ease of cleaning agent
baffles, the more complex equipment is removal; and low toxicity. Solvents,
chosen as the worst case. For similar formulated detergents, and commodity
equipment of different sizes, the largest and chemicals should be acceptable for the process
smallest (representing the extremes) may be and for use with pharmaceutical products.
chosen for the formal validation runs (unless Water alone or organic solvent alone may be
one size can be determined as the worst case). used as the cleaning agent, particularly for
If there is no worst case or bracketing readily soluble soils.
involved, then any equipment items in the
group of similar items may be chosen for At the time of design of the cleaning process,
validation runs. Confirmatory validation runs it is important to review and document
(perhaps only one run) are an option for other information about any cleaning agents to be
equipment (not a worst-case) within the used. The established cleaning agents should
group. be reviewed against the vendor’s current
specification sheets and descriptions, including
A specific case of equipment grouping involves material safety data sheets. Those documents
“minor” equipment, such as utensils, small should be available as a minimum requirement
parts, and smaller equipment. In the case of for use of those cleaning agents before
such minor equipment, it may be appropriate evaluating the cleaning process. When
to evaluate a cleaning procedure for those selecting a new cleaning agent or utilizing an
parts and to validate the cleaning process established cleaning agent for a new process,
using equipment grouping. The grouping of the it is important to know all of the ingredients,
parts may involve selection of worst-cases as well as the percentage each constituent
based on complexity, size and functionality. comprises, that are in the cleaning agent.

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Process Equipment Cleaning Validation:

This allows for the establishment of the Water
consistency of cleaning agent formulation over Although the typical use of water is in the pre
time, as well as for selecting a possible marker rinsing, post rinsing, and preparation of use
component for analysis of cleaning agent dilutions, water is also used as a sole cleaning
residues. agent for readily water soluble residues. As a
general rule, the quality of water used in the
Cleaning agents and their vendors should be final rinse should be at least as good as the
qualified in much the same way as a raw water used in the manufacturing of the drug
material and raw material vendor is qualified. product. The water quality used in cleaning
Change control of the cleaning agent should also meet the chemical, microbiological
formulation, as well as notification of and endotoxin levels as appropriate for the
significant changes, should be required of the application.
cleaning agent vendor.
Organic Solvents
During the development of the cleaning cycle, Organic solvents, such as methanol, are used
quantities of cleaning agents, their for cleaning in small-molecule API synthesis
concentration and their addition mode should processes. Solvents are chosen based on the
be studied. Methods of storage, expiration solubility of the manufacturing soils in the
dating, inventory control, and change control solvent. The cleaning process typically involves
of the cleaning agents will help establish and agitating the solvent in the reactor vessel,
maintain a reproducible process. circulating it through pipes, and refluxing the
Water used to prepare cleaning agents and for heated solvent through overhead risers and
equipment rinse should be of suitable quality. condensers.
Generally, water used for final rinse should be The issue of flammability should be considered
the same grade as used for the manufactured for organic solvents. Organic solvents, like
product, e.g., parenteral products should isopropyl alcohol, are also used in finished
utilize Water for Injection and oral products pharmaceutical manufacturing for manual
should employ purified water. cleaning of parts and to facilitate drying of
surfaces.
Types of cleaning agents:
A variety of cleaning agent options is Commodity Alkali
available. These include water, organic A commodity alkali, such as sodium hydroxide,
solvents, commodity alkalis and acids, and is often used for the alkaline wash step. The
formulated detergents. high pH and alkalinity of sodium hydroxide
solutions may enhance solubility of organic
Cleaning
agent shall
process residues and, in some cases, facilitate
be easily hydrolysis. Sodium hydroxide is also widely
available
available, relatively inexpensive and, being a
single component containing no organic
Most
preferable
Composition
of the
carbon, is relatively easy to analyze and
cleaning cleaning validate for cleaning-agent removal. The
agents are agent shall
water based be known higher pH of sodium hydroxide also facilitates
Cleaning
agents the precipitation of salts or oxides of such ions
as calcium, magnesium and iron if those ions
are present during the cleaning process.
However, commodity cleaners, such as sodium
Cleaning
Cleaning
agent shall
agents shall
be non-
hydroxide, may have limited effectiveness for
be non- reactive to
the MOC of
tenaciously adhered or baked-on residues.
toxic
equipment They also have limited wetting characteristics
and soil- suspending ability.

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Process Equipment Cleaning Validation:

Commodity Acids Set-1
An acid washing step may be used alone for
cleaning. The addition of an acid wash step 50 25 10
after the caus- tic wash/rinse may overcome ppm ppm ppm

precipitation and buildup of inorganic

compounds, improve rinsing, and help broaden 5
ppm
1
ppm
Neg
the spectrum of soils cleaned (although at the
expense of adding another cycle). In addition, Set-2
maintaining a clean surface and limiting the
deposition and buildup of iron oxides or other 50 25 10
ppm ppm ppm
contaminants may help minimize the potential
for stainless steel corrosion and rouge
5 1
formation. ppm ppm
Neg

Formulated Detergents Set-3

Formulated detergents are multicomponent
cleaning agents that take advantage of several 50
ppm
25
ppm
10
ppm
different cleaning mechanisms, thus providing
broader spectrum effectiveness. In addition to 5 1
Neg
the mechanisms of alkalinity and hydrolysis ppm ppm

offered by a commodity caustic, a formulated

alkaline detergent might provide improved
wetting and soil penetration, emulsification, Note:
chelation of calcium, iron oxide or other  Use standard manufacturing lighting
inorganic ions, and might facilitate dispersion conditions
of particulates in the wash step.  Coupons not handled during inspection
 Determine minimum residue level that
ESTABLISHMENT OF COQ / VRL / VVR &
all operators / Visual Inspectors
ANGLE OF VIEW:
visually detect the residue
1. Spike 3 replicate sets of coupons  Must detect residue of the desired limit
(stainless steel, or other surface material to be considered acceptable
of interest) at varying residue levels
Set-1 Set-2 Set-3 USES OF VRLS IN A MANUFACTURING
FACILITY

Several opportunities to apply VRLs as a

Negative control spiked with Cleaning Solvent surrogate to surface sampling have been
(Rinse / Swab solvent) identified in manufacturing facilities using
good manufacturing practices (GMPs). Process
2. Dry the area of interest completely
controls and procedures also have been
3. All Coupons visually inspected by min 3
identified to mitigate the risks when applying
Cleaning operators / Visual Inspectors in
VRLs in a GMP facility. Given that VRL
picture-1
determinations for drug product formulations
4. After coupons are inspected, they are
have been established and the relative
swabbed
accessibility to visual inspections with this
equipment, the scope of these applications
Note: Products for this Qualification are
would be primarily applicable to
selected based on color & solubility & category
pharmaceutical manufacturing and primary
and on worst case (if applicable).
packaging operations.

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Process Equipment Cleaning Validation:

As with pilot-plant facilities, VRL data may be If not a new worst case, the VRL of the new
used to develop new or optimize existing compound can be compared with the validated
cleaning procedures. For manual cleaning ARL. If the new compound is less than the ARL,
procedures where the VRL is less than the ARL, visual inspection alone should be satisfactory
the extent of routine documentation and for revalidation of the cleaning procedure for a
cleaning records could be streamlined in a GMP new product.
facility. Once optimal scrub times and rinse
volumes have been validated and incorporated The interval of use (manufacturing campaign)
into the cleaning procedure, visual cleanliness and the interval between end of use and
may be the only critical cleaning parameter cleaning are process parameters that must be
that would require documentation on a routine validated. Theoretically, the more batches a
basis. With VRL data, a check by a second piece of equipment processes, the greater the
person for visual cleanliness confirms soil load, and the more difficult it is to clean.
performance and ensures that the level of Hence, the need to challenge cleaning cycles
residuals is below the acceptable residue level. after campaigns of different lengths.
Nonetheless, some products' physical,
This procedure may obviate the need to record
actual cleaning parameter data (i.e., scrub chemical, and surface adhesion properties do
times and rinse volumes) on a routine basis and not change over the campaign length. For
reduce the volume of GMP documentation that manufacturing these products (dry processing),
must be maintained for marketed drug certain types of equipment do not allow
products. residues to accumulate over time by design.

VRL data and visual inspection may be applied This equipment is sloped for gravity removal of
to support the introduction of new products product, whereby the soil load (both the
into existing validated product matrices. The amount and nature of the soil) after one batch
use of product matrices or bracketing product is comparable to the load after multiple
residues to validate a "worst case" for batches within a campaign (i.e., "freely
multiproduct equipment modules is a common draining"). This can be verified by visual
practice in industry and supported by regulatory inspection on a routine basis. For stable
guidance. Best practices include an evaluation products, manufactured in freely draining
of the different products and intermediates equipment, there should be low-to-no process
with respect to solubility and cleanability. risks with respect to extending a validated
Laboratory studies may be performed to campaign length based on visual inspection.
directly compare the relative cleanability Routine inspections for visual cleanliness would
between the targeted compounds and products. mitigate any potential process risks with
Methodologies for rapid and inexpensive testing carryover of process residuals and confirm
for cleanability have previously been reported. cleaning performance. This same rationale
could be applied to extending validated times
The relative toxicity data for all compounds in for the interval between the end of use and
the matrix should also be reviewed, with the equipment cleaning.
ARL set using the most potent compound. To
Once a cleaning process is validated in a GMP
validate the matrix, validation studies would
manufacturing environment, the process
challenge the cleaning on the worst-case
should be monitored periodically to ensure
compound to remove using an ARL calculated
consistent and robust performance.
for the most potent compound in the matrix. As
Independent visual inspections should be
new products are introduced, toxicity and
incorporated into the periodic assessment
cleanability must be assessed as to whether the
program to confirm that cleaning processes
compound represents a new worst case.
remain in a state of control.

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Process Equipment Cleaning Validation:

A second person should check for visual Valves – Material can be drawn into valve
cleanliness, and the frequency of re-cleaning housings and returned to the product stream at
is an appropriate metric for assessing cleaning a later date resulting in cross contamination.
performance. This additional control helps to All valves in the product stream should be
ensure robustness of the validated cleaning investigated, a cross section dismantled and
tested during validation to ensure that they do
procedure. With an appropriate VRL program,
not present a risk to the outcome.
visual inspection may be used rather than
surface and rinsate testing to demonstrate Pumps and samplers – These pieces of
continued consistent cleaning performance. equipment are very difficult to clean
successfully. It should be determined if they
ANCILLARY EQUIPMENT & UTENSILS &
are really necessary. Can the geometry of the
SAMPLING AIDS COVERING: plant be altered to avoid their usage? If not
they must be included in your cleaning
All product contact pipe work should be exercise.
thoroughly evaluated. The geometry of the
pipe work can play a vital role in a successful Process investigations – It is important that
outcome. Multiple bends, flanges, angles of an understanding of what can go wrong in a
pipework and dead ends, can all result in process is obtained. Sometimes a process error
product retention and possible cross at an earlier date can result in product being
contamination. deposited in an area of the plant where it
normally would not reach. This can then result
There are recorded cases in the industry of in swab failures during cleaning or more
minor changes to pipework geometry resulting critically Product contamination at a later
in cross contamination issues. date. E.g. Over-heating of a vessel can result
in product being deposited in condenser return
Remember – If you change the shape of a lines.
piece of pipework it may no longer clean as
well. Packaging lines – It should be determined
that there are no areas in the line where
Specific areas to be mindful of are: tablets could bounce and get stuck e.g. on the
top of sensors etc. These may then fall off
Service lines – These are small bore lines and later into a different product and cause cross
very difficult to clean. There have been a contamination, patient injury or even death.
number of cases over the years where Screens should be erected at these areas to
investigations into cross contamination issues ensure this cannot ever happen.
have concluded that the service lines were at
fault. Ensure that you have adequate SURFACE AREA CALCULATION INCLUDING ALL
safeguards in place (e.g. non return valves and THE EQUIPMENT TRAIN & ANCILLARY
filters) to ensure these lines do not get
EQUIPMENT / UTENSILS:
contaminated.
Surface area of each of the equipment under
Gaskets – The microscopic nature of materials the train shall be considered in the cleaning
used to make gaskets result in product validation matrix which includes the ancillary
retention and possible swab failure. It is equipment like utensils, material charging
recognized that gaskets are necessary but a hoppers, connected lines and other linked
study should be carried out to ensure that elements which are in-turn the product contact
there are not gaskets in the system that are no areas for effective residual removal measures.
longer required and that all gaskets in the
plant are in good condition to reduce the risks. In specific, these surface areas information is
well available in the documents provided by
the respective manufactures of these
Filter meshes – These are designed to retain
product and therefore can also result in cross equipment and related recommendation of the
contamination if not carefully cleaned. same are also available to capture in our study.

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Process Equipment Cleaning Validation:

MICROBIAL ATTRIBUTES: Aside from the manufacturing and analytical
aspects, it is also paramount to consider
cleaning validation from a microbiology point
of view. This focuses on contamination control
in pharmaceutical and healthcare facilities.
Pharmaceutical manufacturing process can be
subjected to microbial contamination.
Therefore a good cleaning and disinfection
process is necessary to maintain a good
hygiene in facilities.

Disinfectants are used to prevent microbial

contamination of pharmaceutical products.
Where chemical disinfectants are used as part
of contamination control, it is important to
evaluate the efficacy of the disinfectants to
ensure they are fit for purpose.

SO WHY DO YOU HAVE TO EVALUATE THE

EFFICACY OF YOUR DISINFECTANT?
The 1993 U.S. FDA cleaning validation Apart from being a regulatory requirement,
guidance states that “Control of the bioburden you need to establish whether your
through adequate cleaning and storage of disinfectants are effective under the conditions
equipment is important to ensure that they are used. Factors such as the surfaces
subsequent sterilization or sanitization they are used on, contact time, concentration
procedures achieve the necessary assurance of and so on will alter the effectiveness of
sterility”. The PIC/S recommendations call for disinfectants. The test performed by the
disinfectant manufacturer before release does
“the validation of cleaning procedures for the
not mimic the way you use them, and
removal of contaminants associated with the therefore does not establish they are fit for
previous products, residues of cleaning agents purpose.
as well as the control of potential microbial CHOOSING A DISINFECTANT
contaminants”. Control of microbial residues is Disinfectants are usually chosen based on their
thus an important part of cleaning validation. chemical properties and expected
Microbial residues include bioburden and effectiveness against microorganisms. Before
endotoxin. Typically bioburden sampling and evaluating the efficacy of your disinfectant, it
analysis is performed during cleaning is important to consider a few points and ask
validation protocols unless there is a do I have the right disinfectants in place?
documented science and risk rationale for Bactericidal and fungicidal agents – It is
omitting such sampling and analysis. important to use disinfectants that are
effective against bacteria and fungi. This will
Science and risk based rationales for excluding ensure that bacteria and fungi on surfaces are
microbiological testing in protocols may killed.
include manufacturing considerations, such as Sporicidal agents – It is important to have
all solvent processing for small- molecule API disinfectant that are effective against bacteria
manufacture, use of a final alcohol rinse for and fungi but some disinfectants are only
oral dose drug products, use of subsequent effective against vegetative microorganisms.
sterilization cycles, and/or demonstration of Not all disinfectants are effective against
adequate microbial control in sufficiently spores, therefore a sporicide should be added
similar cleaning processes. to the disinfectant rotation.

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Process Equipment Cleaning Validation:

Sterile disinfectant – If disinfectants are used Surface – Make sure the disinfectants are
in a cleanroom (Grade A and B) environment, validated against the surfaces they are used
they should be sterile prior to use. Where on. In some cases, not all surfaces can be
disinfectants are transferred into spray bottles included in the cleaning validation, therefore a
before use, then the bottles should also be risk assessment approach most be adopted to
sterilised. determine the most appropriate surfaces to
use.
Available data – Disinfectant manufacturers
that supply to the pharmaceutical and Use the exact surface present in your facility
healthcare industries perform various tests as a slight modification might affect the
that evaluates the efficacy of their efficacy of the disinfectant. For example if you
disinfectants have a coated vinyl floor within your facilities,
Ask the manufacturer for the available data to then the exact vinyl surface should be used.
help you establish if the selected disinfectants
are good enough. Condition – The validation process should
Note – The test results cannot be taken in apply interfering substances to create a clean
place of a validation. This is because they do or a dirty condition. Substances like Bovine
not represent how the disinfectants are used Serum Albumin can be added to mimic the
in practice against your surfaces and organisms amount of soiling present on surfaces. Select
present in your facilities. the most appropriate condition that mimics
where disinfectants are used.
VALIDATING YOUR DISINFECTANT
The effectiveness of a disinfectant would Temperature – Validation should be
depend on the biocidal properties of the performed under the same temperature the
disinfectant. However, a number of factors disinfectants are used.
can affect the effectiveness depending on the
way it is used. Organisms – Ensure the organisms used covers
a variety so that the bactericidal, fungicidal
The following factors most be considered in and sporicidal ability of the disinfectants can
the validation process to help establish if your be determined.
disinfectants are fit for purpose.
Environmental isolates – Environmental
Contact time – Apply contact times that are isolates should be added to the validation
practical and are actually followed in the process to help prove that the disinfectants are
disinfection process. Shorter contact times can effective against organisms they would
be validated to cover a worst case scenario. encounter on your facilities.
Consider a practical contact time when testing
alcohol as it evaporates within a short period In use state – Disinfectants should be
of time. Some sporicidal agents might need an validated at their in use state. If they are
extended contact time depending on prior transferred to a spray bottle, then it should be
knowledge provided by the manufacturer. validated at that state.

Overview of the surface test process on a stainless steel surface

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Process Equipment Cleaning Validation:

They should also be validated at the end of It is important to consider and evaluate what
their hold time to cover a worst case scenario. information one wants to obtain and what
The concentration at which the disinfectant information can be obtained from use of a
used must also be applied in the validation given analytical procedure.
process.
It is important to emphasize that the thought
The efficacy of a disinfectant can be
demonstrated with a suspension test or a process of why an analytical method is being
surface test. used is critical for having a robust, science and
risk-based approach to cleaning validation.
Suspension test can be used to determine if Just because a method has been used in the
the concentration at which a disinfectant is past does not necessarily mean it will useful
used is effective. for a new application.
Since the disinfectant is tested in a
suspension, it does not mimic the way it is Practical Considerations in Selecting
used in practice. Analytical Methods:
In an ideal world, the best method for a given
A surface test is designed to mimic a possible task could be chosen; in the real world,
contamination on a surface which can be selection of analytical methods may be limited
found in a pharmaceutical or healthcare by practical considerations. In many cases, it is
facility in the presence of an interfering important not that the analytical method be
substance. the best method available but that it be
The Quantitative Surface Test EN 13697 can be adequate for the intended purpose. In
used to validate the efficacy of a chemical
disinfectant. selecting analytical methods, one must
consider readily available methodologies within
Test process – A known level of test a given company. For example, it is not likely
organisms are dried on the surfaces then the that a company will invest in a new analytical
disinfectant is added to the surface and left method if existing methods are adequate for
for the standard contact time used during the intended purpose. New methods may mean
disinfection. capital equipment purchases, training of
analysts and maintenance of the equipment;
The effect of the disinfectant is neutralized the related costs should be weighed against
after the contact time and the recovery of the expected benefits. For example, total
surviving organisms will be used to evaluate organic carbon (TOC) was not widely
the efficacy of the disinfectant.
considered for cleaning validation until TOC
Numerous controls are used to ensure that the replaced the readily oxidizable substances
result is due to the effect of the disinfectant. pharmacopeial method, after which
See figure 5 below for an overview of the test pharmaceutical companies were readily
process on stainless steel. familiar with and comfortable with the
technology.
ANALYTICAL METHOD / TECHNIQUE
(DEVELOPMENT) SELECTION: On the other hand, if a new analytical method
is required because existing in-house methods
In a lifecycle approach to cleaning validation, are not adequate for the intended purpose,
different analytical methods may be
then that new method should be considered.
appropriate for evaluation of residues at the
different stages of the cleaning validation These may be implemented by using contract
lifecycle. The lifecycle stages of cleaning analytical laboratories or by bringing the new
validation are design/development, analytical methodology in-house. A decision on
qualification, and validation maintenance. bringing the method in-house versus using a
Analytical methods may also be used as part of contract laboratory may be based on business
investigations during any lifecycle stage. considerations.

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Process Equipment Cleaning Validation:

TYPES OF ANALYTICAL METHODS: Selection of an analytical method may depend
1) Specific Methods 2) Non-Specific on the nature of the residue as it exists after
Methods the cleaning process. Only if an active
Gives us the exact Related to the ingredient is not degraded during the cleaning
quantification of target residue but process (e.g., surviving high temperatures and
the target residue doesn’t provide its pH extremes in an aqueous environment) does
direct measurement it make sense to use a specific analytical
or quantification method for that active ingredient.
Recommended Recommended after
during cleaning cleaning validation If a specific analytical method for an active
validation or also complement ingredient were utilized following a cleaning
specific methods process that has been demonstrated to
during cleaning degrade that active ingredient, it is likely that
validation residues of the active ingredient would be non-
Can detect Itself can falsify the detectable (i.e. not measurable) by that
interference in measurement of the specific analytical method.
substances other target residue
than residue like because of the In such a case, use of a specific analytical
cleaning agents presence of other method for the degradant or use of a
substances nonspecific method (such as TOC) may be
Examples: HPLC, Examples: pH, considered for measuring residues in a
RP-HPLC with UV, Conductivity, Visual validation protocol. Alternatively, if limits are
Ion Chromatography Detection, and TOC established for the degradation product of an
active ingredient, then a specific analytical
The correct way is to conduct scientific studies method for the degradant may be considered
and then choose the analytical method/s that for use.
accurately detects the compound of interest.
It should be recognized that the proper use of
a nonspecific analytical method may provide a
Specific analytical methods are those which
more robust demonstration of acceptable
measure a certain residue in the presence of
cleaning in a validation protocol, because it
expected interferences. If the target analyte
may have responses from species other than
in a validation protocol is the active
the target residue, yet those responses must
ingredient, such interferences may include
be assumed as due to the target residue.
degradation products and related substances,
However, exceeding the residue limit using a
excipients, cleaning agents and cleaning
nonspecific analytical method provides no
process by-products.
information on the nature of the failure. The
high analytical result may be due to responses
Examples of specific methods include liquid
from the active ingredient, the excipients, the
chromatography (including HPLC, UPLC and
cleaning agent, and/or a combination of those
TLC) and spectrophotometry (including UV,
species.
visible and infrared). Each of these methods
requires the use of an appropriate reference Nothing in this Technical Report should be
standard. In contrast, nonspecific analytical interpreted as saying that, as a general
methods measure a general property, such as principle, specific analytical methods should
conductivity or TOC, which could be due to a be used in preference to nonspecific analytical
variety of analytes or sources. methods.

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Process Equipment Cleaning Validation:

ANALYTICAL METHOD VERIFICATION: Acceptance criteria: There should be no
interference from swab/blank, placebo and
Analytical verification should be performed detergent.
with scientifically sound methods. Determination of LOD and LOQ

The analytical methods should be validated Definition:

before use in cleaning validation, unless they LOD: Limit of detection.
are compendial methods.
The limit of detection is the lowest
ANALYTICAL METHOD VALIDATION: concentration of the analyte in a sample that
Analytical method validation and recovery can be detected, but not necessarily
study shall be performed once the quantified, under the stated experimental
composition, manufacturing and cleaning conditions.
procedure of drug substances and drug product LOQ: Limit of quantitation.
is finalized. The limit of quantitation is the lowest
concentration of the analyte in a sample that
The method of analysis from finish product can be determined with acceptable precision
test procedure should be selected. First choice and accuracy under the stated experimental
is the existing assay/RS/dissolution method by conditions.
modifying injection volume if required to In order to determine LOD and LOQ, solutions
achieve at least 50% lower LOQ than swab of standards at different concentration levels
maximum allowed residue (MAR) value. If the should be injected, and LOD and LOQ will be
method is not working, it is necessary to measured by examining the slope and
develop a new method using more sensitive regression line or by using the signal-to-noise
instrument like LCMS/MS. ratio method.
After selection of analytical cleaning
methodology, analytical method validation and Acceptance criteria for LOD and LOQ
recovery study for cleaning validation sample Signal-to-noise ratio for limit of detection
should be carried out. should be about 3:1.
Key parameters to be measured in analytical Signal-to-noise ratio for limit of quantitation
method validation for the cleaning validation should be about 10:1.
sample are: The obtained LOQ value should be at least 50%
• Specificity. of MAR value.
• LOD and LOQ determination.
• LOQ precision. Precision of LOQ
LOQ standard preparation
• Linearity and range.
Prepare a standard solution as per required
• Recovery on different plates at LOQ to
concentration in determination of LOD and
150% of MAR value.
LOQ.
• Solution stability.
Acceptance criteria
Specificity The % RSD of six replicate injections at LOQ
Definition: Specificity of an analytical level should not be more than 15.0%.
method is its ability to measure accurately and
specifically the analyte of interest without Linearity and range
interferences from blank, blank swab and Linearity: The linearity of an analytical
placebo. method is its ability to elicit test results that
Blank swab preparation: The head of the are directly, or by well-defined mathematical
swab should be allowed to fall into a suitable transformation, proportional to the
test tube, and the desired volume of medium concentration of analyte in sample within a
(diluent) should be added. given reference range.

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Process Equipment Cleaning Validation:

Range: The range of an analytical method is Acceptance Criteria
the interval between the upper and lower Individual recovery and mean recovery scores
levels of analyte (including these levels) that shall be NLT 70% for all surfaces in the
have been demonstrated to be determined concentration range other than LOQ. For LOQ
with precision, accuracy and linearity using it shall be NLT 50%.
the method as written. The range is normally Alongside the product manufacture, the
expressed in the same units as test results analytical method is of critical importance
(e.g., percentage, parts per million, etc.) when assessing the cleanliness of
obtained by the analytical method. pharmaceutical manufacturing equipment.
Linearity test should be performed at In order to satisfy this requirement, it is key to
minimum 5 levels over the range of LOQ to ensure a high level of confidence in the
150%. generation of results derived through the use
Acceptance criteria of the method. This, in turn, is underpinned by
The correlation coefficient (r) should not be the development of a suitable, fit-for purpose
less than 0.990 over the working range. analytical method, designed not only to be
specific to the analyte, but also able to ensure
Recovery study Definition: its ability to quantify at the prescribed residue
The accuracy of an analytical method is the limits.
closeness of test results obtained by that On the subject of residue limits, this is very
method to the true value. The true value is much a subject in its own right. The regulatory
that result which would be observed in the authorities do not set limits for specific
absence of error. Accuracy may often be products. The key factors to bear in mind when
expressed as percentage recovery by approaching this with respect to a given
determination of known added amounts of pharmaceutical product:
analyte. • Defined limits should be logical
Accuracy tests should be performed on
• They should be practical and
different MOC of equipment like stainless
achievable (in terms of method
steel, glass, PFA, Halar, Teflon, plastic,
sensitivity)
Tefzel, acrylic, neoprene, EPDM, Hypalon,
• Verifiable
silicon and PP plate. Accuracy tests should be
performed in triplicate at the minimum of An approach for limit setting should be
each of four levels (LOQ, 50% of the limit, identified early on since this will have a direct
100% of the limit, and 150% of the limit) impact on the analytical test method and its
ability to detect the analyte(s) at the required
Coating and drying level.
The desired volume should be spread with the Determining cleanliness can prove to be a very
help of a pipette on a predefined template of challenging task, with the aim being to
the respective plate and the solvent should be measure trace residues (target analytes) on the
allowed to evaporate. surfaces. The residue must initially be
After swabbing, the active content should be extracted from a surface, recovered from the
extracted from the swab in a glass vessel with extraction matrix and then suitably quantified.
the medium (diluent) in order to achieve Note that sampling is usually performed via
concentration at each of four levels (LOQ, 50% direct methods (swabbing), however indirect
of the limit, 100% of the limit, and 150% of the strategies (such as rinse samples) may also be
limit). used, though the latter is not a preferred
Swabbing shall be done in accordance with the approach.
procedure described in an earlier section of
this Best Practices Document. Very often, the starting point in the
development of a cleaning method would be
This procedure should be performed for all based upon a previously developed assay
recovery test preparations. method.

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Process Equipment Cleaning Validation:

The main aspects to be borne in mind are This can potentially have very real positives
attainment of suitable sensitivity to quantify from a manufacturing perspective as it will
at the limits, specificity (between the target enable much more rapid turn-around time for
analyte and other matrix components) and a the analytics, thereby reducing down-time for
curtailed run time to allow the requisite high the plant. Whilst TOC may be suitable in
sample throughput that is generally needed certain cases, these would be limited to
when analyzing swab samples. manufacturing lines that have proven control
of the cleaning process and hence where TOC
In many respects, the requirements for results (i.e. non-specific, gross contamination)
validating cleaning methods are closely are determined to be well below the specified
aligned with a standard assay, evaluating residue limits. If this is not the case, then it
factors such as specificity, accuracy would be necessary to develop specific
(recovery), linearity, sensitivity, precision, methods (such as HPLC) to determine the
robustness and solution stability. However, levels of a given active(s).
one area that does require some time is the
swabbing technique itself. A large part of the Recovery experiments essentially underpin all
development procedure itself is focused upon other validation parameters since the residue
deriving a swabbing procedure that allows must be:
acceptable recovery of API residues from the 1. Successfully extracted from a surface
required surface types. Furthermore, the
2. Recovered from the extraction matrix
choice of swab surface used will be dictated
by conducting a plant walk-around and 3. Appropriately quantified
subsequent risk assessment of the
manufacturing plant and determination of the
If the method is shown to have sufficient
key ‘risk’ areas where residues are most likely accuracy, then all of these parameters can be
to remain following manufacture. evaluated as a single entity. If inadequate
results are obtained then each of the steps
would need to be investigated individually to
identify which of the component steps is
responsible for the poor recovery, and allow
screening of other solvents or swab material
that may improve recovery. It should provide
assurance that an analyte can be analysed in a
Swabbing of a stainless steel coupon
matrix, which, for a finished product, would
It should be noted that there is currently an include excipients, impurities or perhaps
increasing shift towards the use of Total solvents used in the manufacture of the actual
Organic Carbon (TOC) Analysis to determine API. If a cleaning agent is used, its composition
residues following cleaning of the should also be considered. An evaluation of
manufacturing plant. The increasing view is specificity should first be conducted to ensure
that apart from looking at specific active the absence of any interference between
traces, a ‘crude’ evaluation of contamination matrix components and the target analyte.
should be considered. The advantages of TOC
over more traditional HPLC methods are the Another key factor to be considered
throughout the development process is the
ability to evaluate the overall contamination,
stability of the analytical samples; that is, the
and, reduced time and cost for the
ability of the active substance to degrade once
development, validation and subsequent
in the extraction solvent.
analysis.

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Process Equipment Cleaning Validation:

If appropriate expiry dates are not set, Three types of sampling recoveries are
significant degradation could occur, leading to discussed below: swab sampling recovery, rinse
apparent low swab levels, which could actually sampling recovery and “visual examination”
be attributable to the instability of the active recovery. For swab and rinse sampling,
and not representative of the levels actually recovery studies may be performed as part of
swabbed from the equipment surfaces – the analytical method validation or they may
potentially giving a result that “passed” which be performed as separate studies once it is
should actually fail. determined that the analytical method can
appropriately measure residues in solutions.
There is such an array of validation
parameters that could be discussed, however Sampling recovery studies are laboratory
this article cannot possibly do each of these studies involving coupons of sampled
justice. However, in terms of analytical equipment of different materials of
method validation, there should be no construction (such as stainless steel, glass,
unexpected surprises. All of the critical PTFE, and EPDM) spiked with residues to be
parameters to be assessed should be identified measured.
and evaluated prior to commencement of the
General Considerations
formal validation. The method development
Recovery studies may not be required for
should therefore be used to obtain the initial
certain residues that are known to be readily
information to set the limits stipulated within
soluble (e.g., as defined in the USP or Merck
a validation protocol and hence build in
Index and used well below the solubility limit
Quality by Design.
(such as sodium hydroxide or phosphoric acid
used as cleaning agents), provided the residues
RECOVERY ESTABLISHMENT (PLANT / LAB):
are not reactive with or absorbed into the
• A key feature of any cleaning validation
surface.
protocol is having sampling methods and
In performing recovery studies for swabbing
analytical methods that can accurately
and rinse sampling, the amount of material
assess the levels of residues on the
spiked onto coupons should represent an
sampled surface.
amount equal to what could be present at the
residue limit. If additional levels are spiked,
• One regulatory expectation is that the levels should represent levels of actual values
sampling method be challenged in present in cleaning validation protocols. It
conjunction with the analytical method to should be recognized that spiked levels at
determine the percentage recovery of the extremely low levels may give lower recovery
sampling method. percentages due to the inherent variability of
the analytical method at those low levels.
Recovery Studies Approach
Sampling recovery studies are generally The spiked residue should represent the same
required to adequately demonstrate that a residue present at the end of the cleaning
residue, if present on equipment surfaces, can process. In actual fact, the residues present at
be adequately measured or quantified by the the end of cleaning may include a combination
combination of the analytical method and the of active ingredient, cleaning agent, excipient,
sampling procedure. These studies provide a and/or degradation products. It is common
scientific basis for utilizing those sampling and practice, however, to only spike the active
analytical methods to measure residues. The ingredient when doing recovery studies for the
objective should be to establish a reproducible active ingredient, and to only spike with
level of recovery from the equipment cleaning agent when doing recovery studies for
surfaces. cleaning agent.

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Process Equipment Cleaning Validation:

Spiking of the active ingredient in its final Swab/Wipe Recovery
formulation may be considered when spiking For this section, the term swab or swabbing is
of the active ingredient alone is not practical. used; however, descriptions for swab recovery
Finally, drying and/or holding times of spiked studies also apply to wipe sampling, except as
coupons should be appropriate for the nature noted. For swab recovery studies, coupons are
of the residue. spiked in a controlled manner with solutions of
the sampled residue, allowed to dry, and
If the active degrades during the cleaning sampled with the swabbing procedure to be
process, it is common practice to perform utilized in the cleaning validation protocol.
recovery studies by spiking with the active The swab is extracted in a suitable solvent and
ingredient itself, unless there is information the amount of residue measured in that solvent
that indicates the degradation products may sample. The amount recovered is compared to
have a significantly different recovery level the amount spiked on the coupon and the
from the active ingredient itself. Furthermore, result is expressed as percent recovery.
if the degradation product has unusual safety Because swabbing is a manual procedure,
or solubility concerns, recovery studies by typically each person performs a recovery
spiking directly with that degradant should be study with three replicates.
considered. Because of possible concerns
It is preferable to have at least two people
about degradation of the active ingredient
perform swabbing recovery studies for each
after completion of the cleaning process, but
combination of residue and surface type. The
before sampling, that maximum time interval
recovery percentage established by the study
between spiking and sampling should be
may be defined in different ways, but typically
considered in performing recovery studies.
is defined as the lowest average recovery of
any one swab operator. An acceptable swab
Recovery values should be established for all
recovery depends on how that swab recovery is
surfaces sampled. For swab and rinse
being used. If the recovery is performed to
sampling, one approach for this is to perform
qualify the sampling method without
recovery studies on all surfaces. An alternative
correction of either a limit or an analytical
is to perform one residue study on a surface
result then a recovery percentage such as 70%
which through documented evidence is
or more is typically required. If the recovery
equivalent (in terms of percent recovery) to
percentage is used to correct a residue limit or
other surfaces for which a formal recovery
an analytical result then a recovery of 50% or
study is not performed. This is essentially a
more is typically required. An upper limit for
grouping or family approach for recovery
percent recovery should be established to deal
studies. Equivalence for establishing the group
with studies where the measured recovery is
or family may be established based on
greater than 100%. Recoveries of less than 50%
published studies or in-house data. Another
typically require a written rationale of why
approach is to exclude formal recovery studies
that percentage is appropriate.
for sampled surfaces constituting less than a
small percentage (such as 1% or 2%) of the
As part of the swab method development,
total equipment surface area; in such cases,
spiking of residue directly onto the swab head
the recovery value used for that excluded
to determine recovery (release) from the swab
surface is the lowest recovery of any other
head material may be done. Such a study
surface type for which a formal sampling
should also be considered if recovery levels
recovery study was performed, or the
from spiking of surfaces is unacceptable, and it
minimum acceptable recovery percentage
is desired to find the cause of the low
required by the company’s procedures.
recovery.

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Process Equipment Cleaning Validation:

At a minimum, recovery values are generally Rinse Recovery
performed at the residue limit on the surface Rinse recovery studies address the validity of
(e.g., in μg/cm2). While it is possible to rinse sampling for that residue. They
perform recoveries at different spiked levels, demonstrate that if the residue were on a
in general there is little value to such surface, that residue would be effectively
additional spiked levels because of the removed and could be analyzed in the rinse
variability of the sampling procedure. It is solution. Rinse recovery studies address the
prefer- able to perform additional replicates U.S. FDA’s “dirty pot” and “baby/bath water”
at the one residue limit rather than studies at analogies. Rinse recovery studies, like swab
additional levels. Acceptable variation for recovery studies, can be performed on coupons
recovery results at one spiked level is typically that have been spiked with solutions of the
on the order of 15-30% RSD. If recovery studies target residue and then allowed to dry. For
are done by more than one swab operator, it is swab recoveries, it is necessary to perform the
also appropriate to have a criterion for exact swabbing procedure to be used in the
determining acceptable variation between cleaning validation protocol. For rinse
operators. sampling, in contrast, the exact rinsing
procedure (except for the special case of
Examples of criteria used include variation of extraction sampling) cannot be duplicated in
no more than a maximum amount between the laboratory. However, it is possible to
average percentage values, or variation of no simulate the rinsing procedure in the
more than a maximum relative percentage laboratory. Where possible, the conditions of
between average percentage values. Use of the simulated rinse should be the same as the
statistical tests for significance is generally not equipment rinsing situation.
necessary for such determinations.
This includes selection of rinsing solvent as
well as the temperature of the rinsing sol-
Swab recovery studies are typically performed
vent. In other cases, the rinsing conditions
on a nominal coupon surface area using the
should be selected as the same or a worst case
same area as is swabbed during sampling for
as compared to the equipment rinsing
protocol execution. This area is typically
situation. For example, the ratio of solvent to
either 25 cm2 or 100 cm2 while wiping studies
sampled surface area should be the same or
are done on larger areas. In sampling
lower in the recovery study as compared to the
manufacturing equipment for a protocol, it is
equipment rinsing situation.
not always possible to swab a 10 cm X 10 cm
area (it might be necessary to swab a 5 cm X One method of simulating the rinse process is
20 cm area). Furthermore, it might not be to suspend a spiked coupon above a clean
practical to swab exactly 100 cm2 (an area of collection vessel, and cascade rinse solution
60 cm2 or 128 cm2 may be required because across the surface into the collection vessel.
of the specific equipment geometry). In such Another method is to spike the bottom of a
cases, the recovery percentage based on beaker of the appropriate material of
sampling 10 cm X 10 cm may be applied to construction, allow the residue to dry, add
each of those cases. If such an approach is rinse solution to the beaker and apply gentle
used, a range of acceptable surface area (such agitation for a time which approximates the
25% to 150% of the nominal sampled area) time of the final rinse. The rinse solution is
should be established. However, if the either pipetted or decanted from the beaker
sampled area for equipment surfaces in a and analyzed. A third option, used in cases
protocol varies from the nominal value, the where a beaker of suitable material of
residue limit for that sample should be construction is not available, is to place a
adjusted based on the actual surface area spiked coupon in the bottom of a beaker and
swabbed. perform a simulated rinse as in the second
method.

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Process Equipment Cleaning Validation:

Since laboratory rinse sampling studies are Swab sample solution stability study (to be
generally not operator dependent, three performed for any one plate)
replicates by one operator may be adequate to Swab recovery sample solution of 100%
determine the percent recovery. Acceptable obtained during the recovery study should be
percent recoveries are typically established at kept at between 2 to 8°C and at room
the same levels and conditions as for swab temperature for up to 72hours.
recovery studies.
“Recovery” in Visual Inspection Acceptance Criteria
This process is actually the determination of a The difference in the initial value and value
quantitative “visual detection limit”. If visual obtained after specific interval for swab
examination is used to supplement swab or recovery solutions should not be more than
rinse sampling, such determination of a visual 5.0% (Absolute).
detection limit may be done but is not
required. A visual detection limit under Swab sample stability study (to be performed
specified viewing conditions can be for any one plate)
determined by spiking coupons of the
equipment surface materials with solutions of  The desire volume (in ml) of the recovery
the residue at different levels (in μg/cm2), study solution at 100% level should be
and having a panel of trained observers spread on template of the specified area,
determine the lowest level at which residues and the solvent should be allowed to
are clearly visible across the spiked surface. evaporate by using a hair dryer.
 The area should be swabbed vertically
The significance of such a visual detection and horizontally in a unidirectional
limit is that if equipment surfaces are method, so as to cover the entire
determined to be visually clean under the surface, with Texwipe swab moistened
same (or more stringent) viewing conditions in with 1 ml of purified water.
a cleaning validation protocol, the level of the  The above swab should be kept for 72
residue is below the visual detection limit. hours (at below 27°C and between 2 to 8°
Appropriate viewing conditions include C), and the swab recovery solution
distance, lighting and angle. The visual limit prepared as per procedure given in
depends on the nature of the residue as well recovery study.
as the nature of the surface (e.g., stainless  The same procedure should be followed
steel vs. PTFE) and the visual acuity of the for 72 hours in order to study swab
inspector. Typical values reported in the sample stability.
literature for a visual detection limit are 1-4
μg/cm2. For this determination, a percent ANALYTICAL RESIDUE LIMITS
recovery is not established; the purpose is to ESTABLISHMENT:
establish a value where residues are clearly
visible so that any surface observed as visually For drug actives in drug product manufacture,
clean is clearly below that value. this is typically determined as one-one
thousandth (0.001) of minimum daily dose of
SAMPLE SOLUTION STABILITY / SAMPLE the drug active in a maximum daily dose of the
SOLUTION STORAGE CONDITION next drug product. This approach is an
ESTABLISHMENT: alternative to the acceptable daily exposure
Stability Study: (ADE) approach for non-highly hazardous active
The solution stability of standard solution ingredients for manufacture in non-dedicated
should be determined at between 2 to 8°C and equipment. This is expressed in the following
at room temperature for up to 72hours. equation:

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Process Equipment Cleaning Validation:

ARL = MDD × SF ARL = SDI
LDD LDD
Where: Where:
ARL = the acceptable residue level in the next ARL = the acceptable residue limit in the next
drug product drug product
MDD = the minimum daily dose of the active of SDI = the safe daily intake of the residue
the cleaned product LDD = the largest daily dose of the next drug
SF = the safety factor, which is typically 0.001 product to be manufactured in the same
LDD = the largest daily dose of the next drug equipment
product to be manufactured in the same
equipment For residues for which the concern is a possible
deleterious effect on stability, performance or
ARL Based on Toxicity: There are typically efficiency of a subsequent product or process,
two types of calculations based on the toxicity the ARL must be determined directly based on
of the residue for either drug product or API an understanding of the products, the process,
manufacture. and the expected effect.

One approach is the Risk-MaPP Acceptable For example, for an in vitro diagnostic, the
Daily Exposure (ADE) approach, which may be acceptable level of residue of a previous
applicable to residues of drug actives, product may be determined based on the
intermediates, and degradants. The limit is effect on stability or performance of that next
generally based on a No Observable Adverse in vitro diagnostic. That level may be
Effect Level (NOAEL) or other relevant determined by spiking studies of residue in the
toxicological data. For highly hazardous drug in vitro diagnostic to determine effects on
actives, using the ADE approach is generally stability and/or performance (e.g., false
required in order to justify manufacturing positives or false negatives).
those active ingredients in non-dedicated
equipment. For non-highly hazardous drug TRAINING:
actives, the ADE approach is an alternative to Training involves the steps taken to assist the
the dose-based approach. prospective sampler in learning the technique
of sampling/inspection. For purposes of this
A second approach may be the use of LD50 section, “sampling” and “sampler” also include
values for limits for residues like cleaning “inspection” and “inspector” for visual
agents which do not have a dose. evaluation. Qualification involves the process
of “certifying” that the prospective sampler
Other ARL Determinations
can appropriately sample.
For residues which are genotoxic, one
Training always precedes qualification. At a
alternative approach used when the NOEL
minimum, training involves reading of the
values are not available is to determine the
sampling procedure and demonstrating the
SDI using the Threshold of Toxicological
correct procedure by a trained sampler. During
Concern principle which, based on an
the reading and demonstration, the trained
U.S. FDA determination about safe levels in
sampler provides commentary on the rationale
foods, is established at 1.5 μg/day. for certain practices or aspects of the sampling
procedure. Demonstration of technique may
While this may be appropriate for oral doses, also utilize a visual indicator on the swabbed
it may not be appropriate for injectable since surface which assists the trainee in seeing
the U.S. FDA determination was based on safe consequences of poor technique. The last step
levels in foods (which are taken orally). The in training is demonstration of the correct
ARL is expressed in the following equation: procedure by the prospective sampler.

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Process Equipment Cleaning Validation:

Qualification processes used for sampling will The need for retraining and/or requalification
depend on the type of sampling performed. should also be addressed as part of change
Qualification may involve merely control for the swabbing procedure as well as
demonstration of correct technique (that is, when swab sampling “operator error” is
the last step of the training process), or it may suspected in the investigation of a
involve a “test” that challenges the trainee’s nonconforming result.
ability to perform the activity correctly (e.g.,
Key Issues for Training for Rinse Sampling
perform visual inspection using an array of
coupons where some are soiled and others are
not or perform swab sampling for a known soil The major concern for accuracy in rinse
residue level on coupons). Either type of samples is to prevent contamination of the
qualification may be repeated on a regular rinse sample. This contamination may come
basis or upon any retraining of a sampler. from for example, the sampling port,
environment around the sampling port, and/or
Retraining may be conducted based on the operator.
suspected operator error in a swabbing
process, or it may be done because an Steps to prevent contamination may include
operator has not performed a swabbing event adequately flushing or cleaning the port prior
over a certain time frame. to taking a sample, as well as avoiding sample
contamination due to the use of isopropanol on
Key Issues for Training for Swab Sampling: gloves or use of isopropanol to clean the port
(prior to sampling) if TOC is the analytical
procedure.
Four keys to consistency in swab sampling
training are emphasis on consistency of
In training rinse samplers to take a grab sample
wetting the swab head, consistency of the
swabbing motion (including overlapping for the final rinse of a CIP cycle, timing of the
strokes), consistency in applied pressure, and sampling process is critical. Typically, the very
consistency in swabbing of the correct surface last portion of the rinse is sampled but it may
be acceptable to sample before that time if
area. It is assumed, of course, that the correct
such sampling represents a worst case.
swab, the correct number of swabs, and the
correct wetting solution (if any) for the swab However, once process rinsing is complete,
are utilized. A fifth factor for some types of there is no way to go back and collect a rinse
swab sampling (such as sampling involving TOC sample (unless a separate sampling rinse is
analysis) is the emphasis on preventing performed).
external contamination of the swab, such as Since the consistency of rinse sampling is less
from the presence of volatile organics in the operator dependent, there may be no need for
atmosphere around the sampling location. routine retraining and/or requalification of
operators; however, the need for retraining
Since swab sampling is not unlike manual and requalification should also be addressed as
cleaning processes in that it depends on a part of change control for the rinse sampling
person for a high degree for consistency, procedure as well as when rinse sampling
consideration should be given to have swab “operator error” is suspected in the
samplers retrained and/or re-qualified on an investigation of a nonconforming result.
established basis. Retraining may involve the Training for Visual Inspection:
same process as for initial training or may Training for visual inspection depends on
involve only portions of that initial training. whether the visual inspection is part of a
Requalification generally involves a repeat of protocol execution, routine monitoring, or
the initial qualification process. laboratory “limit of detection” determination.

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Process Equipment Cleaning Validation:

In any case, it is preferred to have a visual CONCLUSION:
inspection SOP so that training can be for that • Cleaning validation is challenging
SOP. Visual acuity of visual inspectors for – These challenges are further enhanced if a
either type of visual examination should be facility is used to manufacture multiple
addressed. products
– The manufacturing process can have
For training of visual inspectors in a protocol multifactorial inputs which can make the
execution, key issues are access to sites for cleaning process very difficult
viewing, appropriate lighting, and the ability • There is an increased focus from the
to discern the difference between residues on regulators on manufacturing firms to ensure
the surface and surface imperfections. An robust process are in place to control
important element of visual inspection training contamination and is supported by
is to know when to call for further analysis to scientific rationale
determine the nature of the residue. • Documentation and records is an important
For example, if what appears to be rouge is and essential part of compliance
seen on the equipment, the presence of that • Continued process verification and trending
residue should be noted. Determining whether provides a better understanding of cleaning
that residue causes a failure in the cleaning processes than periodic re-validation
process is a separate decision. • Establishment of Cleaning process design is
the key element in the cleaning validation
The procedure for visual inspection for program.
laboratory “limit of detection” determination • Risk based approach of Cleaning process
is generally different from that of visual design through all multifactorial aspects
inspection during protocol execution because will always help in establishing the process
the objective is different. The objective is to with all the Critical aspects of Cleaning,
determine at what level a certain residue can sampling, monitoring, analyzing, assessing,
be consistently seen across a spiked surface in authorizing and re-reviewing / re-defining
order to correlate a visual detectability limit the process parameters to achieve the
with a level of known residue(s) below that Quality Attributes of targeted / desired
spiked level. This procedure may be in a state of compliance while execution and
separate SOP or may be incorporated in an demonstration.
overall SOP for visual inspection. In addition to
the same elements that are included in
training for protocol execution, a key
consideration for training in this procedure,
which involves viewing spiked coupons, is a
careful distinction between a visually clean
surface, a partially soiled surface (in which
residue is apparent only over a portion of the
spiked area), and a “fully” soiled surface.
Furthermore, the determination of a “visual
limit” in the laboratory should be done under
conditions similar (or worst case) as compared
to visual examination of equipment in a
protocol. This includes considerations of
lighting, distance, and angle of viewing

Note: In continuation to this article, there will be another two Phases (parts) as described in the Cleaning
Validation Policy (refer first page)

Abstract: From the Guidelines & Regulations

 P a g e | 44

References:

1. FDA Guide to Inspections Validation of Cleaning Processes, Section IV. Evaluation of Cleaning
Validation, July 1993, U.S. Food and Drug Administration (FDA), www.fda.gov.
2. International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Pharmaceutical Development
– Q8(R2), August 2009, www.ich.org
3. GUIDANCE ON ASPECTS OF CLEANING VALIDATION
4. IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS by APIC
5. TGA Regulatory Guidance & Cleaning Validation – a regulatory perspective
6. White paper by GMMP faudler-Stains & ISPE official magazine
7. PDA Technical Report No. 29
8. EMA/CHMP/CVMP/SWP/246844/2018
9. Rouge Formation and Remediation by Richard Chai STERIS
10. Cleaning validation guidance of USFDA, EDQM, PMDA, TGA, USFDA & WHO
11. Developing A Science-, Risk-, & Statistics-Based Approach To Cleaning Process Development &
Validation By Thomas Altmann, Alfredo Canhoto, Michel Crevoisier, Igor Gorsky, Robert Kowal,
Mariann Neverovitch, Mohammad Ovais, Osamu Shirokizawa, and Andrew Walsh

Abstract: From the Guidelines & Regulations